Cytarabine Induction Research Articles

Core Binding Factor Acute Myeloid Leukemia of the Elderly Treated with Conventional Chemotherapy: A Collaborative Study of the French CBF AML Intergroup

Acute Myeloid Leukemia with rearrangements of CBFα or β (CBF-AML) are associated with a younger age and with a good prognosis when treated with intensive chemotherapy. CBF are infrequent in elderly patients (Appelbaum BJH 2006) and are associated with a better outcome as compared to other AMLs. Complete Remission (CR) rate and Event Free Survival (EFS) seemed to be lower than what was observed for younger patients. However, only limited data are available on the characteristics and outcome of CBF-AML in the elderly. We presents the results of a retrospective analysis of 150 patients with t(8;21) or inv(16) older than 60 years who received conventional induction chemotherapy in 17 centres of the french CBF AML intergroup (GOELAMS/ALFA groups). All patients received conventional anthracyclin + cytarabine induction therapy. Post-remission therapy consisted of low dose maintenance chemotherapy (87 patients 58%), intermediate or high dose cytarabine (47 patients, 31%) or Melphalan with autologous (SCT: 9 patients 6%). Median age was 67 years (range 60–82y). Inv(16) was found in 88 pts (58%) and t(8;21) in 62pts (42%). Additionnal chromosomal abnormalities were identified in 66 patients (44%) including 16 with trisomy 22 (11%) only in pts with Inv(16), 19 (13%) with loss of sex chromosome and 7 (5%) with del 9q mostly found in t(8;21). 132 patients achieved CR after 1 or 2 induction courses (88% CR rate), 3 pts had refractory diseasea and 15 died early (10%). 17 pts (11%) required ICU transfer during induction. Induction mortality was significantly related to poor performance status (p<0.001) and High WBC count at diagnosis(p=0.015). With a median follow-up of 17 months, Overall Survival (OS) and EFS were respectively 24 and 19 months. By multivariate analysis of factors influencing OS and LFS are presented in the Table. Outcome was favorable for Inv(16) patients (OS=27 months, EFS=22 months) compared to t(8;21) patients (OS=21 months, EFS=14 months). Interestingly, the benefit of intensive consolidation was limited to t(8;21) AML (EFS NR vs 11 months, p=0.002). No impact of age as a continuous variable could be demonstrated. After relapse, Median Overall survival was 5 months with a significantly better outcome in Inv(16) patients and if relapse was delayed (more than 12 months after CR1). No impact of age on outcome after relapse could be demonstrated. This large series of elderly patients with CBF-AML show that these patients must be offered standard induction which leads to high CR rate whatever the age. Nevertheless, the majority of them relapse with conventional post-remission treatment and the impact of intensive chemo seems limited. Alternative strategies of post-remission therapy are thus warranted including new cytotoxic drugs as well as targeted molecules.VariableRR Overall survivalp=RR Event Free Survivalp=High WBC count2.56 [1.464–4.491]0.0012 [1.104–3.562]0.022ECOG (0–1 vs 2–4)5.12 [2.878–9.112]< 0.0012.76 [1.457–5.215]0.002Deletion 9q5.06 [2.125–12.05]< 0.0013.32 [1.445–7.629]0.005ICU admittance during induction5.18 [2.744–9.764]< 0.0012.86 [1.216–6.717]0.016use of High Dose Cytarabine0.373 [0.196–0.708]0.003NSNS

Acute myeloid leukemia with t(8;21)(q22;q22) preceded by breast granulocytic sarcoma

Granulocytic sarcoma (GS) is a rare extramedullary tumor mass composed of immature cells derived from the hematopoietic myeloid series. It is usually associated with leukemia and other myeloproliferative disorders but can also occur without overt hematologic diseases. The breast has been reported to be an uncommon site of presentation. We report a case of acute myeloid leukemia preceded by GS of the breast. The immunohistochemistry revealed myeloperoxidase, CD68 and CD43 positivity, thus indicating a diagnosis of GS. Conventional cytogenetic analysis of peripheral blood cells showed t(8;21)(q22;22). Complete remission was achieved with Daunorubicin and Cytarabine induction therapy followed by three courses of high-dose Cytarabine consolidation. The patient remains in continuous complete remission at 27 months.

Impact of CRi on the Outcome of Elderly Patients with Acute Myeloid Leukemia.

New international recommendations of response for treatment of acute myeloid leukemia (AML) include morphologic complete remission with incomplete blood count recovery (CRi). This response criteria was defined following evaluation of new drugs used for the treatment of AML in first relapse (Sievers et al., JCO 2001; 19:3244–3254). The objective of our study was to determine the outcome of elderly patients with newly diagnosed AML achieving CRi. Between 1995 and 2006, 240 patients aged 65 years or older with previously untreated acute non promyelocytic leukemia received a conventional anthracycline and cytarabine induction chemotherapy at a single institution. Median age was 71 years (range, 65–85). One hundred and nineteen patients achieved a complete response (CR) (50%), 15 patients achieved CRi (6%), 69 patients had persisting leukemia (29%), and 37 died during remission induction therapy (15%). Patients who reached a CR or CRi after 1 or 2 cycles of induction chemotherapy proceeded to consolidation. Only 9 patients in CRi received this consolidation chemotherapy course (60%) and none had intensification (intermediate-dose cytarabine and/or autologous stem cell transplantation) whereas for patients achieving CR, 88% (n=104) and 69% (n=82) had consolidation and intensification, respectively (p=0,01 and p=0,03). The median overall survival (OS) was respectively 9 and 18 months for patients in CRi and CR (p=0,08). OS was significantly lower for patients in CRi younger than 70 years (5 versus 17 months for CR, p=0,02). By landmark analysis, there was no difference in OS between patients in CRi and a group of 67 patients with induction failure surviving at less 40 days (p=0,14). Disease-free survival (DFS) and remission duration were not significantly different between patients in CRi and CR overall (5 and 8 months, and 5 and 7 months, respectively), but we found a difference for patients younger than 70 years (p=0,004 and p=0,009 for DFS and remission duration, respectively). There was significantly more multilineage dysplasia in patients achieving CRi (8 versus 33, p=0,009) and platelet count at diagnosis were lower (44 G/L versus 82 G/L). Cytogenetic did not differ between the two groups. Our results show that the outcome of elderly patients who achieved CRi is inferior to patients in CR, especially for patients younger than 70 years. Although this response criteria seems to indicate activity, we were not able to found a difference with patients who did not achieve CR. This result will be revaluated in a larger study. Our data also suggest that patients with CRi have different initial disease characteristics. [Display omitted]

Phase IB Study of PKC412, an Oral FLT3 Kinase Inhibitor, in Sequential and Simultaneous Combinations with Daunorubicin and Cytarabine (DA) Induction and High-Dose Cytarabine Consolidation in Newly Diagnosed Adult Patients (pts) with Acute Myeloid Leukemia (AML) under Age 61.

FLT3 (fms-like tyrosine kinase) activating mutations, either an ITD (repeat of 3->100 amino acids in the juxtamembrane region) or a point mutation in the activation loop, occur in blasts from 30% of AML patients (pts). ITD mutations are associated with a relatively poor prognosis. PKC412 is a multi-targeted kinase inhibitor that has clinical activity in mutant (reduction in peripheral blasts in 70%) and wild type (reduction in peripheral blast in 30%) FLT3 AML, but rarely produces complete remissions (Stone et al, Blood 2005; Estey et al, ASH 2003). We conducted a phase Ib trial with DA (daunorubicin 60 mg/m2 d 1–3 and cytarabine 100 mg/m2/d by IVCI x 7d) induction and post-remission therapy (cytarabine 3 gm/m2/3h q 12h, d1,3, and 5 for 3 cycles) plus PKC412 at 100 mg bid po continuously beginning on day 8 (arm 1) or day 1 (arm 2) (n=15) or an amended schedule: day 8–21 (arm 1) or day 1–7, 15–21 (arm 2) (n=15) in previously untreated adult AML pts ≤ age 60. Results demonstrated safety, but poor tolerability due to nausea and vomiting (Giles, et al, ASH 2004). The study was then amended to include the same chemotherapy, but with 50 mg PKC412 po bid (previously shown to lead to plasma levels sufficient to inhibit FLT3) on day 8–21 (arm 1) or day 1–7, 15–21 (arm 2); tolerability improved to acceptable levels with no patients withdrawing due to nausea, vomiting, or diarrhea (Stone at al, ASH 2005). The study has completed accrual (40 pts enrolled after the PKC412 50 mg po bid amendment) with 38 pts (26 with wild type FLT3 (FLT3wt) blasts and 12 with mutated FLT3 (FLT3mut) blasts) evaluable for efficacy and 37 pts for safety. Complete response (CR) occurred in 27/38 (71%). The CR rate in FLT3wt pts was 18/26 (69%); 9/13 (69%) pts achieved CR in each of the arms. CR occurred in 11/12 (92%) FLT3mut pts. CR rate in FLT3mut pts was 7/7 (100%) in Arm 1 and, 4/5 (80%) in arm 2. 4/11 CR pts relapsed after 7, 7, 10 and 15 months; 7 pts remain in first CR for 3–15 months. No drug-related deaths were reported. One patient withdrew due to Grade 4 increase in alkaline phosphatase. The most common serious Grade 3–4 side effects reported to date include thrombocytopenia 6/19 (31.5%), anemia 5/19 (26%) and neutropenia 5/19 (26%) in pts on arm 1; thrombocytopenia 2/18 (11%), anemia 1/18 (5.5%) and neutropenia 2/18 (11%) in pts on arm 2. All Grade 3–4 events were transient and/or reversible. No Grade 3 or 4 nausea and vomiting occurred in either arm. In conclusion, PKC412 at 50 mg po bid can be given safely and tolerably in newly diagnosed adult AML pts ≤ 60 years old in combination with DA and high dose cytarabine. The CR rate and preliminary DFS in FLT3mut pts is encouraging. A phase III study of chemotherapy +/− PKC 412 at 50 mg po bid on d8–21 per cycle in newly diagnosed pts ages 18–60 with mutant FLT3 AML is planned.

Addition of Cladribine to Induction/Consolidation Regimen Does Not Impair Peripheral Blood Stem Cell Mobilization and Bone Marrow Harvest for Autotransplantation in Acute Myeloid Leukemia Patients

Background The previous study by the Polish Adult Leukemia Group has demonstrated that addition of cladribine to standard DNR+AraC induction potentiates the antileukemic activity. The goal of this study was to compare the efficacy of bone marrow or peripheral blood hematopoietic cell collection in patients who obtained remission after daunorubicine plus cytarabine induction with cladribine (DAC-7) or without addition of cladribine (DA-7) in preparation for autotransplantation. Patients and Methods Sixty-six patients aged 41 years (range, 17–58 years) were included in this study: 33 cases in the DAC-7 and 33 in the DA-7 arm. Hematopoietic cells were collected from the bone marrow (ABMT, n = 29) or from the peripheral blood (ABCT, n = 37) using cytopheresis after administration of AraC (2 × 2 g/m 2) on days 1, 3, 5 and subsequent G-CSF (10 μg/kg) from day 7 as mobilization therapy. Results The numbers of harvested CD34 + cells were similar in the DAC-7 and DA-7 pretreated patients both after harvesting from peripheral blood (2.55 × 10 6/kg vs 2.5 × 10 6/kg) and from bone marrow (1.62 × 10 6/kg vs 1.55 × 10 6/kg), respectively. The proportion of patients with sufficient material for autologous bone marrow transplantation was higher in the DAC-7 compared with the DA-7 arm. All patients engrafted; hematopoietic recovery was similar in both subgroups. Conclusion Addition of cladribine to a standard DA induction does not impair the harvesting of hematopoietic cells and their engraftment after autotransplantation.

Phase IB Study of PKC412, an Oral FLT3 Kinase Inhibitor, in Sequential and Simultaneous Combinations with Daunorubicin and Cytarabine (DA) Induction and High-Dose Cytarabine Consolidation in Newly Diagnosed Patients with AML.

Activating mutations in FLT3 (fms-like tyrosine kinase), either an ITD (repeat of 3–33 amino acids in the juxtamembrane region) or a point mutation in the activation loop, occur in blasts from 30% of AML patients, are associated with poor prognosis, and represent an attractive therapeutic target. PKC412 is a multi-targeted kinase inhibitor which has clinical activity in mutant (reduction in peripheral blasts in 70%) and wild type (reduction in peripheral blast in 30%) AML, but rarely produces remissions (Stone et al, Blood 2005; Estey et al, ASH 2003). We combined DA induction (daunorubicin 60 mg/m2 d 1–3 and cytarabine 100 mg/m2/d by IVCI x 7d) and post-remission therapy (cytarabine 3 gm/m2/3h q 12h, d1,3,5 for 3 cycles) plus PKC412 in previously untreated AML patients less than or equal to age 60 in a phase Ib trial. Results with the original dose schedules of PKC 412: 100 mg po bid from day 8 continuously (arm 1) or day 1 continuously (arm 2) (n=15) or an amended schedule: day 8–21 (arm 1) or day 1–7, 15–21 (arm 2) (n=15) demonstrated safety, but poor tolerability due to nausea and vomiting (Giles, et al, ASH 2004). We now report results with a new amendment in which pts receive the same chemo regimen plus PKC412 at a reduced dose of 50 mg po bid (previously has been shown that PKC at 50 mg bid produces plasma levels sufficient to inhibit FLT3) on day 8–21 (arm 1) or day 1–7, 15–21 (arm 2).None of the 19 pts treated to date have had drug-related death; the most common drug related toxicities during induction and consolidation cycles were nausea (53%), vomiting (47%), ALT increase (32%), AST increase (26%), diarrhea (26%) and rash (21%); all were transient and/or reversible. No Grade 3 or 4 nausea and vomiting were recorded. As of this report, 4 pts have completed the study, and 7 pts are still on study receiving consolidation after achieving CR. Causes of discontinuation include resistant disease (5), transplant after achieving CR (2), and non-drug related toxicity of sepsis and neutropenia (1). All 19 patients are evaluable for response: 9/12 (75%) achieved CR in Arm 1 and 5/7 (71%) achieved CR in Arm 2. Six out of six (100%) FLT3mut patients and 8/13 (62%) FLT3WT patients achieved CR. When a comparison of CR rate is made across all 49 patients in this study overall, there was a significant difference between the FLT3WT CR = 17/32 (53%), and FLT3mut CR=10/11 (91%) (p=0.033 by Fischers exact test). Median follow-up is short, 5 months (1–15). All ten FLT3mut patients that entered CR are alive with only one known relapse (at 15 months post-CR). Conclusions: PKC412 at 50 mg po bid can be given safely and tolerably in newly diagnosed ≤ 60 years old AML patients in combination with DA and high dose cytarabine. These combinations merit further study especially in patients with mutant FLT3 AML.

Adaptive randomized study of idarubicin and cytarabine alone or with interleukin-11 as induction therapy in patients aged 50 or above with acute myeloid leukemia or high-risk myelodysplastic syndromes

A higher complete remission (CR) rate was observed in patients with acute myeloid leukemia (AML) who, on a prior randomized study of induction therapy, received gemtuzumab ozogamicin (GO) plus interleukin-11 (IL-11) rather than GO alone. An adaptive randomized phase III study of the addition of IL-11 to idarubicin and cytarabine (IA) induction in 100 patients ≥50 years of age with AML or high-risk myelodysplastic syndrome (MDS) was conducted. Median patient age was 67 years (range 50–82). Twenty-four of the 45 (53%) patients randomized to IA plus IL-11 achieved CR. Eight (33%) subsequently relapsed, 4 (17%) died in CR; median time to treatment failure (TTF) was 37 weeks. Twenty-nine of the 55 (53%) patients treated without IL-11 achieved CR. Eight (28%) subsequently relapsed, 2 (7%) died in CR; median TTF was 46 weeks. Median overall survivals were 21 and 59 weeks for the IA plus IL-11 and IA cohorts, respectively ( p = 0.271, log rank test; 0.435, Gehan–Breslow test). Ten episodes of the following grade 3 or 4 cardiopulmonary toxicities were observed in patients receiving IA plus IL-11, 12 such episodes in those receiving IA alone: atrial fibrillation, pleural effusions, myocardial infarction, bradycardia or hypotension. Two patients in each arm experienced grade 3 peripheral edema. There was no significant difference in incidence of any grade 3 or 4 adverse event, including thrombocytopenia, between treatment arms. There was no significant impact on CR rates, TTF, survival, or toxicity of adding an IL-11 regimen to IA induction in patients ≥50 years of age with AML.

Addition of Purine Analogues to Induction/Consolidation Regimen Does Not Impair Peripheral Blood Stem Cell Mobilization and Bone Marrow Harvest for Autotransplantation in Acute Myeloid Leukemia.

In the previous study by the Polish Adult Leukemia Group (PALG 1999 Study) we demonstrated that addition of cladribine to standard daunorubicine + cytarabine (DA-7) induction potentiates antileukemic activity of the regimen in acute myeloid leukemia (AML). However, there is a concern that the treatment with purine analogues may affect a successful collection of hematopoietic cells for transplantation (autoHCT).The goal of this study was to compare the efficacy of peripheral blood and bone marrow hematopoietic CD34+ cell harvest in patients who both in induction and consolidation were treated with or without purine analogues and who were intended for autoHCT.Sixty-seven AML patients, aged 41 (17–58) years, were included in this study; 33 patients received cladribine-containing regimen (DAC-7), one patient - fludarabine-containing regimen (DAF-7), 33 patients received standard treatment (DA-7, HAM, HD cytarabine). In the DAC-7 treated patients cladribine was also given as a adjunct to second HD cytarabine consolidation. AutoHCT using bone marrow (autoBMT) or peripheral blood (autoBCT) as a source of hematopoietic cells was performed in first complete remission after completion of consolidation therapy. An additional course of AraC 2x2g/m2 on days 1, 3, 5 + G-CSF 10 mg/kg since day 7 was used as mobilization in case of autoBCT.The number of collected CD34+cells/kg was similar for patients pre-traeted with purine analogues and those not receiving purine analogues: 2.55 (0,79-9,25) x106/kg vs 2.5 (1,41–23,5) x106/kg (p=NS) for peripheral blood and 1.62 (0,32–3,01) x106/kg vs 1.55 (0,5–2,45) x106/kg (p=NS) for bone marrow, respectively. In 90% and 95% of patients for both subgroups sufficient number of hematopoietic cells for transplantation could not be collected (p=NS). The proportion of unsuccessful bone marrow harvest was significantly lower for patients pre-treated purine analogues with purine analogues compared to those not receiving purine analogues (90% vs 56%, p=0,04), wheras not difference was found with respect to peripheral blood cell collection (95% vs 62%, p=NS). All patients who received autoHCT engrafted. The time to neutrophil and platelet recovery was similar for both study subgroups.We conclude that treatment with purine analogues in course of induction/consolidation therapy does not impair the hematopoietic cell harvest and does not decrease a chance to perform autoBCT or autoBMT in AML patients.

Phase 1 Study of PKC412, an Oral FLT3 Kinase Inhibitor, in Sequential and Concomitant Combinations with Daunorubicin and Cytarabine (DA) Induction and High-Dose Cytarabine (HDAra-C) Consolidation in Newly Diagnosed Patients with AML.

The Fms-like tyrosine kinase 3 (FLT3), a receptor expressed in 80% of AML patients, is constitutively activated in 25–35% of adult AML patients due to mutations, in the form of either ITDs or activating loop point mutations, most commonly at D835Y. PKC412 is an oral multi-targeted tyrosine kinase inhibitor known to potently inhibit both activated wild type (WT) and mutated (mut) FLT3 kinase. PKC412 (100 mg po bid) was tested in a phase IB study in newly diagnosed AML patients between 18 and 60 years of age (both WT and mut FLT3) in combinations with DA for induction therapy (up to 2 cycles) and HDAra-C for consolidation (up to 3 cycles).Study design: PKC412 was given daily beginning on Day 8 (Arm 1) or Day 1 (Arm 2) of induction chemoRX in cycle 1. Primary endpoints were PK, tolerability, and safety as defined by fewer than 2 drug-related deaths in the initial cohort of 6 pts per arm (stage 1) and fewer than 4 drug-related deaths among the total 20 pts per arm (stage 2) during induction.Results: 15 pts were enrolled (median age 50; 1 FLT3 ITD+, 14 WT; ): 7 in Arm 1 and 8 in Arm 2. Cytogenetic prognostic categories of the 15 patients were: 0 (good), 9 (intermediate) and 6 (bad). Of the 15 pts, 14 were evaluable for toxicity; 1 pt did not receive PKC412; no drug-related deaths were observed during induction therapy. The most common G3 drug-related toxicities included: nausea (46%), vomiting (32%), transaminitis (18%), and hyperbilirubinemia (18%), all were transient and/or reversible. 13/15 patients were evaluable for response: 2 pts were not evaluated: one pt never received PKC412 and one pt did not complete the full-course of induction chemoRx; 3/7 (43%) achieved a CR in Arm 1 and 3/6 (50%) achieved a CR in Arm 2. 3 pts have completed the study (Days 143, 141, 132) and one pt is ongoing (Day 127). Because of the high rate of G3 nausea and vomiting, the study was amended, (5 patients are ongoing) such that PKC412 is given with each cycle of chemoRx on either Days 1–7 and 15–21 (Arm 1), or on Days 8–21 (Arm 2).Conclusions: PKC412 can be given safely in newly diagnosed AML patients in combinations with DA and HDAra-C chemoRx. An update of this study, along with PK data of PKC412, daunorubicin, and Ara-C levels will be presented.

Daunorubicin, Cytarabine and Fludarabine (DAF) for the Treatment of Relapsed/Refractory Acute Myeloid Leukemia. Phase II Study by the Polish Adult Leukemia Group (PALG).

In 1992–93 a synergistic interaction of ribonucleotide reductase inhibitors (fludarabine, cladribine) and cytarabine (AraC) resulting in increase of Ara-CTP concentration in myeloblasts was proved. In the previous study by the Polish Adult Leukemia Group (PALG 1999 Study) we demonstrated that addition of cladribine to standard daunorubicin + cytarabine induction potentiates antileukemic activity of the regimen in acute myeloid leukemia (AML).The goal of the current study was to assess the safety, tolerance and antileukemic activity of a new DAF regimen consisting of daunorubicin 60 mg/m2/d iv 1–3, AraC 200 mg/m2 ci 1–7, and fludarabine 25 mg/m2/d 1–5.Twenty-five AML patients aged 40 (range 19–62) years with primary refractoriness 60% (n=15) or in relapse 40% (n=10) were included in the study between 2003–2004. DAF was administered as a second (n=24) or as a third line of induction treatment (n=1).Twelve patients (48%) achieved complete remission (CR), 1 (4%) had partial remission (PR), and 10 (40%) did not respond (NR, leukemia regrowth). Two patients died in aplasia from infectious complications (8%).All patients developed severe thrombocytopenia and granulocytopenia (WHO grade III or IV). Median time to neutrophil >0.5 G/L recovery and platelet >50 G/L recovery equaled 21 d. (11–30) and 20 d. (11–27), respectively.Eleven (44%) patients exerienced severe (WHO grade III or IV) neutropenic infections (bacterial n=9, fungal n=2). Other serious adverse events were infrequent: vomiting 24% (n=6), mucositis 24% (n=6). Severe hepatotoxicity, nephrotoxicity and cardiotoxicity was not observed.Median hospital stay lasted 28 (11–41) days. Patients required 5.5 (0–13) PRBC transfusions and 5.5 (1–14) platelet transfusions. Hematopoietic growth factors were not administered.Results of this phase II study indicate that DAF is a relatively well-tolerated and safe regimen with high anti-leukemic potency in relapsed/refractory AML. Based on these findings a randomized, multicenter study comparing DAF to the standard DA induction has been designed for newly diagnosed AML patients.

Mitoxantrone and Cytarabine Induction, High-Dose Cytarabine, and Etoposide Intensification for Pediatric Patients With Relapsed or Refractory Acute Myeloid Leukemia: Children’s Cancer Group Study 2951

To evaluate the response rate, survival, and toxicity of mitoxantrone and cytarabine induction, high-dose cytarabine and etoposide intensification, and further consolidation/maintenance therapies, including bone marrow transplantation, in children with relapsed, refractory, or secondary acute myeloid leukemia (AML). To evaluate response to 2-chlorodeoxyadenosine (2-CDA) and etoposide (VP-16) in patients who did not respond to mitoxantrone and cytarabine. Patients with relapsed/refractory AML (n = 101) and secondary AML (n = 13) were entered. Mitoxantrone and cytarabine induction achieved a remission rate of 76% for relapsed/refractory patients and 77% for patients with secondary AML, with a 3% induction mortality rate. Cytarabine and etoposide intensification exceeded the acceptable toxic death rate of 10%. The response rate of 2-CDA/VP-16 was 8%. Two-year overall survival was estimated at 24% and was better than historical control data. Patients with secondary AML had similar outcomes to relapsed or refractory patients. Initial remission longer than 1 year was the most important prognostic factor for patients with primary AML (2-year survival rate, 75%), whereas for patients with primary AML, with less than 12 months of initial remission, survival was 13% and was similar to that of refractory patients (6%). Mitoxantrone and cytarabine induction is effective with reasonable toxicity in patients with relapsed/refractory or secondary AML. The cytarabine and etoposide intensification regimen should be abandoned because of toxicity. Patients with relapsed AML with initial remissions longer than 1 year have a relatively good prognosis.

Segmental Coecal Cytomegalovirus Colitis During Fludarabine, Cytarabine and Mitoxantrone Induction Chemotherapy for Myelodysplastic Syndrome

We report the case of a 59-year-old woman treated for a refractory anemia with excess blasts (RAEB) who developed cytomegalovirus (CMV) colitis during induction therapy combining fludarabine, cytarabine and mitoxantrone. CMV infection occurred rarely during cytarabine and anthracyclin based induction therapy for acute myelogenous leukemia or RAEB. CMV infection is usually observed in immunocompromised patients but some cases have been recently observed in patients after autologous stem-cell transplantation with or without CD34+ stem-cell selection. We discuss this case and issues arising from it in relation to the use of combination of high-dose cytarabine and fludarabine.

Patterns of failure with increasing intensification of induction chemotherapy for acute myeloid leukaemia.

Patterns of failure were studied in two consecutive randomized trials of intensified induction therapy carried out by the Australian Leukaemia Study Group (ALSG) between 1984 and 1991 to determine the impact of dose intensification. Patients received standard dose cytarabine and daunorubicin (7-3), 7-3 plus etoposide (7-3-7) or 7-3 plus high-dose cytarabine (HIDAC-3-7) chemotherapy. Patients with FAB M3 morphology were excluded. Time to failure (TTF) was defined as the time from randomization to induction death or removal from study for non-responders, or to relapse or death in complete response (CR) for complete responders. An estimated 86% of 470 de novo patients with acute myeloid leukaemia failed within 10 years of randomization, as a result of death in induction in 17% of the randomized patients, failure to achieve CR in a further 17%, relapse in 44% and death in CR in 8% of patients. An estimated 66% of patients failed as a result of refractory disease or relapse within that period (disease-related failures). Multifactor analysis identified age and peripheral blast count as the most significant pretreatment factors associated with overall TTF. These factors, together with cytogenetics, were significantly associated with disease-related failures. High-dose cytarabine in induction significantly decreased the disease-related failure rate as did allogeneic transplantation in first CR. The impact of high-dose cytarabine did not depend on the cytogenetic risk group.

Therapy of acute myeloid leukemia.

The Eastern Cooperative Oncology Group (ECOG) has recently reviewed the outcome for more than 1,400 patients with previously untreated AML entered on five successive clinical trials.5,6 Each trial included daunorubicin and cytarabine for induction. Successive trials in this analysis included postremission therapy with increasingly more intensive consolidation. Among 1,414 patients,62% achieved CR, but 76% have relapsed or died. The overall survival (OS) rate for all patients at 5 years is only 15%. Patients aged 55 years or older fared particularly poorly. The 5-year OS rate was 9%33% for patients less than 55 years of age and 6%-15% for patients aged 55 years and older.5,6 Among patients less than age 55 years, both the DFS and OS increased with more intensive postremission strategies.

Pancreatitis and fatal ARDS following high-dose cytarabine induction for acute myelogenous leukemia

Objective. To describe a case of fatal acute respira tory distress syndrome (ARDS) and pancreatitis aris ing from high-dose cytarabine induction therapy. Case Summary. A 50-year-old male without a history of hepatobiliary disease and with a diagnosis of acute myelogenous leukemia was treated with high-dose cytarabine therapy. Tumor lysis occurred promptly; the white cell count reached a nadir of 100/mm 3 3 days after initiation of therapy. Severe mid-epigastric pain, fever, hypotension, and increased lipase and amylase occurred on the 6th day of cytara bine therapy. Cytarabine was discontinued 6 days after initiation. Serum amylase and lipase were persis tently elevated; respiratory failure due to ARDS ensued, and the patient expired of refractory hypoxemia. Discussion. Cytarabine-associated pancreatitis is a rare occurrence. Literature reports have described pancreatitis after high-dose cytarabine therapy for induction of remission of ALL and acute myelogenous leukemia. Pancreatitis resolved in all reported cases on discontinuation of cytarabine. In our patient, drug-induced pancreatitis likely provoked the onset of ARDS, which concluded with fatal respiratory failure. The absence of positive cultures decreased the likeli hood of sepsis-induced ARDS; the time course of cytarabine administration was temporally associated with the development of pancreatitis. Conclusions. Acute pancreatitis is a rare but potentially fatal event associated with high-dose cy tarabine therapy.

Chemotherapy

Chemotherapy

Granulocyte Colony-Stimulating Factor (Filgrastim) Accelerates Granulocyte Recovery After Intensive Postremission Chemotherapy for Acute Myeloid Leukemia With Aziridinyl Benzoquinone and Mitoxantrone: Cancer and Leukemia Group B Study 9022

AbstractThis study evaluated the effect of filgrastim (granulocyte colony-stimulating factor [G-CSF]) on the duration of granulocytopenia and thrombocytopenia after intensive consolidation therapy with diaziquone (AZQ) and mitroxantrone for patients less than 60 years of age with acute myeloid leukemia (AML) in complete remission. Patients less than 60 years of age with AML who achieved complete remission (CR) with daunorubicin and cytarabine induction therapy, were scheduled to receive three sequential courses of high-dose cytarabine, cyclophosphamide/etoposide, AZQ, and mitroxantrone in a pilot study to determine their tolerance of these three sequential consolidation regimens. The initial patients treated with AZQ and mitoxantrone experienced prolonged bone marrow suppression and, therefore, subsequent cohorts were treated with G-CSF, 5 μg/kg, beginning the day after completion of the third cycle of chemotherapy. There was a marked decrease in the duration of granulocytopenia less than 500/μL in two groups of patients receiving two different dose levels of AZQ and the same dose of mitoxantrone compared with patients not receiving the G-CSF. There was also a decrease in the need for hospitalization, as well as the duration of hospitalization. There was a trend towards shortening of the duration of thrombocytopenia, as well. The duration of complete remission and overall survival was similar in patients who received or did not receive G-CSF. G-CSF markedly shortened the duration of granulocytopenia in patients with AML receiving intensive postremission consolidation with AZQ and mitoxantrone. There was no adverse effect on CR duration or survival.

Treatment of adult acute leukemia.

In 1996 progress has been made toward a better understanding of acute leukemias, their biology, the effects of different intensity or subtype-specific chemotherapy, and the contribution of bone marrow transplantation. In acute lymphoblastic leukemia, high-dose cytarabine in induction and in postremission treatment improves the cure rate, whereas dose reduction of daunorubicin in older patients worsens response and increases mortality. After acute promyelocytic leukemia has been successfully treated by retinoids, another subtype-specific chemotherapy containing high-dose methotrexate has overcome the primarily poor prognosis of B-cell acute lymphoblastic leukemia. The leukemic stem cell of acute myeloid leukemia representing minimal residual disease, producing disease progression in the patients, and initiating long-term growth in cultures or immunodeficient mice appears as a primitive multipotent cell. Leukemic transformation is reflected either by the specific balanced chromosome translocations or by chromosome deletions or losses. They are associated with histories of cytotoxic drugs such as epipodophylotoxins and anthracyclines or alkylating agents. Alternatively, both kinds of aberrations develop spontaneously with ethnic differences in special subtypes. Cytogenetics also determine favorable and unfavorable prognosis both for chemotherapy and bone marrow transplantation. In acute lymphoblastic leukemia high-risk and nonstandard-risk patients seem to benefit from allogeneic transplantation, whereas in acute myeloid leukemia there is no adequate basis for risk-adapted stratification between treatment modalities. New prospects lie in a more successful use of the effects of treatment intensification possibly supported by autologous blood stem cell transplantation. On the basis of standardized treatment, future clinical research can address the role of biologic features of the individual leukemia such as specific chromosome aberrations, fusion genes, expression of oncogenes, and monitoring of minimal residual disease.

High-Dose Cytarabine Induction for Acute Myeloid Leukemia

In a recent article, Bishop et al’ state that high-dose cytarabine has not previously been used as induction for untreated acute myeloid leukemia (AML). In fact, high-dose cytarabine has been used by itself: with am~acrine,~ and with daunorubicin4 in this role. Additionally, doses of cytarabine significantly above those considered standard had previously been used by other groups for initial induction’ with daunorubicin. The report by Bishop et all builds on these previous experiences and clearly supports a role for high-dose cytarabine as initial therapy, as we and other groups have reported.

A randomized study of high-dose cytarabine in induction in acute myeloid leukemia [see comments

High-dose cytarabine (ara-c) may overcome cytarabine resistance in leukemic blasts. It has been used as a successful salvage and in postremission therapy but not as initial induction treatment. Patients aged 15 to 60 years, presenting with newly diagnosed acute myeloid leukemia (AML) were randomized to receive either high-dose cytarabine, 3 g/m2 12 hourly on days 1, 3, 5, and 7 for 8 doses, daunorubicin 50 mg/m2 days 1 to 3, etoposide 75 mg/m2 days 1 to 7, (HIDAC-3–7) or standard dose cytarabine 100 mg/m2 continuous intravenous infusion for 7 days with daunorubicin and etoposide at the same dose and schedule as above (7–3–7). Patients could receive a second or third induction course if complete remission (CR) was not achieved. All patients received the same postinduction consolidation therapy (5–2–5) for 2 courses. Eligible patients had no prior chemotherapy or myelodysplastic disease. Patients have been followed for a median of 4.5 years. Of 301 patients treated, complete response (CR) was achieved in 71% with HIDAC- 3–7 and 74% with 7–3–7. For patients in CR, the estimated median remission duration was 45 months with HIDAC-3–7 and 12 months with 7–3– 7 (P = .0005 univariate analysis, P = .0004 multivariate analysis). The estimated percentage of patients relapse free 5 years after achieving a CR was 49% on HIDAC-3–7 and 24% on 7–3–7. Patients in CR tended to survive longer with HIDAC-3–7 but there were no overall survival differences between the two arms. HIDAC-3–7 was associated with significantly more toxicity in induction with more leukopenia, thrombocytopenia, nausea, and vomiting and eye toxicity (all P &lt; .001) but a similar incidence of severe central nervous system and cerebellar toxicity compared to 7–3–7. The consolidation treatment was the same in both arms but caused significantly more leukopenia and thrombocytopenia in patients previously treated with HIDAC-3–7 induction (P &lt; .0001). We conclude that a dose-effect exists for cytarabine in AML and that HIDAC- 3–7 prolongs remission duration and disease-free survival and is tolerable when used as initial induction therapy in patients with de novo AML.