Cytosine Arabinoside, Idarubicin and Divided Dose Etoposide for the Treatment of Acute Myeloid Leukemia in Elderly Patients

Elderly patients with acute myeloid leukemia (AML) have an unfavourable prognoses due to low remission rates, short remission durations, and a high treatment related toxicity. Therefore, new chemotherapy regimens with curative potential, decreased toxicity, and applicability to the majority of these patients are still needed. For remission induction, AML patients ≥ 61 years of age received one to three induction courses of the DIVA regimen (idarubicin 10 mg/m²/d days 1 and 3, etoposide 2 × 60 mg/m²/d every 12 hrs. days 2 to 5, and cytarabine 100 mg/m²/d as continuous i.v. infusion days 1 to 5). After achieving CR, patients received two additional courses of DIVA as consolidation therapy. Forty-two consecutive patients with de novo and secondary AML with a median age of 68 years were entered into this trial while six patients were judged ineligible for medical reasons. 62% of the patients achieved a CR, lasting for a median of 26 weeks. Toxicity was mainly hematologic with an early death rate of 12%. The median overall survival for all patients was 38 weeks, and 51 weeks for the 26 patients who achieved CR. Outcome was not significantly different for patients with de novo compared to secondary AML. In conclusion, DIVA showed a promising antileukemic activity and acceptable toxicity as remission induction therapy for de novo and secondary AML in this negligible selected group of elderly patients. However, relapse rate was high, indicating the need for novel approaches for consolidation and maintenance therapy.     

Amsacrine and Continuous-Infusion High-Dose Cytosine Arabinoside as Induction Therapy for Patients with Newly-Diagnosed Acute Myelogenous Leukemia

The overall cure rate of adults with newly-diagnosed acute myelogenous leukemia (AML) treated with continuous infusion high-dose cytarabine (CIHDAC) is comparable to that with standard-dose ara-C plus anthracycline or amsacrine (AMSA). We tested whether the addition of AMSA to CIHDAC improves the outcome of adults with untreated AML. 75 patients with untreated AML were treated with AMSA (75 mg/m²/day x 4) plus CIHDAC (1.5 g/m²/day x 4) for induction and, if in complete remission (CR), early and late intensification. Results were compared to those in 129 patients treated on a previous study with CIHDAC alone. The principal comparison in both groups was between those 117 patients (AMSA/CIHDAC n = 52, CIHDAC n = 65) who met the initial eligibility criteria for the AMSA/CIHDAC study (risk of early mortality ≤. 1) and who were treated at a time when relatively few eligible patients were excluded (19% in the AMSA/CIHDAC group, 34% in the CIHDAC group). There was no difference between regimens in CR rate, remssion duration, or survival in this cohort. When attention was turned to all 204 patients, outcome was superior with AMSA/CIHDAC very largely as a result of outcome in patients with APL. Aside from these patients, addition of amsacrine to CIHDAC did not appear to be productive.     

Low Dose Cytosine Arabinoside Therapy in Myelodysplastic Syndrome and Acute Myeloid Leukemia

Four patients with acute myeloid leukemia (AML) and three withmyelodysplastic syndrome (MDS) were given low dose cytosinearabinoside (Ara-C) therapy. One patient with de novo AML andtwo patients having refractory anemia with excess of blasts(RAEB) achieved responses. Although the responses lasted foronly a short duration (2–3 months), the therapy was welltolerated and not accompanied by severe complications, whilesevere cytopenia was a frequent side effect with transfusionsbeing necessary in most patients. This therapy could be clinicallyeffective for certain types of AML and MDS (especially RAEBand RAEB in transformation).     

Pattern of Liver Disease Following High-Dose Cytosine Arabinoside (HDARAC) Therapy in Children with Acute Myeloid Leukemia

The occurrence of liver disease and its relation to HBV markers were investigated in ten children with AML who were given HDARAC as late consolidation therapy. None of them developed jaundice or biochemical evidence of cholestasis. During therapy, SGPT values were normal in 5/10 patients, while in the other 5 a sharp increase was noted. These enzyme elevations followed an unusual timing, peaking just before each infusion of HDARAC. Evidence of long-lasting hepatocellular necrosis after therapy withdrawal was found in 8/8 cases. One child died of fulminant type B hepatitis and HBsAg positivity was found in 2/10 patients during therapy and 3/8 after withdrawal of the drug. Three children developed HBV antibodies during the observation period. We conclude that the use of HDARAC in childhood leukemia is not associated with major evidence of direct drug hepatotoxicity while it clearly affects the natural outcome of viral hepatitis     

Bioavailability and Pharmacokinetic Features of Etoposide in Childhood Acute Lymphoblastic Leukemia Patients

The bioavailability and pharmacokinetic characteristics of etoposide were studied in 12 relapsed B-lineage acute lymphoblastic leukemia (ALL) patients after both intravenous (i.v.) infusion and oral administration. Following a 1 hour i.v. infusion of SO mg/m² etoposide, the elimination half-life ranged from 49.8 min to 509.4 min (mean ± SD = 218.6 ± 134.7 min), the MRT ranged from 71.8 to 734.9 min (mean ± SD = 315.4 ± 194.3 min) and the systemic clearance of etoposide ranged from 15.7 to 38.0 ml/min/m² (mean ± SD = 24.1 ± 7.0 ml/min/m²). The AUC ranged from 2234.9 to 5427.0 μM±min) (mean ± SD = 3827.8 ± 1069.5 μM±min) and V_c ranged from 2026.9 to 13505.2 rnl/m² (mean ± SD = 6825.4 ± 3278.5 ml/m²). The maximum plasma etoposide levels ranged from 6.0 to 28.4 μM (mean ± SD = 13.6 ± 6.3 μM). The bioavailability of oral etoposide was determined by comparing the AUC following i.v. infusion to the AUC following oral administration in the same patient. The overall bioavailability (mean ± SD) was 60.6 ± 22.4% (ranged from 17.6% to 91.2%). The elimination half-life following oral administration (mean ± SD) was 209.8 ± 196.3 min (ranged from 51.0 to 794.2 min). The time required to reach the maximum plasma etoposide concentration was 145.4 ± 118.7 min (ranged from 23.7 to 396.9 min). To our knowledge, this is the first report concerning the bioavailability of etoposide in pediatric leukemia patients. All of the other pharmacokinetic properties of etoposide in pediatric B-lineage ALL leukemia patients reported here were similar to those described previously.     

Treatment of Philadelphia Chromosome Positive (Ph +) Chronic Myelogenous Leukemia in Blast Crisis and Ph + Acute Leukemia with High Dose Cytosine Arabinoside (HDARAC)

High dose cytosine arabinoside (HDARAC) was administered to eleven patients in the blastic phase of Philadelphia (Ph) chromosome positive chronic myelogenous leukemia (CML). Four patients presented in blastic phase and in seven patients blastic transformation had evolved from a previous chronic phase. All patients had been heavily pretreated with chronic phase drugs (hydroxyurea, myleran) or a protocol designed to treat the chronic phase (L-5 protocol) and with blastic phase regimens (anthracycline/araC combination or vincristine/prednisone). One of 11 patients achieved a complete remission (365 + days) and two patients achieved a partial response. No cytogenetic remissions were observed. The other patients were considered treatment failures with 3/8 surviving less than one month after therapy. Blasts were, at least temporarily, eliminated in all patients receiving at least 7 doses of HDARAC, although repopulation was rapid. HDARAC may be satisfactory therapy for accelerated phase CML but is minimally active in blastic phase CML.     

Effect of Dose Ratio on Mitoxantrone and Daunorubicin in Acute Myeloid Leukemia: A Systematic Review and Meta-analysis of Randomized Controlled Trials

PurposeTo investigate the effects of mitoxantrone and daunorubicin in induced chemotherapy on complete remission (CR), death during induction therapy, overall survival (OS), disease-free survival (DFS), and relapse in patients of all ages with acute myeloid leukemia (AML).MethodsWe searched published reports at the Medline, Embase, and Cochrane Databases as well as other databases from inception through July 2019. There was no restriction on date of publication or language (PROSPERO registration CRD42018095843).ResultsWe enrolled 12 randomized controlled trials that included data of 4583 AML patients whose disease was untreated or relapsed/refractory, and compared the CR, death during induction therapy, DFS, and OS between mitoxantrone and daunorubicin. Mitoxantrone significantly increased the CR rate (relative risk = 1.07; 95% confidence interval [CI], 1.01, 1.14; P = .03) and DFS (hazard ratio = 0.87; 95% CI, 0.79, 0.96; P = .005) compared to daunorubicin. However, there was no significant difference in death during induction therapy (relative risk = 1.00; 95% CI, 0.81, 1.24; P = .99) and OS (hazard ratio = 0.94; 95% CI, 0.87, 1.01; P = .077) between the two drugs.ConclusionAlthough more studies are needed to compare mitoxantrone with higher-dose daunorubicin, the results showed that compared to daunorubicin, mitoxantrone can significantly improve CR and DFS in patients of all ages. These findings suggest that mitoxantrone may be a better choice than daunorubicin as an induction chemotherapy agent for AML patients, especially in developing countries.     

Incidence of Post Transplant Myelodysplasia/Acute Leukemia in Non-Hodgkin's Lymphoma Patients Compared with Hodgkin's Disease Patients Undergoing Autologous Transplantation Following Cyclophosphamide, Carmustine, and Etoposide (CBV)

Secondary malignancies, particularly myelodysplasia (MDS), are serious events following high dose therapy with autologous stem cell support. We observed a higher frequency of secondary malignancies in patients with Hodgkin's disease (HD) than in patients with non-Hodgkin's lymphoma (NHL) undergoing high dose therapy with the same non-TBI conditioning regimen. Three hundred patients with Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) were treated with Cyclophosphamide, carmustine and etoposide and autologous stem cell support from 1986 through 1994. Median follow up of survivors is 3.9 years. Five-year survival is 51 % for HD and 48 % for NHL. Eleven patients developed second malignancies (9/150 treated for HD vs. 2/150 treated for NHL) a median of 2.4 years from transplantation and 5.2 years from initial diagnosis. Six patients had myelodysplasia or acute leukemia (MDS/AML) and 5 had lymphomas or solid tumors. Actuarial risk of MDS/AML at five years for patients transplanted for non-Hodgkin's lymphoma is 3 % (95 % CI 0.6-9.6%). HD patients had significantly different pretreatment characteristics than patients with NHL. A Cox model showed that greater number of prior relapses and prior radiation therapy were significant risk factors for the development of MDS/AML. These data suggest that Cβ V is associated with a lower risk of secondary MDS/AML than TBI containing regimens and that much of the risk is associated with the pre-transplantation therapy. The use of autotransplantation early in the course of therapy for relapsed lymphoma might prevent some cases of MDS/AML.     

Oral Idarubicin and Low Dose Cytarabine as the Initial Treatment of Acute Myeloid Leukemia in Elderly Patients

Idarubicin (IDR) is an anthracycline that can be administered orally. Low dose cytarabine (LDARAC) has been commonly used in the treatment of acute myeloid leukemia (AML) in elderly patients. A comination of oral IDR (20 mg/m² for 3 days) and LDARAC (10 mg/m² q12 hours for 10 days) was given in 32 patients aged 65 to 82 years (median 76) with de novo AML. Eight patients whose marrow remained blastic by day 20 received a second course (IDR for 2 days and LDARAC for 5 days). Complete remission (CR) was achieved in 13 cases (40.5%), (one course 12, two courses 1). There was 1 early death, 3 deaths in aplasia, 2 partial remissions and 13 failures. All but 5 patients were entirely managed in hospital. The median duration of neutropenia was 18 days and only 1 patient obtained CR without therapeutic aplasia. The extrahematologic toxicity was mild with 3 reversible cardiac events. These results are comparable to those obtained with conventional chemotherapy and this regimen could be proposed as induction treatment of AML in elderly patients.     

急性白血病并发播散性热带念珠菌血症的临床分析

[目的]提高对急性白血病(AL)并发播散性热带念珠菌血症临床特征的认识。[方法]回顾性分析3例AL并发播散性热带念珠菌血症临床表现、诊治过程和转归。[结果]在3例患者中,中性粒细胞(ANC)缺乏时出现持续发热、鹅口疮;B超均发现肝内类圆形或椭圆形多发低回声,血培养均示热带念珠菌生长。3例患者采用两性霉素B(AmpB)联合5氟胞嘧啶治疗后体温正常。[结论]AL并发播散性热带念珠菌血症的诊断需结合病史、临床表现、实验室检查及影像学检查综合判断;选用两性霉素B联合5氟胞嘧啶治疗有较好的临床疗效。     

A Prospective,Open-Label Noncomparative Study with Piperacillin-Tazobactam Monotherapy as Management of Fever in Patients with Acute Leukemia

Abstract

We evaluated the efficacy of piperacillin-tazobactam monotherapy as empiric therapy of fever in acute leukemia patients in a total of 80 consecutive febrile episodes. The overall success rate was 75% with success without modification in 34% (afebrile at 72 h) and an overall death rate of 10%. No significant differences were seen in correlation between clinical outcome and phases of underlying disease. The success without modification was higher in patients with fever of unknown origin (FUO) than in those with documented infections (47% and 25% respectively). There were no significant differences in correlations between clinical response and degree of neutropenia. Our study suggests that empirical first-line monotherapy with piperacillin-tazobactam may be a reasonable option in patients with acute leukaemia, although in documented infections the response is frequently inadequate.     

Risk Effects of GST Gene Polymorphisms in Patients with Acute Myeloid Leukemia: A Prospective Study

Glutathione S-transferase (GST) enzyme levels are associated with risk of many cancers, including hematologictumours. We here aimed to investigate the relationships between GSTM1, GSTT1 and GSTP1 polymorphisms andthe risk of AML. Genotyping of GSTs was based upon duplex polymerase-chain-reactions with the confrontingtwo-pair primer (PCR-CTPP) method in 163 cases and 204 controls. Individuals carrying null GSTT1 genotypehad a 1.64 fold risk of acute leukemia relative to a non-null genotype (P<0.05). A heavy risk was observed inthose carrying combination of null genotypes of GSTM1 and GSTT1 and GSTP1 Val allele genotypes whencompared with those carrying wild genotypes, with an OR (95% CI) of 3.39 (1.26-9.26) (P<0.05). These findingsindicate that genetic variants of GST and especially the GSTT1 gene have a critical function in the developmentof AML. Our study offers important insights into the molecular etiology of AML.     

Induction and Persistence of Complete Remission in a Resistant Acute Myeloid Leukemia Patient after Treatment with Recombinant Interleukin-2

A complete and persistent clinico-hematologic remission was obtained in an M4 acute myeloid leukemia patient after treatment with recombinant interleukin 2 (rIL2) alone. After two autologous bone-marrow transplantations and in the third relapse with 10% persistent blasts in the marrow, the patient was treated with two intensive courses of rIL2 given by continuous infusion over a period of 13 days. rIL2 administration was accompanied by significant side effects and followed by notable hematological, clinical and immunological modifications. Complete remission was achieved after these two courses and has been maintained with monthly low-dose cycles of rIL2 given on an out-patient basis. Eighteen months after starting treatment with rIL2 the patient is well and in persistent remission.     

Successful Rescue in a Patient with High Dose Methotrexate-Induced Nephrotoxicity and Acute Renal Failure

We describe the case of a 35-year old male who developed acute renal failure following high dose methotrexate therapy for Burkitt's non Hodgkin lymphoma. Serum methotrexate levels reached 37 μmol/l, and remained higher than 1 μmol/l for more than a week. Folinic acid rescue was intensified to 200-400 mg intravenously every 4 hours. As methotrexate binds markedly to proteins, plasma exchange was initially chosen, 4 sessions being performed from day 2 to day 4. The methotrexate pharmacokinetic profile was not significantly modified during plasma exchange, and serum drug level was 3 μmol/l. Continuous veno-venous hemodiafiltration was therefore performed from day 5 to day 10. This procedure also seemed ineffective, with evidence of low ultrafiltrate clearance. No extrarenal toxicity was observed in our patient. Thus, conventional extrarenal procedures appear to have a limited role in the setting of overexposure to methotrexate. The use of very high doses of folinic acid in our case probably played a major role in the eventual favorable outcome.     

Outcome of Adult Patients with Acute Myeloid Leukemia who Failed to Achieve Complete Remission after one Course of Induction Chemotherapy: A Report from the BGMT Study Group: For the BGMT

Between 50 and 75% of adult patients with de novo acute myeloid leukemia achieve complete remission (CR) but 25 to 40% of them require more than one course of induction chemotherapy to achieve CR. In order to investigate the impact of this situation on the overall outcome of patients we conducted a retrospective analysis of 130 patients, resistant to a single induction course from among three consecutive protocols, using the same induction regimen employed by the BGMT study group. This group of patients has a particularly poor prognosis with relapse and survival rates of 70% and 14% respectively at 5 years. For these patients, being in CR after two induction courses appears to be a major prognostic factor for outcome, since the 5-year Kaplan-Meier survival probability is significantly better (29%, range 17-46) than of those patients with resistant disease (5%, range 2-13). However, results are worse than when complete remission is obtained after a single course. Thus, post remission treatment should have a powerful anti-leukemic effect in preventing relapse. Allogeneic bone marrow transplantation is a preferential strategy in this setting but to be effective this should be performed as early as possible. Furthermore, these results indicate that allogeneic bone marrow transplantation from an alternative donor should be considered in the absence of HLA identical sibling.     

Cell Cycle Parameters as Biological Predictors of Prognosis in AML: A Review and Update of Cell Cycle Kinetics and Remission Induction/Duration in Acute Leukemia

Although the prognostic and clinical significance of cell cycle kinetic studies in neoplastic diseases has been inconclusive at worst and controversial at best, new advances in techniques to study cell cycle characteristics have dramatically improved our ability to more accurately measure the parameters of labeling index (LI), S-phase time (Ts) and total cell cycle time (Tc), and subsequently to find any correlations which would enable us to use these as prognostic indicators. Data from 285 patients with acute myeloid leukemia (AML) who were given in-vivo infusion of the thymidine analogue bromodeoxyuridine (BrdU) prior to chemotherapy show differences in mean labeling indices derived from bone marrow aspirates versus biopsies-being 9.2% and 22.2% respectively. The Tc and Ts were obtained by double labeling the aspirates with tritiated thymidine in-vitro. In 102 uniformly treated patients with standard risk de novo AML, correlations between cell cycle parameters thus measured and clinical data were sought. Although no relation of cell cycle characteristics to remission induction outcome was observed, patients with below median biopsy LI and above median Tc showed longer remission durations (p = 0.02 and 0.04). We conclude that patients with slowly cycling leukemias have longer and more durable remissions most probably as a result of retarded regrowth of leukemic myeloblasts between courses of consolidation therapy.     

Postremission therapy with repeated courses of high-dose cytarabine,idarubicin, and limited autologous stem cell support achieves a very good long-term outcome in European leukemia net favorable and intermediate-risk acute myeloid leukemia

Consolidation treatment in acute myeloid leukemia (AML) patients achieving complete remission (CR) is warranted. High-dose cytarabine (HDAC) is considered first choice in favorable risk and an option in intermediate-risk AML. However, its optimal dose and schedule, as well as the benefit of additional chemotherapy agents remain controversial. Herein, we report on the long-term outcome of consecutive unselected AML patients treated with repeated courses of HDAC, with the addition of idarubicin, followed by autologous peripheral blood stem cell (PBSC) support, in order to limit toxicity, according to Northern Italy Leukemia Group (NILG) AML-01/00 study (EUDRACT number 00400673). Among 338 patients consecutively diagnosed from 2001 to 2017 at our center, 148 with high-risk AML (adverse cytogenetic, isolated FLT3-internal tandem duplication mutation, refractory to first induction) were addressed to allogeneic stem cell transplant. All other cases, 186 patients (55%), median age 53 (range 19–75), were considered standard-risk and received the NILG AML-01/00 program. After achieving CR, patients were mobilized with cytarabine 8 g/sqm to collect autologous CD34+-PBSC and received three consolidation cycles with HDAC (20 g/sqm) plus idarubicin (20 mg/sqm) per cycle, followed by reinfusion of limited doses of CD34+ PBSC (1-2x106/kg). The program was completed by 160 (86%) patients. Toxicity was acceptable. Neutrophils recovered a median of 10 days. Treatment-related mortality was 3/160 (1.8%). After a median follow-up of 66.4 months, overall survival (OS) and relapse-free survival (RFS) at 5-years were 61.4% and 52.4%, respectively. Twenty-eight selected patients aged >65 had similar outcomes. According to European leukemia net-2010 classification, the OS and RFS at 5-years were 76.4% and 65% in favorable risk, without differences between molecular subgroups, 52.3% and 47.2% in Intermediate-I, 45.2% and 36.5% in Intermediate-II risk patients, respectively. In conclusion, consolidation including repeated courses of high dose cytarabine and idarubicin, with limited PBSC support, proved feasible and very effective in nonhigh risk patients. The incorporation of novel agents in its backbone may be tested to further improve patient's prognosis.     

Sequential Cis-Platinum and Fludarabine with or without Arabinosyl Cytosine in Patients Failing Prior Fludarabine Therapy for Chronic Lymphocytic Leukemia: A Phase II Study

Patients with chronic lymphocytic leukemia (CLL) who fail fludarabine (Fluda) therapy have a poor response to subsequent salvage regimens and a poor prognosis. This study was undertaken to determine the efficacy and toxicity of a cis-platinum, (cis-p)fluda and arabinosyl cytosine (ara-C) combination in patients who were refractory to fluda or had relapsed following prior fluda therapy for CLL. Forty-one patients who had progressive CLL were treated on study. Eleven patients (27%) were sensitive to fluda and thirty (73%) refractory prior to study entry. Therapy consisted of cis-p 100mg/m² continuous intravenous (IV) infusion over 4 days, fluda 30 m/m² IV over 15 minutes on Days 3 and 4 either given alone (PF) or with ara-C 500 mg/m IV over 1 hour on Day 4 (PFA). The median number of PF or PFA courses received was two. No patient achieved a complete response. Eight patients (19%) achieved a partial response (PR), 28 were taken off study with progressive or refractory disease and 5 had induction deaths. The overall median survival was 6 months, 15 months in responding patients, and 4 months in non-responding patients. Rai stage 1-11 patients had a median survival of 7 months and stage 111-IV patients had a median survival of 3 months. Major toxici-ties (myelosuppression, sepsis, renal failure and tumor lysis syndrome) were frequent.

In conclusion, it can be said that the PF and PFA regimens have equivalent modest activity in patients with progressive CLL following prior fluda therapy, predominantly among patients whose disease was sensitive to fluda at last prior exposure. Ara-C did not add to the activity of the cis-plfluda combination in this study group.     

Incidence and Management of Proven and Probable Fungal Infections in Patients with Acute Leukemia: A Single Center Experience

Abstract

The incidence of fungal infections and the role of liposomal amphotericin B (Ambisome) in proven and probable infections were evaluated in acute leukemic patients, intolerant to conventional amphotericin B. During 1999-2002, 307 febrile episodes occurred in 231 patients. Fungi were responsible for 3% of bloodstream infections. Ambisome was employed in 5 fungal sepsis (1 Candida albicans, 1 C. famata, 1 C. tropicalis, 1 C. krusei, 1 Geotrichum capitatum) 2 Aspergillosis, 2 probable fungal pneumonia cases. A favorable response was achieved in 78% of patients (4 fungemia, 2 aspergillosis, 1 probable), an unfavorable response in 1 C. krusei fungemia and in 1 probable pneumonia. Our antimicrobial pattern docu-mented a high resistance rate to azoles. We concluded that Ambisome is an effec-tive and well tolerated agent and its introduction has changed the outcome for many patients, although in some refractory diseases other strategies must be con-sidered.