Acute myelogenous leukaemia in older patients at St Bartholomew's Hospital: outcome with mitoxantrone and cytarabine

Elderly patients (age >60 years) with AML who are selected for curative treatment frequently receive anthracycline/cytarabine containing regimens. The anthracendione mitoxantrone (MTN) in combination with cytarabine (Ara-C) produces comparable complete remission rates to other regimens and may be less toxic. Over a 12 year period, 75 patients (median age 67 years, range 60-83 years) referred with newly diagnosed AML were treated with MTN and ara-C. MTN was administered at 12 mg/m(2)/day intravenously for three days in the first 26 patients, and 10 mg/m(2)/day intravenously for five days in a subsequent 49 patients. Ara-C was administered at a dose of 100 mg/m(2) twice daily intravenously for seven days. Complete remission (CR) was achieved in 34 out of 75 patients (45%). The median disease-free survival overall was 7.5 months (one month to nine and a half years). The median survival was one year for patients in whom CR was achieved, compared to four months in patients whom treatment failed (P=0.001). Age alone was predictive of achievement of CR, whilst presentation karyotype, serum LDH and patient age correlated with overall survival. These results confirm that although elderly patients have a poor outcome, prognostic factors can be identified that influence treatment outcome in this important group of patients.     

Results of conventional-dose cytosine arabinoside and idarubicin in elderly patients with acute myeloid leukemia

Summary Conventional-dose Ara-C (200 mg/m² d 1–5) combined with idarubicin (12 mg/m² d 1–3) was employed as remission induction and consolidation therapy in 23 elderly AML patients with a median age of 66 years (range, 60–75) with AML according to the FAB criteria (M1n=3, M2n=10, M4n=6, M5n=2, M6n=2), eligible for the study. In seven patients earlier MDS had been documented by previous bone marrow aspirates. The CR rate after one induction course was 65% (15/23). Toxicity was acceptable, with four patients dying during the chemotherapy-induced hypoplasia (4/23). Although 80% of the CR patients received two additional cycles of Ara-C and idarubicin as consolidation therapy, only two patients are still in continuous complete remission more than 12 months after achieving CR. The median disease-free survival of the CR patients was 11.5 months and the median survival of the entire group was 10 months. We conclude that conventional dose Ara-C/idarubicin is an effective protocol for inducing complete remission in elderly patients with AML, but that consolidation therapy consisting of two courses of the same regimen does not produce a relevant rate of long-term disease-free survival.     

Salvage treatment for primary resistant acute myelogenous leukemia consisting of intermediate-dose cytosine arabinoside and interspaced continuous infusions of idarubicin: A phase-II study (no. 06901) of the EORTC Leukemia Cooperative Group

 Twenty-one patients with acute myeloid leukemia (AML) who failed to enter complete remission (CR) after first-line standard-dose remission-induction therapy with 7 days of cytarabine and 3 days of daunorubicin were treated with a salvage regimen containing intermediate-dose cytosine arabinoside (Ara-C) 2×500 mg/m²/day during 7 days in combination with continuous infusions of idarubicin 12 mg/m²/day on days 1, 3, and 5. Twenty patients were considered primary resistant, and one patient had a partial remission after two remission-induction courses. Overall, 11 patients (52%, 95% confidence interval: 30–74%) entered CR. Three patients died during hypoplasia and seven patients had resistant disease or a partial remission. The remission rate in this study compares favorably with the results obtained in similar patient categories. The toxicity of this salvage regimen was remarkably mild. No extramedullary toxicity was observed except for hepatic dysfunction in seven patients. The median duration of remission was 8.5 months, and ultimately, all complete remitters have relapsed except the patient who died from infectious complications after allogeneic bone marrow transplantation (BMT). This study shows that new intensive chemotherapy regimens may be effective after failure of primary treatment. Salvage regimens containing intermediate/high-dose Ara-C and/or alternative anthracyclines or anthracenes should be induced in the treatment of young patients with de novo AML. Received: 12 September 1995 / Accepted: 24 November 1995     

Intensive chemotherapy with idarubicin, cytarabine, etoposide, and G-CSF priming in patients with advanced myelodysplastic syndrome and high-risk acute myeloid leukemia

In an attempt to improve the complete remission (CR) rates and to prolong the remission duration especially in elderly patients >50 years of age, we have used a combination chemotherapy of idarubicin (10 mg/m² IV×3 days), cytarabine (AraC, 100 mg/m² CIVI×7d), and etoposide (100 mg/m²×5 days) in combination with granulocyte colony-stimulating factor (G-CSF) priming [5 mg/kg SQ day 1 until absolute neutrophil count (ANC) recovery] for remission induction. Responding patients received two consolidation courses of idarubicin, AraC, and etoposide, followed by a late consolidation course of intermediate-dose AraC (600 mg/m² IV every 12 h×5 days) and amsacrine (60 mg/m² IV×5 days). A total of 112 patients (57 male/55 female) with a median age of 58 years (range: 22–75) have been entered and are evaluable for response: 19 refractory anemia with excess of blast cells in transformation (RAEB-T), 84 acute myeloid leukemia (AML) evolving from myelodysplastic syndrome (MDS), and 9 secondary AML after chemotherapy/radiotherapy. The overall CR rate was 62%, partial remission (PR) rate 10%, treatment failure 16%, and early death rate 12%. The CR rate was higher in patients 60 years (68 vs 55%), mainly due to a lower early death rate (5 vs 21%, p<0.001). After a median follow-up of 58 months, the median overall survival is 14.5% and median duration of relapse-free survival 8 months. After 60 months, the probability of CR patients to still be in CR and alive is 16% (20% in patients 60 years and 13% in patients >60 years), while the probability of overall survival is 12% (15% in patients 60 years and 9% in patients >60 years). Compared to our previous trial (AML-MDS Study 01-92) which was done with identical chemotherapy but no G-CSF priming in 110 patients with RAEB-T, AML after MDS, or secondary AML (identical median age, age range, and distribution of subtypes), the CR rate in all patients, as well as CR rate, overall survival, and relapse-free survival in patients >60 years have significantly been improved. Thus, intensive chemotherapy with G-CSF priming is both well tolerated and highly effective for remission induction in these high-risk patients.     

All-trans retinoic acid plus low doses of cytarabine for the treatment of “poor-risk” acute myeloid leukemias

Summary Thirteen refractory/resistant AML patients no suitable for additional aggressive chemotherapy, were treated with a combination including all -trans retinoic acid (45 mg/m² sine die) and low doses of Ara-C (20 mg/m² subcutaneously, twice in a day, days 1–10, every 28 days). Ten patients were évaluable; 8 of them achieved a complete remission, two patients with an important tumor burden, failed to achieve a response. One complete remission patient relapsed after 7 months but is still receiving the same therapy and is now in partial remission. We believe this combination effective as inducer of complete remission in those AML patients which cannot tolerate additional heavy treatments. The role of tumor burden in affecting response to therapy remains to be still evaluated.     

Treatment of acute myelogenous leukaemia in patients aged 50–65: idarubicin is more effective than zorubicin for remission induction and prolonged disease-free survival can be obtained using a unique consolidation course

From December 1987 to June 1992, 251 patients aged 50–65 with de novo acute myelogenous leukaemia (AML) were recruited to a multi-institutional randomized clinical trial. Induction therapy consisted of Ara-C (200 mg/m², continuous infusion, days 1–7) with either zorubicin (ZRB) (200 mg/m², i.v., days 1–4) or idarubicin (IDR) (8 mg/m², i.v., days 1–5). Consolidation therapy consisted of a single course of intensive chemotherapy with high-dose Ara-C (3 g/m², 3 h infusion, q 12 h, days 1–4) and m-Amsa (100 mg/m²/d, i.v., days 5–7).
The complete remission (CR) rate was (73%) with Ara-C/IDR versus (60%) with Ara-C/ZRB ( P  = 0.033). In multivariate analysis, factors found to be significant in predicting CR were normal karyotype and treatment with IDR. With a median follow-up of 73 months, the median disease-free survival (DFS) duration of all CR patients and the probability of CR at 6 years were 17 months and 29%. In multivariate analysis the only factor associated with an increased DFS duration was a normal karyotype. The median event-free survival (EFS) duration for all evaluable patients and the median overall survival duration for all eligible patients were respectively 7 and 12 months without any difference between induction arms.
The study shows that in patients aged 50–65 idarabicin is more effective than zorubicin for remission induction. However, the type of anthracycline did not influence overall survival duration. Using a unique consolidation course, we observed a prolonged DFS which compares favourably with results obtained with more prolonged consolidation therapy or maintenance treatment.     

Randomized trial of response-oriented individualized versus fixed-schedule induction chemotherapy with idarubicin and cytarabine in adult acute myeloid leukemia: the JALSG AML95 study

A multicenter, prospective, randomized study was conducted to compare a response-oriented individualized remission induction therapy with a standard fixed-schedule induction therapy, using idarubicin (IDR) and cytarabine (Ara-C), in adult patients with acute myeloid leukemia (AML). Newly diagnosed patients with AML of age less than 65 were randomly assigned to receive either of the two schedules. Both groups received IDR (12 mg/m²) for 3 days and Ara-C (100 mg/m²) for 7 days. In the individualized group, if the bone marrow on day 8 did not become hypocellular with less than 15% blasts, patients received additional IDR for one more day and Ara-C for 2 or 3 more days. Patients achieving complete remission (CR) received the same post-remission therapy. The CR rate was 79.4% for the individualized group (n = 209) and 81.9% for the fixed group (n = 221) (p = 0.598). At a median follow-up of 81 months, 7-year predicted overall survival was 37% for the individualized group and 39% for the fixed group (p = 0.496), and 7-year predicted event-free survival was 22% for the individualized group and 23% for the fixed group (p = 0.546). Thus, the present study could not demonstrate any advantage of a response-oriented individualized induction therapy over a fixed-schedule induction therapy in this protocol setting.     

Increasing the dose of aclarubicin in low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor (CAG regimen) can safely and effectively treat relapsed or refractory acute myeloid leukemia

It is difficult for relapsed and refractory acute myeloid leukemia (AML) patients to achieve complete remission (CR). The CAG regimen [low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor (G-CSF)] has been used to treat relapsed and refractory AML patients, and showed good therapeutic efficacy. It is unknown, however, whether increasing the dose of aclarubicin in CAG regimen could treat relapsed or refractory AML safely and effectively. We evaluate the efficacy and tolerability of increasing the dose of aclarubicin in CAG regimen, in 37 relapsed or refractory AML patients. All patients were treated with CAG regimen including low-dose cytarabine (10 mg/m² every 12 h, days 1–14), aclarubicin (5–7 mg/m² every day, days 1–14), and G-CSF (200 μg/m² every day, days 1–14) priming. After a single course of therapy, the overall response [CR + partial remission (PR)] rate of all patients was 78.4 % (29/37), in which the CR rate was 62.2 % (23/37). There was no early death. The median overall survival was 6 months (range 2–36 months). Myelosuppression was ubiquitous, but tolerated. No severe non-hematologic toxicity was observed. Thus, increasing the dose of aclarubicin in CAG regimen can be used safely and effectively in the treatment of relapsed or refractory AML.     

FLAG (fludarabine,cytosine arabinoside,G-CSF) for refractory and relapsed acute myeloid leukemia

 Twenty-two patients with refractory or relapsed AML were treated with FLAG [25 mg/m² fludarabine daily (days 1–5), 2 g/m² daily Ara-C (days 1–5) and 400 μg/m² daily G-CSF (day -1 till the absolute neutrophil count was >500/μl)]. Median age was 46 years (range 24–63). Eight patients had leukemia which was primarily refractory to conventional regimens, six were in first, seven were in second, and one was in third relapse. Overall, 11 of 22 (50%) patients achieved complete remission (CR), three had a partial response (PR), and seven did not respond (NR). One patient died of an early cerebral hemorrhage. The median remission duration from achievement of CR after FLAG was 9.9 months and median survival was 13.0 months. One patient is alive in CR at 31.9 months. Hematological toxicity of the regimen was severe. The median time to neutrophil recovery (ANC >500/μl) was 21 days (range 18–33). A median of seven red cell units (range 0–22) and of six platelet concentrate units (range 3–28) had to be given. Median duration of febrile neutropenia was 2 days (range 0–20 days) and patients were on i.v. antibiotics for a median of 16 days (range 0–51). There was no death from infection. Nonhematological toxicity was remarkably low, with almost no neurotoxicity and no major hepatotoxicity. In conclusion, FLAG seems to be an efficient and well tolerated regimen. It may be particularly useful for patients who have a sibling or unrelated donor for subsequent allogeneic bone marrow transplantation. Received: 27 August 1996 / Accepted: 17 September 1996     

Sequential mitoxantrone,daunorubicin, and cytosine arabinoside for patients with newly diagnosed acute myelocytic leukemia

Mitoxantrone (M) is a synthetic aminoanthraquinone with anti-leukemic activity in patients with daunorubicin (D) resistant acute leukemia. The Cancer and Leukemia Group B (CALGB) has undertaken a limited access pilot study in which M, 12 mg/m², over 30 min, daily for 3 days, and cytosine arabinoside (Ara-C), 100 mg/m²/day by constant infusion for 7 days were used for the induction of newly diagnosed patients with AML. Responding patients were consolidated with daunorubicin, 45 mg/m²/day for 3 days, and 7 days of Ara-C. After a second consolidation identical to induction, no further therapy was given. Twenty-nine patients with a median age of 50 years (range 18–72) were entered in the study; 18 were males and 11 females. Twenty-four (83%) patients achieved CR, 1 patient achieved a PR, and 4 died in induction from leukemia-related causes. Two patients died in CR from consolidation-related neutropenic sepsis and two additional patients died in CR. Of 24 patients, 7 remain disease-free at a median follow-up interval of 8 years. The regimen is active and well tolerated. The duration of disease-free survival in responding patients is consistent with that seen in similar regimens using intensification chemotherapy without prolonged maintenance. Am. J. Hematol. 56:214–218, 1997. © 1997 Wiley-Liss, Inc.     

A multicenter, open, noncomparative, phase II study of the combination of cladribine (2-chlorodeoxyadenosine), cytarabine, granulocyte colony-stimulating factor and mitoxantrone as induction therapy in refractory acute myeloid leukemia: a report of the Polish Adult Leukemia Group

Purine nucleoside analogues, cladribine (2-chlorodeoxyadenosine, 2-CdA) and fludarabine (FAMP) are active agents in acute myeloid leukemias (AMLs). Synergistic interaction between FAMP or 2-CdA with cytarabine (cytosine arabinoside, Ara-C) has been demonstrated in preclinical and clinical studies. The current multicenter phase II study was initiated to evaluate the efficacy and toxicity of induction treatment consisting of 2-CdA (5 mg/m²), Ara-C (2 g/m²), mitoxantrone (MIT, 10 mg/m²) and granulocyte colony-stimulating factor (G-CSF) (CLAG-M) in refractory AML. In case of partial remission, a second CLAG-M was administered. Patients in complete remission (CR) received consolidation courses based on high-dose Ara-C and MIT with or without 2-CdA. Forty-three patients from five centers were registered: 25 primary resistant and 18 relapsed. CR was achieved in 21 (49%) patients, 20 (47%) were refractory and 2 (5%) died early. Hematologic toxicity was the most prominent toxicity of this regimen. The overall survival (OS; 1 year) for the 42 patients as a whole and the 20 patients in CR were 43% and 73%, respectively. Disease-free survival (1 year) was 68.6%. None of the analyzed prognostic factors influenced the CR and OS probability significantly. We conclude that CLAG-M regimen has significant antileukemia activity in refractory AML, which seems to be better than the activity of many other regimens. The toxicity of the treatment is acceptable.     

Homoharringtonine in combination with cytarabine and aclarubicin in the treatment of refractory/relapsed acute myeloid leukemia: a single-center experience

To assess the efficacy and toxicity of HAA regimen (Homoharringtonine 4 mg/m²/day, days 1–3; cytarabine 150 mg/m²/day, days 1–7; aclarubicin 12 mg/m²/day, days 1–7) as a salvage therapy in the treatment of refractory and/or relapsed acute myeloid leukemia (AML), 46 patients with refractory and/or relapsed AML, median age 37 (16–65) years, participated in this clinical study. The median follow-up was 41 (10–86) months. Eighty percent of patients achieved complete remission (CR), and the first single course of re-induction HAA regimen resulted in CR rate of 76.1 %. The study protocol allowed two courses of induction. The CR rates of patients with favorable, intermediate and unfavorable cytogenetics were 90 %, 88.9 %, and 37.5 %, respectively. For all patients, the estimated 3-year overall survival (OS) rate was 42 %, and the estimated relapse free survival (RFS) at 3 years for the 36 CR cases was 49 %. The toxicities associated with HAA regimen were acceptable. HAA is a good choice in cases with refractory/relapsing AML for salvage chemotherapy, preferably with a high-efficacy and low-toxicity profile.     

High-dose cytosine arabinoside and daunorubicin postremission therapy in adults with de novo acute myeloid leukemia

A total of 149 consecutive de novo AML patients aged 50 years or less (median age = 37 years) were enrolled in this prospective multicenter trial initiated in May 1985. All patients received the same induction and early consolidation therapy with daunorubicin (DNR), cytosine arabinoside (Ara-C), and etoposide (DAV). High-dose Ara-C/DNR therapy included Ara-C at 3 g/m², in 12 doses (HD-Ara-C/DNR I) and eight doses (HD-Ara-C/DNR II), followed by DNR 30 mg/m² for 3 days. A complete remission (CR) was achieved in 104 (70%) patients; 61 complete responders received at least one cycle with HD-Ara-C/DNR. If those patients who were transplanted in first CR (n=26), were not considered, the median relapsefree-survival (MRFS) of the remaining 78 patients was 15 months, with a probability of relapse-free survival (RFS) at 116 months of 30% (95% CI, 20–40%) after a median follow-up of 95 months. The MRFS of the HD-Ara-C/DNR consolidated patients was 25 months, with a probability of RFS at 116 months of 37% (95% CI, 24–50%). If all patients who were transplanted (n=44) were not considered, the median survival time (MST) was 18 months with a probability of being alive at 118 months of 24% (95% CI, 16–33%). MST of the HD-Ara-C/DNR consolidated patients was 58 months with a survival probability of 46% (95% CI, 31–60%) at 118 months. Prognostic factor analysis did not reveal any significant influence of age, sex, FAB subtype, white blood cell count, hemoglobin level, thrombocyte count, LDH, or response to the first induction course on RFS of the HD-Ara-C/DNR consolidated patients. In summary, HD-Ara-C/DNR consolidation can improve the long-term outcome of a subgroup of de novo AML patients. Further improvement of the outcome seems to depend on the identification of patients with an inferior outcome under that strategy who might benefit from alternative treatment strategies.     

Daunorubicin,cytarabine and fludarabine (DAF) for remission induction in relapsed or refractory acute myeloid leukemia. Evaluation of safety,tolerance and early outcome—Polish Adult Leukemia Group (PALG) pilot study

In 1992–1993, synergistic interaction of ribonucleotide reductase inhibitors (fludarabine, cladribine) and cytarabine (Ara-C) increasing Ara-CTP concentration in myeloblasts was proved. Based on these findings and encouraging results of the addition of cladribine to standard daunorubicin+Ara-C induction regimen (DAC) in acute myeloid leukemia (AML), the Polish Adult Leukemia Group (PALG) conducted a pilot study on the administration of cytarabine, daunorubicin, and fludarabine (DAF) as a reinduction treatment of AML to assess tolerance, toxicity, and early outcome. The DAF regimen consisted of daunorubicine 60 mg m⁻² day⁻¹ iv on days 1–3 and fludarabine 25 mg m⁻² day⁻¹ iv on days 1–5 given before cytarabine 200 mg m⁻² day⁻¹ in ci on days 1–7. Thirty-four AML patients with median age 39, 24% relapsed and 76% refractory, were included into the study between September 2003 and August 2004. Achieved response rate in the whole study population was 56%; n = 16 patients with complete remission (CR), and n = 3 patients with partial remission (PR). Fifteen of 16 patients achieved CR after the first course of therapy. Only 9% of total population died before the assessment of remission. All patients developed severe neutropenia. Serious infections were observed in 47% of the cases. Severe thrombocytopenia was observed in 72% of the patients. All patients required substitution of platelet concentrates (median 4), and PRBC (median 5). Severe alopecia, mucositis, vomiting were of low frequency. Liver, kidney, or circulatory failure, diarrhea, or polyneuropathy were not observed. The probability of overall survival (OS) for 1 year for the whole study population (34 patients) and the group of 16 patients in CR was: 44% (95% confidence interval [CI] 36–52%) and 69% (95% CI 55–83%), respectively. The probability of leukemia-free survival (LFS) for 1 year was 38% (95% CI 22–54%). Summarizing, DAF regimen used as the induction therapy in relapsed/refractory AML was well tolerated with acceptable toxicity and early efficacy.     

Sequential intermediate-dose cytosine arabinoside and mitoxantrone for patients with relapsed and refractory acute myelocytic leukemia

Based on in vitro evidence of time-dependent synergistic kill of HL-60 leukemia cells exposed to Ara-C and mitoxantrone, 44 patients with relapsed or refractory AML and 3 with blastic CML were treated with a timed sequence of both drugs. There were 25 females and 22 males, with a median age of 53 (range 21-75). Of 31 patients with relapsed AML, 24 had one prior remission, 6 had two and 1 had three. Of these, 15 had failed a second reinduction attempt. Thirteen patients were primarily refractory to induction with Ara-C plus daunorubicin. Each dose of Ara-C, 500 mg/m2, was followed after 6 hr by mitoxantrone, 5 mg/m2, and the sequence was repeated four to six times (44-68 hr) in different cohorts of patients. All but two patients (one with blastic CML and one in relapse and refractory) are evaluable for response and toxicity. Of 16 patients in relapse without prior reinduction 7 achieved CR and 3 PR (62% response rate); there were 3 CR in the 14 patients who were in relapse and refractory (21% response rate) and 4 CR and 1 PR (35% response rate) in the 14 patients with primary anthracycline resistance. Five of seven patients previously exposed to mitoxantrone achieved CR. Response lasted from 2 to 42 months, with two patients alive and in continuing remission at 34 and 42 months. Average marrow recovery was seen after 25 days and time to remission was 30 days. Six patients died in induction (four from sepsis and two from the tumor lysis syndrome) and 21 had progressive disease. Chemotherapy was well tolerated with minor nausea and vomiting in 13 patients, moderate in 20, and severe in 2. Most patients did not have evidence of drug-induced mucositis: it was minor in 9 and moderate in 2. Renal dysfunction was attributable to the use of nephrotoxic antibiotics. Hepatic dysfunction was reversible and was minor in 10 patients, moderate in 13, and severe in 3. Sequential, timed administration of intermediate-dose Ara-C and mitoxantrone is an active and well-tolerated antileukemic regimen.     

Maintenance lenalidomide in combination with 5‐azacitidine as post‐remission therapy for acute myeloid leukaemia

In this Phase 1b study, the safety and tolerability of maintenance therapy, comprising lenalidomide (0–25 mg, days 5–25) in combination with azacitidine (50–75 mg/m², days 1–5) every 28 d, was explored in 40 patients with acute myeloid leukaemia (AML) in complete remission after chemotherapy. Eligibility included AML in first complete remission (CR1) with adverse risk karyotype (n = 8), fms‐related tyrosine kinase 3‐internal tandem duplication (FLT3‐ITD) (n = 5), age ≥60 years (n = 31) or AML in second remission (CR2) (n = 14). Dose‐limiting toxicity was not reached. Common toxicities were haematological, infection, injection pain, constipation, fatigue and diarrhoea. In CR1, median relapse‐free (RFS) and overall survival (OS) was 12 and 20 months, respectively. In CR2, median RFS was 11 months, with median OS not yet reached. Among 29 patients with intermediate cytogenetic risk, RFS was 50% at 24 months. There were five patients with concomitant FLT3‐ITD and nucleophosmin (NPM1) mutation; none have relapsed and all are still alive after 17–39 months. Maintenance lenalidomide/azacitidine augmented the function of cytotoxic T lymphocytes, particularly in patients with NPM1 mutation. The lenalidomide/azacitidine maintenance combination was effective in suppressing residual DNA (cytosine‐5‐)‐methyltransferase 3 alpha (DNMT3A)‐positive disease, resulting in sustained remission in patients with concurrent NPM1 mutation. Azacitidine/lenalidomide as maintenance therapy for high‐risk AML warrants further exploration.     

Fractionated gemtuzumab ozogamicin and standard dose cytarabine produced prolonged second remissions in patients over the age of 55 years with acute myeloid leukemia in late first relapse

Gemtuzumab ozogamicin (fGO), a humanized anti‐CD33 monoclonal antibody linked to calicheamicin in combination with intensive chemotherapy gives high response rates in adult acute myeloid leukemia (AML) patients in relapse. However, reduced intensity chemotherapy in combination with fractionated GO has not been tested in aged relapsing patients. Patients from our institution with CD33+ AML aged 55 years or more in first late relapse (≥6 months) were proposed participation in a GO compassionate use program. Induction therapy consisted in fractionated GO (fGO; 3 mg/m², days 1, 4, 7) with standard‐dose cytarabine (200 mg/m²/day, 7 days). Patients were consolidated with two courses of GO and intermediate dose cytarabine. Twenty‐four patients (median age 68 years) received fGO with cytarabine. Median follow‐up was 42 months. The response rate was 75%, including complete remission (CR) in 16 patients and CR with incomplete platelet recovery (CRp) in two patients. Two‐year overall survival (OS) was 51% (95% CI: 28–69) and 2 years relapse‐free survival (RFS) was 51% (95%CI: 25–72). Duration of second CR (CR2) was longer than first CR (CR1) in 9 out of 18 patients. Minimal residual disease (MRD) was negative in evaluable patients in CR2, particularly in NPM1 mutated cases. Toxicity was in line with that of the same fractionated single agent GO schedule. Fractionated GO with low intensity chemotherapy produced high response rates and prolonged CR2 in aged AML patients in first late relapse. Am. J. Hematol. 89:399–403, 2014. © 2013 Wiley Periodicals, Inc.     

Combination of fludarabine, amsacrine, and cytarabine followed by reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation in patients with high-risk acute myeloid leukemia

Sequential use of chemotherapy and reduced-intensity conditioning (RIC) with allogeneic stem cell transplantation (SCT) has been proposed to improve the treatment outcomes in patients with high-risk acute myeloid leukemia (AML). Here, we present our experience with this procedure in a cohort of 60 AML patients with primary induction failure (n?=?9); early, refractory, or ≥ second relapse (n?=?41); or unfavorable cytogenetics (n?=?10). A combination of fludarabine (30 mg/m²/day), cytarabine (2 g/m²/day), and amsacrine (100 mg/m²/day) for 4 days was used. After 3 days of rest, RIC was carried out, consisting of 4 Gy total body irradiation, antithymocyte globulin (ATG-Fresenius), and cyclophosphamide (fludarabine, amsacrine, and cytarabine (FLAMSA)-RIC protocol). Prophylactic donor lymphocyte infusions (pDLIs) were given in patients with complete remission (CR) and without evidence of graft-versus-host disease ≥120 days after SCT. The median time of neutrophil engraftment was 17 days. CR was achieved in 47 of 60 patients (78 %). Eleven patients received pDLIs resulting in long-term CR in eight of them. Non-relapse mortality after 1 and 3 years was 25 and 28 %, respectively. With a median follow-up of 37 months (range, 10–69), 3-year overall survival and 3-year progression-free survival were 42 and 33 %, respectively. In a multivariate analysis, dose of CD34(+) cells >5?×?10⁶/kg (p?=?0.005; hazard ratio (HR)?=?0.276), remission of AML before SCT (p?=?0.044; HR?=?0.421), and achievement of complete chimerism after SCT (p?=?0.001; HR?=?0.205) were significant factors of better overall survival. The use of the FLAMSA-RIC protocol in suitable high-risk AML patients results in a long-term survival rate of over 40 %.     

Phase II study of mitoxantrone and cytarabine in acute myeloid leukemia

Thirty-eight patients with acute myeloid leukemia (AML) were treated with mitoxantrone (Mto) combined with cytarabine (Ara-C). Five patients had received no previous treatment for acute myeloid leukemia, seven were refractory to treatment with standard first-line chemotherapy, eight had relapsed during treatment, and 18 had relapsed after treatment was stopped. Eleven of these relapses were early (within 6 months of stopping treatment). Mto was given for 5 days by iv bolus injection at a dose of 10 mg/m2 to 12 patients and at 12 mg/m2 to 26. Ara-C was given at a dose of 1 g/m2 twice daily by a 2-hour infusion for 3 days to 37 patients. One patient received Ara-C at a dose of 500 mg/m2 twice daily for 3 days. Toxicity was acceptable except for cerebellar toxicity in two patients, which was irreversible in one. Twenty-two patients (56%) achieved complete remission (CR), and four achieved partial remission (10%). Seventy-five percent of the patients who had relapsed during treatment and 58% of those who had relapsed after treatment was stopped achieved CR. Eleven patients remain in CR at a median time of 10 months (range, 3-17) after treatment. In five patients remissions have lasted greater than 1 year, one in a patient treated in second relapse and one in a patient treated in third relapse. Mto and Ara-C appear to be effective salvage therapy in acute myeloid leukemia and should be considered for incorporation into first-line induction regimens.     

Fludarabine,cytarabine, and attenuated‐dose idarubicin (m‐FLAI) combination therapy for elderly acute myeloid leukemia patients

We performed a phase II trial to evaluate the efficacy and safety of the modified fludarabine, cytarabine, and attenuated‐dose idarubicin (m‐FLAI) regimen in elderly acute myeloid leukemia (AML) patients. Elderly (≥60 years) AML patients who had not previously received chemotherapy were enrolled in the study. Patients received two consecutive cycles of m‐FLAI chemotherapy as an induction. The m‐FLAI regimen comprised fludarabine (25 mg/m², days 1–4), cytarabine (1,000 mg/m², days 1–4), and attenuated‐dose idarubicin (5 mg/m², days 1–3). The primary end point was complete remission (CR) rate. Secondary end points were overall survival (OS), event‐free survival (EFS), and treatment‐related mortality (TRM). There were 108 patients (median age 68.4 years, M:F = 64:44) enrolled in the study. CR was achieved in 56.5% of patients, and the TRM rate was 21.3%. Median OS and median EFS were 10.2 and 6.6 months, respectively. The mortality at 30 and 60 days was 15 and 21%, respectively. Performance status and comorbidity did not have prognostic value in this patient cohort. Bone marrow expression of CD117 was associated with increased EFS and OS. m‐FLAI is an effective induction regimen for previously untreated AML in elderly patients. In addition, bone‐marrow CD117 expression is an independent favorable prognostic factor in elderly AML patients. (ClinicalTrials.gov number, NCT01247493). Am. J. Hematol. 2013. © 2012 Wiley Periodicals, Inc.