Idarubicin Dose Escalation During Consolidation Therapy for Adult Acute Myeloid Leukemia.

Purpose Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy. Patients and Methods Patients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m2 daily for 5 days, etoposide 75 mg/m2 daily for 5 days, and idarubicin 9 mg/m2 daily for either 2 or 3 days (standard and intensive arms, respectively). The primary end point was leukemia-free survival (LFS). Results Two hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3-internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation ( P < .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95% CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm ( P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3-internal tandem duplication and NPM1 gene mutation subgroups. Conclusion An increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity.

A randomized trial of prophylactic palifermin on gastrointestinal toxicity after intensive induction therapy for acute myeloid leukaemia.

Gastrointestinal toxicity, including oral mucositis, is a frequent complication of intensive combination chemotherapy for acute myeloid leukaemia (AML) and contributes substantially to treatment-related mortality. We conducted a placebo-controlled randomized trial to evaluate the efficacy of palifermin (keratinocyte growth factor), given at 60 µg/kg per daily IV for 3 d before and after chemotherapy, for mucosal protection in adult patients with previously untreated AML receiving induction therapy with idarubicin, high-dose cytarabine and etoposide. Among 155 randomized patients, there was no statistically significant difference in the rate of grade 3 and 4 oral mucositis (primary study endpoint) between the two treatment arms (three in palifermin arm (4%), 8 in placebo arm (10%; P = 0·21); however, when considering the severity of oral mucositis (World Health Organization grade 0-4), there was evidence of reduced rates of higher grades of oral mucositis in the palifermin arm (P = 0·0007, test for trend). There was a statistically significantly lower rate of grades 3 and 4 gastrointestinal adverse events in the palifermin arm (21% vs. 44% in placebo arm; P = 0·003), mainly due to a reduction in severe diarrhoea (8% palifermin, 26% placebo; P = 0·01). Palifermin has activity as a mucosal protectant in AML patients receiving intensive chemotherapy. This trial is registered at ACTRN012605000095662.

A phase II study of liposomal daunorubicin, in combination with cyclophosphamide, vincristine and prednisolone, in elderly patients with previously untreated aggressive non-Hodgkin lymphoma.

Liposomal daunorubicin (DaunoXome) was substituted for doxorubicin in the CHOP regimen, aiming to reduce toxicity and maintain or improve efficacy in elderly patients. Eligibility criteria included: age >or=60 years; previously untreated aggressive non-Hodgkin Lymphoma (NHL) and performance status (PS) 0-2. Treatment was cyclophosphamide 750 mg/m(2), vincristine 1.4 mg/m(2) (maximum 2 mg), and DaunoXome 100 mg/m(2) i.v. on day 1, prednisolone 100 mg po on days 1-5 and G-CSF 5 microg/kg/day sc, for 6-8 cycles. For the 51 patients, median age was 70 years (range 60-88), 94% had diffuse large B-cell lymphoma (DLBCL) and 55% were high-intermediate or high-risk according to the age-adjusted international prognostic index. A mean of 6 cycles was delivered, with dose reductions of DaunoXome in 8.3% of cycles. The combined CR and CRu rate was 65.2%, survival was 566 days and 5-year survival 35%. Three deaths occurred during treatment and may have been related to COP-X. Only 4 (7.8%) of the remaining patients had >or=10% reduction in LVEF. However, 35% of patients were hospitalised during treatment, mostly for febrile neutropenia. The response rate to COP-X was similar to that expected with CHOP, with low cardiac toxicity. The high rate of infectious complications suggests that the DaunoXome dose used may be too high for this patient group. These results support further investigation of this regimen in patients with aggressive NHL.

Oncolytic Coxsackievirus A21 as a novel therapy for multiple myeloma.

Oncolytic viruses are attractive biological agents for the control of human malignancy. This study assessed the capacity of Coxsackievirus A21 (CVA21) to target and destroy multiple myeloma (MM) and precursor aberrant plasma cells in vitro using established MM cell lines and 15 patient bone marrow (BM) biopsies [n = 10 MM and five monoclonal gammopathy of undetermined significance (MGUS)]. Cell surface analysis revealed that all tumour cells lines expressed high levels of intercellular adhesion molecule-1 (ICAM-1) and decay-accelerating factor (DAF), the receptor molecules to which CVA21 can bind, leading to subsequent cell-entry and infection. MM cell lines were remarkably susceptible to CVA21 lytic infection, producing 100-1000-fold increases in viral progeny within 24 h. In contrast, normal peripheral blood cells were refractile to CVA21 infection. Furthermore, challenge of patient BM biopsies with CVA21 for 48 h resulted in specific purging of up to 98.7% of CD138+ plasma cells, with no significant decrease in progenitor cell function. Data generated in this study suggests that CVA21 virotherapy may have potential applications as a systemic anti-tumour agent for MM, or in the ex vivo purging of malignant plasma cells prior to autologous stem cell transplantation.

Genetic variations in benzene metabolism and susceptibility to multiple myeloma.

We have previously shown that deficiency in the biotransformation enzyme glutathione-S-transferase theta (GSTT1) is a risk factor for multiple myeloma (MM). The present case-control study of 102 MM patients and 205 controls revealed a significant trend in increasing risk of MM with inheritance of multiple putative 'high risk' genetic variants in related pathways of benzene detoxification. Individuals who carried polymorphisms for GSTT1 null and/or high activity microsomal epoxide hydrolase (mEH 113YY+139HR or 113YY+139RR or 113YH+139RR) and/or low activity NAD(P)H:quinone oxidoreductase 1 (NQO1 187PS/SS) were 1.65, 2.49 and 13 times more likely to have MM (P(trend)=0.001).

Hospital in the home (HITH) care following autologous stem cell transplantation for lymphoma and multiple myeloma.

BACKGROUND: Advances in outpatient and supportive care and increased pressure on hospital bed usage has led to the investigation of hospital in the home (HITH) management following autologous haematologous stem cell transplantation (AutoHSCT) for patients with multiple myeloma or lymphoma. DESIGN: The Newcastle Mater Hospital Haematology Unit together with the Mater Acute Care Community Service (MACCS) developed a protocol for HITH care following AutoHSCT. OUTCOMES: Clinical outcomes of the protocol were audited: 40% (13) of patients were suitable candidates for HITH care post transplantation. Of these 84.6% (11) were readmitted to the haematology unit within seven days of discharge from hospital. CONCLUSION: Our preliminary experience suggests that with adequate infrastructure support and rigorous patient selection this model of care is both safe and feasible.

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.

The 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 x 3; cytarabine 3 g/m2 twice a day on days 1, 3, 5, 7; etoposide 75 mg/m2 x 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 x 5, idarubicin x 2, etoposide x 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.

Induction with oral chemotherapy (CID) followed by early autologous stem cell transplantation for de novo multiple myeloma patients.

In an effort to minimise induction therapy-related toxicity, avoid unnecessary hospitalisation and facilitate early ASCT, we have prospectively evaluated an outpatient-based oral chemotherapeutic regimen, cyclophosphamide, idarubicin, dexamethasone (CID) in patients with previously untreated multiple myeloma (mm). Patients subsequently underwent ASCT conditioned with melphalan 200 g/m(2). A total of 36 newly diagnosed MM patients were enrolled between February 1997 and March 2000. In all 136 cycles of CID were administered requiring only four unplanned hospital admissions. Grade 3 or 4 haematological toxicities were documented following 14 cycles (10%). There were no treatment-related deaths. Response rates (PR + CR) based on an intention-to-treat basis were 66% (23 of 35, 9% CR) post-CID and 80% (28 of 35, 34% CR) post-ASCT. In all, 28 of the 35 patients remain alive with a median follow-up for surviving patients of 40 months (range, 30-67 months). Progression-free survival from the time of diagnosis was 32 months (range, 3-55+ months). Median overall survival from diagnosis has not been reached with an estimated overall survival at 4 years of 77%. CID in combination with early ASCT is an effective and well-tolerated antimyelomatous regimen and is a practical alternative to more toxic and invasive therapeutic approaches.

Xenobiotic gene polymorphisms and susceptibility to multiple myeloma.

Genetic variations in the activity of xenobiotic enzymes may predict susceptibility to multiple myeloma (MM). In a case-control study, 90 Australian Caucasians with MM had significantly higher incidences of GST T1 null, PON1 BB and NAT2 slow acetylation genotypes, but no difference in polymorphism frequencies for GST M1, NAT1, and CYP1A1 when compared to 205 controls.

Methionine synthase genetic polymorphism MS A2756G alters susceptibility to follicular but not diffuse large B-cell non-Hodgkin's lymphoma or multiple myeloma.

Lymphoproliferative diseases are characterized by chromosomal aberrations, and susceptibility may depend on inherited activity of enzymes required for DNA synthesis and methylation. We analysed genetic polymorphisms for methionine synthase (MS) A2756G, methylenetetrahydrofolate reductase (MTHFR) C677T and MTHFR A1298C in Caucasians with non-Hodgkin's lymphoma (NHL; n = 151), multiple myeloma (MM; n = 90) and 299 control subjects. The MS 2756 AG/GG genotypes were significantly under-represented in NHL (26.2%) vs control subjects (37.2%; P = 0.02), and conferred a 2.4-fold lower risk of follicular (odds ratio = 0.41, 95% confidence interval: 0.19-0.88, p = 0.02) but not diffuse large B-cell lymphoma. MM patients showed no significant difference in the polymorphisms compared with control subjects.

Telomere length in haemopoietic stem cells can be determined from that of mononuclear blood cells or whole blood.

Telomere length can be used to predict the replicative capacity of haematological progenitor cells and may be an important prognostic factor for the onset of cellular immune dysfunction. However, such measurements require invasive bone marrow (BM) biopsies and laborious stem cell isolations that are impractical in a clinical setting. Previous studies have used peripheral blood (PB) cells as an indicator of stem cell telomere length without demonstrating a correlation. In this study, we examined the telomere length in PB, isolated mononuclear cells (MNC) and BM aspirates from each of 19 patients ranging in age from 45 to 81 years. Correlation analysis confirmed that mean telomere length of BM aspirates was equivalent to that of PB (r = 0.85, P < 0.001), or MNC (r = 0.94, P < 0.001). Since BM is a heterogeneous population of cells, we have also shown in 13 separate patients that the mean telomere length in isolated peripheral blood stem cell (PBSC) harvests was equivalent to that of isolated CD34+ stem cells (r = 0.83, P < 0.001). Thus, telomere length in haemopoietic stem cells can be determined from that of whole or fractionated PB in future studies of haematological disorders.