Australasian Leukaemia And Lymphoma Group Research Articles

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

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. 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. 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. 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. Phebra.

Final Analysis of the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 Trial: All-Trans Retinoic Acid (ATRA), Intravenous Arsenic Trioxide (ATO) and Idarubicin (IDA) As Initial Therapy for Acute Promyelocytic Leukemia (APL)

▪BACKGROUNDThe combination of ATRA and anthracycline-based chemotherapy has traditionally been regarded as the gold standard for induction and consolidation in previously untreated APL patients (pts), with ATO usually reserved for relapse. Recent data in Sanz low-risk (LR) and intermediate-risk (IR) APL indicate ATRA + ATO is superior to ATRA + chemotherapy (N Engl J Med 2013), but the optimal therapy for high-risk (HiR) pts remains unclear. In an attempt to improve anti-leukemic efficacy whilst limiting reliance on anthracyclines for all risk categories of APL, the ALLG incorporated ATO into an ATRA + reduced chemotherapy backbone, and the results of an interim analysis with a median follow-up of 2 years (yr) have been published (Blood 120:1570, 2012). Herein, we report results of the protocol-specified final analysis, conducted when all surviving pts had been followed for at least 2 yr after completion of consolidation.METHODS As published, APML4 protocol treatment comprised: (i) induction with ATRA (45 mg/m2 d1-36), IDA (12 mg/m2 d2,4,6,8), ATO (0.15 mg/kg d9-36), prophylactic prednisone (1 mg/kg d1-10) and aggressive hemostatic support; (ii) consolidation with ATRA and ATO (continuous in cycle 1, intermittent in cycle 2); (iii) 2 yr oral maintenance with ATRA, 6-mercaptopurine and methotrexate. Between 2004-2009, 124 evaluable pts were accrued, and median follow-up by the censor-reversing Kaplan-Meier method in this final analysis is 4.2 yr.RESULTS Median age was 44 (3-78) yr, median white cell count was 2.4 x 109/L (0.1-85.8), and median platelet count 22 x 109/L (2-173). Risk groups were 33 LR, 67 IR, 23 HiR, 1 unknown. FLT3 mutations were present in 44%, and 11% had ≥ 2 additional cytogenetic abnormalities (2+ACA). There were 4 (3.2%) deaths during induction (myocardial infarction d1, cerebral hemorrhage d3 and d7, cerebral edema and seizures d30). Grade 3-4 non-hematological adverse events included differentiation syndrome in 14%, and frequent but reversible biochemical hepatic and gastrointestinal toxicity. Q-Tc prolongation > 500 msec occurred in 14%, but there were no cases of ventricular arrhythmias or torsades de pointe. Significant neurological and cutaneous toxicity were infrequent.After induction, 118 pts (95%) achieved hematological complete remission; 112 commenced consolidation, and all were in molecular remission after cycle 2. A total of 5 relapses and 3 deaths have occurred post-induction, but none of the deaths were attributable to protocol therapy. Severe adverse events were less common during the chemotherapy-free consolidation cycles, especially cycle 2. The frequency of grade 3-4 neutropenia was 62% in cycle 1 and 27% in cycle 2, but there was no grade 3-4 thrombocytopenia.The following table lists event-free survival (EFS), disease-free survival (DFS), overall survival (OS) and cumulative incidence of relapse (CIR):TableAll ptsLRIRHiR2 yr5 yr2 yr5 yr2 yr5 yr2 yr5 yrEFS92%90%97%97%93%89%83%83%DFS97%95%100%100%97%93%95%95%OS94%94%97%97%96%96%87%87%CIR3%5%0%0%3%7%5%5%In univariate analysis, 2+ACA predicted for inferior DFS (P = .04), whereas age > 70 was associated with increased risk of early death (ED, P = .02), inferior EFS (P = .0002), and inferior OS (P = .001). Neither Sanz risk category nor FLT3 mutation status was significantly correlated with these outcome endpoints (all P > .05). In multivariate analysis, the significant associations of 2+ACA (P = .04 for DFS) and age > 70 (P = .0002 for EFS, P = .005 for OS) were retained. In addition, Sanz risk category was correlated with EFS (P[trend] = .003) and OS (P[trend] = .02).When compared with our previous ALLG APML3 trial (ATRA + IDA for induction and consolidation without ATO; Haematologica 2012), treatment with APML4 was associated with substantial and statistically significant improvements (see Figure) in EFS (P = .002), DFS (P = .001) and OS (P = .02). The significance of trial assignment was retained in multivariate analysis when APML3 and APML4 data were combined.CONCLUSIONS APML4 is a potent anti-leukemic regimen with manageable toxicity and a low ED rate. EFS and OS remain impressive with mature follow-up, and were influenced primarily by advanced age and Sanz risk category. The CIR was 5%, and was only associated with 2+ACA. Our results support the inclusion of ATO in induction and consolidation as front-line therapy for APL whilst simultaneously limiting cumulative anthracycline exposure. [Display omitted] DisclosuresOff Label Use: Arsenic trioxide is currently only registered in the US, Europe and Australia for the treatment of relapsed APL. This report includes its use in the initial treatment of APL.

A phase III randomized trial of high‐dose CEOP + filgrastim versus standard‐dose CEOP in patients with non‐Hodgkin lymphoma: 10‐year follow‐up data: Australasian Leukaemia and Lymphoma Group (ALLG) NHL07 trial

Increasing dose intensity (DI) of chemotherapy for patients with aggressive non-Hodgkin lymphoma (NHL) may improve outcomes at the cost of increased toxicity. This issue was addressed in a randomized trial aiming to double the DI of myelosuppressive drugs. Between 1994 and 1999, 250 patients with previously untreated aggressive NHL were randomized to treatment with six cycles of 3-weekly standard (s) or intensive (i) chemotherapy: s-CEOP-cyclophosphamide 750, epirubicin 75, vincristine 1.4 mg/m(2) all on day 1, and prednisolone 100 mg days 1-5; i-CEOP-cyclophosphamide 1,500, epirubicin 150, vincristine 1.4 mg/m(2) all on day 1, and prednisolone 100 mg days 1-5. Primary endpoint was 5-year overall survival (OS). Relative to s-CEOP patients, i-CEOP patients achieved a 78% increase in the DI of cyclophosphamide and epirubicin. Despite this, there was no significant difference in any outcome: 5-year OS (56.7% i-CEOP; 55.1% s-CEOP; P = 0.80), 5-year progression free survival (PFS; 41% i-CEOP; 43% s-CEOP; P = 0.73), 5-year time to progression (TTP; 44% i-CEOP; 47% s-CEOP; P = 0.72), or complete remission (CR) + unconfirmed CR (CRu) rates (53% i-CEOP; 59% s-CEOP; P = 0.64). Long-term follow up at 10 years also showed no significant differences in OS, PFS, or TTP. The i-CEOP arm had higher rates of febrile neutropenia (70 vs. 26%), hospitalisations, blood product utilisation, haematological and gastrointestinal toxicities, and lower quality of life scores during treatment, although without significant differences 6-month later. In the treatment of aggressive NHL in the prerituximab era, increasing DI did not result in improved outcomes, while at the same time lead to increased toxicity.

Lymphoma studies by the Australasian Leukaemia and Lymphoma Group

The Australasian Leukaemia and Lymphoma Group (ALLG) can trace its origins to 1973. It now encompasses virtually all the major hospitals in Australia and New Zealand that treat leukaemias and lymphomas. Over the years the Group as a whole, and members individually, have participated in many clinical treatment trials for aggressive lymphomas. Initially trials were conceived and carried out locally, but in recent years, in addition to continuing its own studies, the Group has been a major contributor to international trials including two that have been particularly influential, known as MInT and CORAL. The MInT study confirmed the value of adding rituximab to standard chemotherapy for aggressive lymphomas; CORAL helped define optimum methods of autografting for relapse. The ALLG has contributed and continues to contribute to the improving outcome for patients with aggressive lymphomas.

Utility of a clinical risk score to identify high‐risk patients with de novo acute myeloid leukaemia in first remission after high‐dose cytarabine (HiDAC) based induction chemotherapy

Utility of a clinical risk score to identify high‐risk patients with <i>de novo</i> acute myeloid leukaemia in first remission after high‐dose cytarabine (Hi<scp>DAC</scp>) based induction chemotherapy

A Randomised Dose De-Escalation Safety Study of Oral Fludarabine, ±Oral Cyclophosphamide and Intravenous Rituximab (OFOCIR) As First-Line Therapy of Fit Patients with Chronic Lymphocytic Leukaemia (CLL) Aged ≥65 Years – End of Recruitment Analysis of Response and Toxicity of the Australasian Leukaemia and Lymphoma Group (ALLG) and CLL Australian Research Consortium (CLLARC) CLL5 Study

AbstractAbstract 436 Background:Combination immunochemotherapy with fludarabine (F), cyclophosphamide (C) and rituximab (R) gave superior progression free and overall survival compared to FC in the CLL8 Study. The median age in CLL8 was 61 years compared to a median age for overall CLL patients of 72 years. There is ongoing debate regarding the tolerability and safety of FCR in elderly patients, and what are the most appropriate criteria for selection of therapy. Methods:Previously untreated patients with progressive CLL aged ≥65 were randomised to one of three treatment regimens FR5, FCR3 and FCR5 as follows: (i) F 24mg/m2 po D1-5 + R (375 mg/m2 C1, 500mg/m2 C2-6) iv D1 (FR5), (ii) F 24mg/m2 po and C 150mg/m2 po D1-3 + R iv D1 (FCR3) or (iii) F 24mg/m2 po + C 150mg/m2po D1-5 + R iv D1 (FCR5), all given at 4 weekly intervals for an intended 6 cycles. The dosage of FCR5 is equivalent to standard 3 day IV FCR in the CLL8 Study. Patients were administered their therapy arm with no dose reduction but fludarabine dose was reduced if the eGFR was 50–69ml/min. Therapy was delayed up to 2 weeks if there was grade 3 or 4 toxicity, and if unresolved after 2 weeks, patients were taken off study. If toxicity resolved to grade 2 or less, therapy proceeded. Results:Recruitment of all 120 randomised patients was completed in July 2012. An analysis was performed with a cut-off date of 5 May, 2012 at which time there were 117 of 120 recruited from 29 centres in Australia and New Zealand. Median age was 71.7 (range 65–83) years. Binet stage at registration was progressive A – 20 (17.1%), B – 55 (47.0%) and C – 42 (35.9%). Response data are shown in table 1 for the total patient cohort - no analysis has been performed to date by treatment arm. Analysis of grade 3 and 4 toxicity events by Cumulative Illness Rating Scale (CIRS) score and age are shown in Tables 2 and 3 with data available at the cut-off date.Table 1Response dataInterim clinical responseFinal clinical responseFinal pathological stagingPost-cycle 3Post-cycle 62 months post-RxComplete Remission2832.9%3954.2%2334.8%Nodular Partial Remission33.5%11.4%913.6%Partial Remission5160.0%2940.3%2943.9%Stable Disease33.5%34.2%57.6%Progressive Disease00.0%00.0%00.0%Total85100.0%72100.0%66100.0%Table 2Grade 3 - 4 Adverse Events by CIRS Score (*1 pt data missing)Pre-treatment CIRS score*Total0–2 (N = 53)3–4 (N = 35)5–6 (N = 15)Haematological30 (56.6%)13 (37.1%)8 (53.3%)51Neutropenia2310740Thrombocytopenia83213Anaemia83011Haemolytic Anaemia1315Febrile Neutropenia/Infection57214Constitutional/Fever/Fatigue/Allergy64111GI/Metabolic/Cardio-respiratory59317Thromboembolism1416Skin/CNS/Tumor lysis/Other72312Table 3Grade 3 - 4 Adverse Events by AgeAge at randomisationTotal65-69 years (N = 42)70-74 years (N = 45)75-79 years (N = 21)80-84 years (N = 9)Haematological20 (47.6%)22 (48.9%)8 (38.1%)2 (22.2%)52Neutropenia17168041Thrombocytopenia670114Anaemia812011Haemolytic Anaemia12115Febrile Neutropenia/Infection437014Constitutional/Fever/Fatigue/Allergy522211GI/Metabolic/Cardio-respiratory464317Thromboembolism32106Skin/CNS/Tumor lysis/Other542112 Conclusions:Oral F(C)R therapy appears generally safe and well tolerated in CLL patients aged ≥65 years requiring first-line treatment according to data available at end of recruitment. Using stringent stopping criteria with delay of 2 weeks for recovery of grade 3 or 4 toxicity but no dose reduction, ∼40% of patients stop early due to toxicity, intercurrent illness or patient choice. Based on the 66 patients with completed Final Pathological Staging 2 months after end of therapy, response rates appear high with an overall response rate (ORR) of 92.3%. For this relatively fit elderly patient cohort, neither a CIRS score of 0 to 6, nor age predicted for grade 3 and 4 toxicity. Disclosures:Mulligan:Roche: Consultancy, Research Funding, Speakers Bureau; Genzyme: Consultancy, Research Funding, Speakers Bureau.

Thalidomide consolidation improves progression-free survival in myeloma with normal but not up-regulated expression of fibroblast growth factor receptor 3: analysis from the Australasian Leukaemia and Lymphoma Group MM6 clinical trial

The translocation t(4;14) is associated with a poor prognosis in myeloma, but its effect in the setting of new drugs such as thalidomide, bortezomib and lenalidomide continues to be investigated, and the role of candidate genes such as FGFR3 (fibroblast growth factor receptor 3) is not yet clarified. In the Australasian Leukaemia and Lymphoma Group (ALLG) MM6 randomized study comparing consolidation thalidomide and prednisolone with prednisolone alone following autologous stem cell transplant, patients on consolidation thalidomide and prednisolone had superior progression-free (PFS) and overall survival (OS). We now show that thalidomide consolidation benefited both t(4;14)-positive (PFS 29 vs. 17 months, p =0.03) and -negative (52 vs. 24 months, p =0.04) disease. PFS for patients with normal FGFR3 expression was significantly better than for those with up-regulated FGFR3 (31 vs. 21 months, p =0.02). Consolidation thalidomide conferred an improved PFS in patients with normal FGFR3 expression (41 vs. 19 months, p =0.02), but there was no improvement in patients with up-regulated FGFR3 (31 vs. 29 months, p =0.76). We conclude that consolidation thalidomide may mitigate the poor prognostic effect of t(4;14), and improves PFS in normal but not up-regulated FGFR3 expression. Thus the level of FGFR3 expression provides additional prognostic information to t(4;14) in myeloma induction and consolidation therapy.

Flow cytometry for the detection of minimal residual disease in acute myeloid leukaemia

The recognition of specific aberrant patterns of leucocyte differentiation antigens on leukemic cells now allows flow cytometry to be used as a tool for assessing treatment response in acute myeloid leukaemia (AML), based on detection of small numbers of abnormal cells surviving therapy, therefore allowing individualisation of patient management. The availability of flow cytometers with eight or more fluorescence detectors, together with a wide range of antibodies conjugated with appropriate fluoro-chromes, has greatly improved the efficiency of identifying leukaemia aberrant phenotypes (LAP), which can be found in more than 90% of AML cases at diagnosis. Knowledge of the LAP profile of a case can then be used to detect abnormal cells in the marrow after chemotherapy, at sensitivities of 10^–4 and lower. Recent data¹ have shown that detection of minimal residual disease (MRD) in AML provides strong independent prognostic information, and can be used to identify patients with good and poor outcomes within standard and intermediate cytogenetic risk groups. A national consortium sponsored by the Australasian Leukaemia and Lymphoma Group (ALLG) is establishing a network to standardise methods, analysis and reporting of flow MRD in AML in Australia.

The Safety and Tolerability of Oral Fludarabine, ±oral Cyclophosphamide and Iv Rituximab Therapy In Previously Untreated Patients with Chronic Lymphocytic Leukaemia (CLL) Aged ≥65 Years – Interim Analysis From the Australasian Leukaemia and Lymphoma Group (ALLG) and CLL Australian Research Consortium (CLLARC) CLL5 Study.

AbstractAbstract 699 Background:Combination immunochemotherapy with fludarabine (F), cyclophosphamide (C) and rituximab (R) gave superior progression free and overall survival compared to FC in the German CLL8 Study. The median age in CLL8 was 61 years compared to a median age for overall CLL patients of 72 years. There is ongoing debate regarding the tolerability and safety of FCR in elderly patients. Arbitrary dose reductions are common practice. Oral FC is more convenient for many older patients. Methods:Previously untreated patients with progressive CLL aged ≥65 were randomised to one of three treatment regimens FR5, FCR3 and FCR5 as follows: (i) F 24mg/m2 po D1-5 + R (375 mg/m2 C1, 500mg/m2 C2-6) iv D1 (FR5), (ii) F 24mg/m2 po and C 150mg/m2 po D1-3 + R iv D1 (FCR3) or (iii) F 24mg/m2 po + C 150mg/m2 po D1-5 + R iv D1 (FCR5), all given at monthly intervals for an intended 6 cycles. The dosage of FCR5 is equivalent to standard intravenous FCR in the CLL8 Study. Patients were administered their therapy arm with no dose reduction. Fludarabine dosing was reduced according to renal function by calculated GFR. Therapy was delayed by 2 weeks if there was any grade 3 or 4 toxicity. If this was unresolved after 2 weeks, patients were taken off study. If toxicity resolved to grade 2 or less, therapy proceeded. Results:Over half the planned patients (65 of 120) were recruited by 1 August, 2010 from 21 centres in Australia and New Zealand with the study having been open for 18 months. Median age is 72 (range 65–85) years. Binet stage at registration was progressive A – 11 (16.9%), B – 32 (49.2%) and C – 22 (33.8%). Randomisations are FR5 – 22, FCR3 – 22 and FCR5 – 21. FISH data is available on 50 patients: 25 with 13q-, 9 with 12+, 4 with 11q−, and 6 with 17p−. P53 functional analysis is available on 15 patients. Interim reasons for cessation of treatment, dose delay and clinical responses are shown in tables 1, 2 and 3 respectively for the total patient cohort. Cessations for reasons other than toxicity occurred in 7 patients: intercurrent illness (N=2) with acute myocardial infarction (AMI) and recurrent episodes of amnesia, and other reasons (N=5). Deaths were recorded for 2 patients due to infection and AMI.Table 1Reason for cessation of treatmentFrequencyPercentCompletion of protocol treatment1346.4%Unresolved Grade 3/4 toxicity >2 weeks828.6%Intercurrent illness27.1%Other517.9%Total28100.0%Table 2Dose delays during treatmentFrequencyPercentYes3061.2%No1938.8%Total49100.0%Table 3Reponses in patients who have completed treatmentInterim staging after 3 cyclesInitial clinical response after 6 cyclesFinal staging 2 months after completionComplete Remission131911Nodular Partial Remission115Partial Remission27910Stable Disease232Progressive Disease000Total433228 Conclusions:Oral F(C)R therapy appears generally safe and well tolerated to date in CLL patients aged ≥65 years requiring first-line treatment. Using stringent stopping criteria with delay of 2 weeks for recovery of grade 3 or 4 toxicity but no dose reduction, about half the patients will stop early due to toxicity or intercurrent illness. Nevertheless, response rates are high. Accrual is ongoing. Disclosures:Mulligan:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer Schering, now Genzyme: Honoraria. Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

The Tolerability of Combination Therapy with Thalidomide and 5-Azacitidine in Patients with Advanced Myelodysplastic Syndromes (MDS).

Abstract 1749Poster Board I-775 IntroductionBoth thalidomide (Thal) and 5-azacitidine (Vidaza; AZA) have single-agent activity in patients (pts) with myelodysplastic syndromes (MDS), but there is limited experience with the combination. The addition of Thal to AZA may improve efficacy, but tolerability of the combination may be limited by side-effects. Patients and MethodsThis analysis included all evaluable pts on the Ph I/II Australasian Leukaemia and Lymphoma group (ALLG) MDS3 study of Thal and AZA. Pts were eligible if they had any FAB subtype of MDS; those with RA and RARS also required clinically significant cytopenias. Pts were excluded if they had previously received Thal or its derivatives or any demethylating agent. All pts were treated with Thal 50mg/d for the first 28d increasing to 100mg/d for a max of 12 Mo treatment and AZA 75mg/m2/d x7d every 28d until progression or prohibitive toxicity. The protocol specified dose delays or reductions for treatment-related toxicities. ResultsA total of 80 pts have been enrolled, with 41 treated between 7/08 – 7/09 currently evaluable. Median age is 68.5y (42-81) with 66% male. FAB MDS category was RA 15%, RARS 10%, RAEB 46%, RAEB-t 10% and CMML 17% with IPSS low 12%, intermed-1 37%, intermed-2 34% and high 12%. Median baseline Hb 88g/L (71-127), ANC 1.91×10 9/L (0.06-87.65) and platelets 75 ×10 9/L (10-399). Median time post diagnosis was 9 Mo. Seventeen pts (41%) remain on treatment with AZA alone (n=3) or both agents (n=14) with a median follow-up of 208d (60-297d). For those still on Thal and AZA median exposure to Thal is 209d (60-297d), with a median 7 cycles of AZA (2-9). For those 27 ceased Thal median exposure was 49d (17-220d) and of 24 ceasing AZA, median number cycles was 2 (1-8). Of 27 pts ceasing one (n=3) or both (n=24) agents; 7 withdrew consent, 3 at investigator decision, 4 for toxicity, 6 progressive disease, 1 lack of efficacy, 2 death (1 respiratory failure in setting of PD and WCC>300, 1 sepsis) and 4 unknown. There were 3 additional deaths within 28d of ceasing study therapy (all with PD); 2 due to sepsis and 1 intracranial haemorrhage. No pt experienced peripheral neuropathy Gr3 or worse. During cycle 1 of the first 40 consecutive patients on treatment, there were 18 episodes of Gr3+ non-haematologic toxicity in 13 patients; this was more likely in those with ECOG 2 (67% v 26%, p=0.053), age>65y (39% v 19%, p=0.175) and baseline ANC'0.5 (75% v 21%, p=0.008). Most of these events were infection related (a recognised risk of underlying MDS and of AZA alone); others occurred on only one occasion each (syncope, postop hemorrhage, respiratory disorder, renal failure, abdominal pain, pain, thrombosis and hypokalemia). ConclusionsThe combination of Thal 50-100mg/d and standard dose AZA is feasible without unexpected toxicity. Infections are common in the first cycle, particularly in pts with baseline neutropenia or impaired performance status. An updated toxicity analysis will be presented. DisclosuresKenealy:Celgene Pty Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Seymour:Celgene Pty Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mills:Celgene Pty Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Szer:Celgene Pty Ltd: Honoraria, Speakers Bureau.

WT1 Expression Levels at Diagnosis and as a Marker of Minimal Residual Disease (MRD) in Patients with Acute Myeloid Leukaemia (AML).

Abstract 2639▪▪This icon denotes an abstract that is clinically relevant.Poster Board II-615 Background.-As wt1 expression is elevated in the majority (80%) of acute myeloid leukemias at diagnosis and relapse, a validated wt1 assay would be a powerful adjunctive tool for evaluation and monitoring of patients during their treatment. Monitoring of disease status with wt1 is applicable to more AML patients in a single assay than any other leukemic marker and includes patients that are cytogenetically normal and may not otherwise be amenable to molecular MRD evaluation. We aimed to analyse wt1 expression in the peripheral blood and bone marrow of patients with de novo AML, when measured at diagnosis, post-induction and post-consolidation; and to correlate these wt1 expression levels with patient characteristics and outcome. Methods-This is a prospective, longitudinal study in which the levels of wt1 expression from 99 patients with de novo AML are measured from bone marrow (59 patients) and peripheral blood (94 patients) specimens at the time of diagnosis and at various time-points along their treatment and clinical courses. The specimens were prospectively stored in the PwC Australasian Leukaemia and Lymphoma Group (ALLG) Tissue Bank. Samples analysed included: 59 bone marrow (bm-wt1) and 94 peripheral blood (pb-wt1) at diagnosis; 54 bm-wt1 and 57 pb-wt1 post-induction; and 46 bm-wt1 and 41 pb-wt1 post-consolidation. 90 of the 99 patients were treated with standard induction chemotherapy on a variety of protocols. RNA was extracted from 107 leukocytes purified from blood and bone marrow using TRIzol® (Invitrogen) extraction. Reverse transcription was performed using Superscript ® (Invitrogen) and RQ-PCR was performed using multiplexed 5' nuclease assay with Black Hole Quencher labelled probes according to published methods. Copy number of wt1 was normalised to 104 copies of ABL. Baseline patient characteristics were correlated with baseline wt1 expression levels and the impact of baseline and post-treatment wt1 expression on leukemia-free survival (LFS) was assessed. Results-99 AML patients were studied: median age 55years, 53% male. Cytogenetic prognostic groups (SWOG) were favourable – 12%, intermediate – 59% and poor – 29%. 90 patients were treated with curative intent and 83% achieved CR, 6% had refractory disease and 11% died during induction. With a median follow-up of 33 months, the median LFS was 12 months and median OS was 24 months. Median pb-wt1 levels at diagnosis were 5122 (range, 1 to 36125) and varied significantly according to: cytogenetic risk group (good risk 12745, intermediate risk 2632, poor risk 4554 (P = 0.009)) and marrow blast percentage (P = 0.02). Diagnostic bm-wt1 showed similar correlations with baseline parameters, but did not reach statistical significance. Median pb-wt1 at relapse was 3781. One of 21 relapsed patients with elevated pb-wt1 expression at diagnosis did not express wt1 at relapse. In a multivariate Cox regression analysis model including age and cytogenetic risk-group, increased expression of wt1 from peripheral blood at diagnosis is predictive of decreased LFS (P=0.04). This correlation was not seen with wt1 measured from bone marrow aspirates. The wt1 expression levels were reduced following induction chemotherapy with a median 2.6 log reduction (range, 0 to 4.2) seen in marrow aspirate and 3.2 log reduction (range, 0 to 4.3) seen in peripheral blood. There was a trend for lower post-induction peripheral blood wt1 to correlate with better LFS when measured as a continuous variable (P=0.067) or undetected vs detected (P=0.051). Lower post-consolidation pb-wt1 significantly correlated with better LFS when measured as a continuous variable (P=0.002) or undetected vs detected (P=0.02) and continued to be significant in multivariate analysis. Bone marrow aspirate wt1 levels post-induction or post-consolidation did not correlate with LFS. Conclusion-This study demonstrates a correlation between wt1 expression levels and known risk factors for early relapse. In the MRD setting, detectable wt1 levels in peripheral blood post-induction and post-consolidation predicted very poor leukaemia free survival. Analysis is ongoing to validate these findings in a uniformly treated cohort of patients enrolled on the current ALLG clinical trial. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

First Analysis of the Australasian Leukaemia and Lymphoma Group (ALLG) Trial of Thalidomide and Alternate Day Prednisolone Following Autologous Stem Cell Transplantation (ASCT) for Patients with Multiple Myeloma (ALLG MM6).

The therapeutic intervention with the greatest impact on survival prolongation for patients with multiple myeloma (MM) is high-dose chemotherapy with ASCT. Unfortunately, relapse is inevitable, thus the identification of strategies that prolong response duration is required. Glucocorticoids are a major component of MM therapy and randomized data suggest that they also have a role in response maintenance following conventional chemotherapy. Thalidomide (T) is effective in both de novo and relapsed MM and synergizes with glucocorticoids at low doses without relevant myelotoxicity. Based on these observations a randomized trial of T combined with maintenance alternate day prednisolone (AP) (ARM 1) vs AP (ARM 2) following ASCT was conducted. Inclusion criteria included age >18 years, non-progressive MM with a maximum of 12 months prior therapy, ECOG <3 and a serum creatinine <2mg/dl. Patients were stratified by transplant centre and pre-ASCT B2microglobulin (B2M) level (<4mg/L versus 4+mg/L). Patients underwent a single ASCT conditioned with melphalan 200mg/m2. At 6 weeks post-ASCT they were re-evaluated and those with no evidence of disease progression were randomized to AP 50mg with or without T 200mg daily. T was limited to a maximum daily dose of 200mg and for a maximum duration of 12 months because of concerns related to toxicity, development of drug resistance and cost. AP was scheduled to continue until disease progression. Both agents could be dose-reduced (minimum doses of 50mg and 12.5mg for T and AP, respectively) in the event of toxicity. All patients received zoledronic acid 4mg IV every 28 days for osteolysis prophylaxis. The primary and secondary end-points of the trial were progression-free (PFS) and overall survival (OS) from the date of randomization, respectively. Analyses were on an intention-to-treat basis. Between January 2002 and March 2005 243 patients from 29 centers were randomized - ARM 1 114 and ARM 2 129. The arms were matched for patient and disease characteristics with a median age of 57 years (range, 26 to 74) and median B2M for both arms of 2.2mg/L. Median follow-up for both arms is 2 years. At the time of randomization 9% vs 11% of patients in ARM 1 and 2, respectively, were in CR (immunofixation negative). 64% of patients were able to complete 12 months of T at a median dose of 100mg. Neurological toxicities were more common in ARM 1 but there were no differences in thrombo-embolic or renal toxicities. Pre-ASCT B2M demonstrated a significant association (p = 0.032) with PFS (Hazard Rate = 1.89, 95% CI 1.05–3.37, for 4+mg/L vs <4mg/L). Post-ASCT ARM 1 demonstrated superior PFS (p = 0.0003). Estimates of PFS at 1, 2 and 3 years were 91% vs 69%, 63% vs 36% and 35% vs 25% for ARM 1 and 2, respectively. As yet no significant survival benefit has been observed although ARM 1 demonstrated superior OS at 2 and 3 years 90% vs 81% and 84% vs 75% (p = 0.1). We conclude that consolidation with low-dose thalidomide in combination with alternate day prednisolone maintenance is an effective and tolerable therapeutic approach that prolongs the duration of disease response following ASCT for MM.

A randomized trial of high-versus conventional-dose cytarabine in consolidation chemotherapy for adult de novo acute myeloid leukemia in first remission after induction therapy containing high-dose cytarabine

AbstractThe value of administering sequential courses of chemotherapy containing high-dose cytarabine in both induction and consolidation therapy for acute myeloid leukemia (AML) has not been assessed in a prospective randomized trial. Two hundred ninety-two AML patients aged 15 to 60 years were enrolled in the Australasian Leukaemia and Lymphoma Group (ALLG) AML trial number 7 (M7) protocol to evaluate this question. All received induction therapy with the ICE protocol (idarubicin 9 mg/m2 × 3; cytarabine 3 g/m2 twice a day on days 1, 3, 5, 7; etoposide 75 mg/m2 × 7). Complete remission was achieved in 234 (80%) patients. Two hundred two patients in remission were then randomized to either a further identical cycle of ICE or 2 attenuated courses (cytarabine 100 mg/m2 daily × 5, idarubicin × 2, etoposide × 5 [IcE]). ICE consolidation therapy was more toxic than IcE, however, the treatment-related death rate was not significantly different. There was no difference between the 2 consolidation arms for relapse-free survival at 3 years (49% for ICE vs 46% for IcE; P = .66), survival following randomization (61% vs 62%; P = .91), or the cumulative incidence of relapse (43% vs 51%; P = .31), and there was no difference within cytogenetic risk groups. Intensive induction chemotherapy incorporating high-dose cytarabine results in high complete remission rates, but further intensive consolidation treatment does not appear to confer additional benefit.

Management of localized low-grade follicular lymphomas.

Long-term follow-up data from Stanford and other centres suggest that 40-50% of patients with clinical stages I and II follicular low-grade lymphoma can be cured by radiotherapy (RT). Relapse generally occurs outside radiation fields and most relapsed patients ultimately die from lymphoma. No randomized data exist to support adjuvant chemotherapy but only one trial of low-intensity chemotherapy was sufficiently powerful to address the question. Nevertheless, data from a large phase-II study from MD Anderson suggest that combined chemotherapy and RT can produce progression-free survival results that are far superior to historical series, with survival at 10 years to be approximately 20% superior to radiation alone. These results have encouraged the development of a joint phase III study by the Trans Tasman Radiation Oncology Group (TROG) and the Australasian Leukaemia and Lymphoma Group (ALLG) in which patients with clinical stage I/II follicular lymphoma are randomized to involved field RT with or without six cycles of cytotoxic chemotherapy. In an era of rapid development in immunological and molecular therapies the potential for improved results with new combinations of more established treatment modalities should not be forgotten. This report reviews the literature on the management of localized low-grade lymphoma and discusses the rationale for the TROG/ALLG study, which began recruitment in early 2000.