Jacques Troncy

Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99–06): a randomised trial

BACKGROUND In multiple myeloma, combination chemotherapy with melphalan plus prednisone is still regarded as the standard of care in elderly patients. We assessed whether the addition of thalidomide to this combination, or reduced-intensity stem cell transplantation, would improve survival. METHODS Between May 22, 2000, and Aug 8, 2005, 447 previously untreated patients with multiple myeloma, who were aged between 65 and 75 years, were randomly assigned to receive either melphalan and prednisone (MP; n=196), melphalan and prednisone plus thalidomide (MPT; n=125), or reduced-intensity stem cell transplantation using melphalan 100 mg/m2 (MEL100; n=126). The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00367185. FINDINGS After a median follow-up of 51.5 months (IQR 34.4-63.2), median overall survival times were 33.2 months (13.8-54.8) for MP, 51.6 months (26.6-not reached) for MPT, and 38.3 months (13.0-61.6) for MEL100. The MPT regimen was associated with a significantly better overall survival than was the MP regimen (hazard ratio 0.59, 95% CI 0.46-0.81, p=0.0006) or MEL100 regimen (0.69, 0.49-0.96, p=0.027). No difference was seen for MEL100 versus MP (0.86, 0.65-1.15, p=0.32). INTERPRETATION The results of our trial provide strong evidence to indicate that the use of thalidomide in combination with melphalan and prednisone should, at present, be the reference treatment for previously untreated elderly patients with multiple myeloma.

Serum Interleukin-6 Levels in Adult Acute Myelogenous Leukemia: Relationship with Disease Characteristics and Outcome

Serum interleukin-6 (IL-6) levels were measured in 58 adult patients with newly diagnosed acute myelogenous leukemia (AML) using an ELISA method in order to find potential clinical correlations. Detectable average levels were 57 +/- 68 pg/ml and 52 patients (90%) had higher cytokine levels than normal donors. IL-6 levels (115 +/- 102 pg/ml versus 36 +/- 40 pg/ml, p = 0.0001) were higher in patients with fever of apparently non infectious origin, and higher levels were associated with higher percentage of blasts in the peripheral blood (R = 0.29, p = 0.04) and in the bone marrow (R = 0.39, p = 0.003), elevated serum LDH level (R = 0.36, p = 0.01), hyperbilirubinemia (R = 0.36, p = 0.008), elevated serum GGT level (R = 0.46, p = 0.003), and elevated serum GOT (R = 0.36, p = 0.008) and GPT levels (R = 0.44, p = 0.004). Highest IL-6 levels were observed in FAB M1 (86 +/- 112 pg/ml), M3 (73 +/- 69 pg/ml), and M6 (92 +/- 60 pg/ml) AML subtypes. Serum IL-6 levels in AML might be related to both non specific inflammatory reactions and the specific biology of the disease.

Continuous-infusion carboplatin in combination with idarubicin or mitoxantrone for high-risk acute myeloid leukemia: a randomised phase II study.

Fifty-three patients of median age 66 years (39 patients > 60 yrs), including 5 with FAB unclassified or secondary acute myeloid leukemia (AML) at diagnosis, 14 with resistant AML, 19 in first and 15 in subsequent relapse, were treated with carboplatin (CBP), 200 mg/m2/day, as a continuous infusion, (days 3 to 7) with mitoxantrone (MIT) or idarubicin (IDA), (12 mg/m2/day) as an i.v. bolus, on days 1 to 3. Results were evaluated after one induction course. Overall, 15 patients (28% [95% confidence interval (CI), 17-42%], 8/28 with IDA and 7/25 with MIT) achieved complete remission (CR). There was no statistical difference between IDA and MIT arms. Fourty-nine percent (95% CI, 35-63%) had resistant disease (53% IDA versus 44% MIT respectively) and 23% (95% CI, 12-36%) died from toxicity (18% IDA versus 28% MIT). Median durations of neutrophils less than 0.5 x 10(9)/l and platelet counts less than 20 x 10(9)/l were 32 and 32 days respectively in the IDA arm and 31 and 26 days respectively in the MIT arm. Severe toxicity included infections (45%), diarrhea (21%), bleeding (9%), vomiting (7%), hyperbilirubinemia (6%), mucositis (4%) (no statistical difference was seen between both arms). Nephrotoxicity was observed in only one case in the IDA arm. Cardiac toxicity included reversible pulmonary oedema in one patient in the IDA arm. No severe ototoxicity was noted. CR patients received maintenance courses with 3 days of CBP and one day of IDA or MIT. Median survival was 2 months (range, 1-30+ months) and 2.5 months (range, 0.5-19.5 months), and median disease-free survival (DFS) 2 months (range, 1-30+ months) and 2.5 months (range, 1-14 months) in the IDA and MIT arms respectively. We conclude that CBP at a cumulative dosage of 1 g/m2 together with intercalating agents (IDA/MIT) has antileukemic efficacy in elderly patients.

Autologous hematopoietic stem cell transplantation for adults with acute myeloid leukemia in complete remission: The Edouard Herriot hospital experience

Abstract We retrospectively assess the long-term outcome and determined prognostic factors correlated with outcomes in adults with acute myeloid leukemia (AML) undergoing autologous hematopoietic stem cell transplantation (HSCT) in our institution over a 19-year period. A total of 78 adults who received autologous HSCT for AML in first complete remission (CR) and of 21 adults in further CR were included in the study. Bone marrow (n = 14) or peripheral blood stem cells (PBSC) (n = 85) transplantation was performed at a median of 2.9 months from CR. Hematologic recovery was significantly reduced in the PBSC group. Five-year cumulative incidences of relapse were 56 and 49%, respectively. Corresponding 5-year probabilities of event-free survival (EFS) were 33 and 35%, while those of overall survival (OS) were 38 and 49%, respectively. In multivariate analyses, cytogenetics was the main prognostic factor for outcome. Treatment-related mortality (TRM) was of 15% at 5 years, but higher in females as compared to males (p = 0.04). We confirmed that long-term EFS can be achieved after autologous HSCT in adult patients with AML. Results in adults who experience a relapse after conventional chemotherapy support the use of autologous HSCT as salvage therapy if such patients achieve a subsequent CR.

A single dose pegfilgrastim for supporting neutrophil recovery in patients treated for high-risk acute myeloid leukemia by the EMA 2000 schedule

Abstract Dose intensity has been demonstrated to be one determinant for treatment efficacy in younger adults with high-risk (relapsed and refractory) acute myelogenous leukemia. Between 2000 and 2006, 56 patients entered the EMA 2000 study and received timed sequential reinduction chemotherapy. From 2004, chemotherapy was also followed by one subcutaneous dose of pegfilgrastim. Thirty-six patients reached a complete remission, while nine obtained a partial remission. Median time to granulocyte and platelet recovery was 34 and 38 days respectively. The major non-hematologic toxicities were severe infections but despite this 23 remitters could proceed to their post-remission treatment, although 13 did not because of severe toxicity or early relapse. The median overall survival was 9·3 months. The EMA 2000 regimen is a highly effective treatment with a response rate of 64% and a low early death rate. The period of critical neutropenia was relatively short in both phases and the supportive use of pegfilgrastim, although showing a trend toward reduced neutropenic period, did not appear to reduce the risk of infection in this group and may not be a critical requirement for reducing the risk of treatment-related toxicity.

The rationale and use of hypomethylation agents in adult acute myeloid leukemia

Background: Epigenetic deregulation of gene expression is a newly recognized mechanism that leads to hematologic malignancies such as leukemia and myelodysplastic syndromes. DNA methylation is one of the most commonly occurring epigenetic events. Objective/methods: The rationale and use of hypomethylation agents in adult acute myeloid leukemia are discussed. Data in this review came from the published literature. Results/conclusion: In leukemias, alterations in DNA methylation are characterized by the hypermethylation of several genes. Hypermethylation represses transcription of the promoter regions of tumor suppressor genes leading to gene silencing. This change is reversible making it an important therapeutic target. Drugs such as methyltranferase inhibitors including 5-azacytidine and 5-aza-2′-deoxycytidine, and histone deacetylase inhibitors are being used in the treatment of these hematological malignancies.

Sequential Chemotherapy with Mitoxantrone, Etoposide and Cytarabine for Previously Treated Acute Myeloid Leukemia: EMA 86 Regimen

EMA 86 regimen, associating mitoxantrone, 12 mg/m2/day on days 1–3, etoposide, 200 mg/m2/day as a continuous infusion on days 8–10 and cytarabine, 500 mg/m2/day as a continuous infusion on days 1–3 and 8–10, was administered to 133 patients. 70 patients had refractory AML and 63 had late first relapse. 60% achieved complete remission (CR), including 44% of refractory patients and 76% late first relapse patients (p = 0.0002). 11% died from therapy-related toxicity. Median survival is 7 months, with 11% survival at 5 years. Median disease-free survival (DFS) is 8 months, with 20% DFS at 5 years.