Efficacy of fractionated gemtuzumab ozogamicin combined with cytarabine in advanced childhood myeloid leukaemia

Gemtuzumab ozogamicin (GO) monotherapy is reported to yield a 20-30% response rate in advanced acute myeloid leukaemia (AML). This study examined the efficacy and tolerability of GO combined with cytarabine (GOCYT) in children with refractory/relapsed CD33(+) AML. Seventeen children received GO 3 mg/m(2) on days 1, 4 and 7 plus cytarabine 100 mg/m(2)/d for 7 d on a compassionate-use basis. Seven patients then received GO-based consolidation. At the outset of GOCYT, two patients were refractory; eight patients were in refractory first relapse; six patients had relapsed after stem cell transplantation (SCT); and one patient [del(5q) therapy-related AML (t-AML)] had not yet been treated. Mean follow-up was 17 months (8-33 months). Ten responses were obtained after GOCYT induction, including complete remission (CR) or CR without complete recovery of platelets (CRp) in six patients (35%). The responses improved in three children who received GOCYT consolidation, increasing the CR + CRp rate to 53%. SCT was subsequently performed in eight responders. Grade 3-4 adverse events consisted of haematological disorders (n = 17, 100%) and documented infections (n = 5, 29%). No cases of sinusoidal obstructive syndrome occurred. Three patients were alive at the cut-off date for this analysis, all of whom had responded to GOCYT. GOCYT combination therapy yielded a high response rate (53%) and showed acceptable toxicity in heavily pretreated children with refractory/relapsed AML. These results warrant a larger prospective study.     

A feasibility study of simultaneous administration of gemtuzumab ozogamicin with intensive chemotherapy in induction and consolidation in younger patients with acute myeloid leukemia

The feasibility of combining gemtuzumab ozogamicin (GO) with intensive chemotherapy as first-line treatment of acute myeloid leukemia (AML) was assessed in 72 patients, aged 17 to 59 years, as a prelude to the United Kingdom Medical Research Council (MRC) AML15 trial. Sixty-four patients received induction chemotherapy (DAT [daunorubicin, ara-C, thioguanine], DA [daunorubicin, ara-C], or FLAG-Ida [fludarabine, ara-C, G-CSF, idarubicin]) with GO on day 1. It was possible to give GO 3 mg/m2 with course 1, but 6 mg/m2 with course 1 or GO in a dose of 3 mg/m2 with consecutive courses was not feasible because of hepatotoxicity and delayed hematopoietic recovery. Thirty-one patients who were treated in consolidation with MACE (amsacrine, ara-C, etoposide) or HidAC (HidAC) and GO (3 mg/m2), and 23 in induction and consolidation, tolerated GO (3 mg/m2) well. Grade 4 liver toxicity and sinusoidal obstructive syndrome was more common in thioguanine-containing schedules (P =.007). Remission with course 1 was seen in 86% of patients. DA or FLAG-Ida with GO in induction achieved complete remission in 91% of patients and 78% of these patients are in continuous complete remission at 8 months. GO given with induction (DA or FLAG-Ida) and consolidation (MACE or HidAC) was well tolerated. These schedules are now being compared in the MRC AML15 trial in patients younger than 60 years.     

Intensive individualized induction therapy with behenoyl cytarabine, daunorubicin and 6-mercaptopurine followed by intensive consolidation including intermediate-dose continuous cytarabine, mitoxantron, etoposide and vinca alkaloids in acute myeloid leukemia in adults.

Forty-one consecutive adult patients with acute myeloid leukemia (AML) were treated with an intensive individualized induction therapy of behenoyl cytarabine, daunorubicin, and 6-mercaptopurine, 29 patients (71%) achieved complete remission (CR). Patients then received three courses of intensive consolidation therapy, including intermediate-dose continuous cytarabine (400 mg/m2, for 5 days) and non-cross resistant drugs such as mitoxantron, etoposide and vincristine. During the course of the consolidation therapy, three patients died of infections and one died of myocardial infarction. Four patients underwent allogeneic bone marrow transplantation. The patients then received six courses of moderately intensive maintenance therapy for 1 year. The predicted 5-year continuing CR and disease-free survival rates of the CR patients were 62% (95% confidence limit, 41% to 83%) and 53% (33% to 73%), respectively. Although the number of patients in this study is small, the present study indicated that it may be possible to cure a fairly large proportion of AML patients by chemotherapy alone, if intensive induction therapy is followed by intensive consolidation therapy.     

Efficacy and toxicity of gemtuzumab ozogamicin in patients with acute myeloid leukemia

Gemtuzumab ozogamicin (GO) is a recently developed antibody-targeted chemotherapeutic agent and has been expected to be less toxic than conventional chemotherapy. We retrospectively evaluated the use of GO in 38 patients. Patients with acute myeloid leukemia (AML) at diagnosis and relapsed AML were treated with 6 and 9 mg/m(2) GO. Efficacy and toxicity of GO were analyzed, as well as several prognostic factors. A complete response (CR) was observed in 12 of 38 patients, including five patients with CR plus incomplete regeneration of platelets. In one patient a partial remission was observed. Twenty-five patients showed no change or progressive disease. The overall response (OR) in patients with AML at diagnosis was 47%, with the best response in patients with primary AML (OR 60%, compared with 21% OR in non-primary AML, P = 0.045). The OR in patients with relapsed AML was 22%. Median white blood cell (WBC) before treatment, CD33 expression on leukemic blasts, and kinetics of response were analyzed as prognostic factors. Median WBC was significantly lower in patients who responded to GO, compared with non-responders (2.1 x 10(9)/L vs. 6.8 x 10(9)/L, P = 0.036). CD33 expression and kinetics of response was not correlated to clinical outcome. Median days to reach 500 x 10(6)/L neutrophils and 100 x 10(9)/L platelets were 36 and 39 d, respectively. Infections and bleedings occurred in 45% and 12%, respectively. This report shows that GO has potent clinical activity and that the OR rate was by far the best in untreated primary AML patients.     

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.     

粒细胞集落刺激因子预激下小剂量Ara-C和ACR治疗复发难治急性髓细胞性白血病及骨髓增生异常综合征

目的:观察并评价在粒细胞集落刺激因子(GCSF)预激下小剂量阿糖胞苷(AraC)联合阿克拉霉素(ACR)方案(以下称AGA方案)治疗复发和(或)难治急性髓细胞性白血病(AML)和骨髓增生异常综合征(MDS)患者有效性和不良反应,从细胞凋亡方面探讨治疗方案的可能机制。方法:对复发难治的18例AML及4例MDS患者行AGA方案治疗。化疗方案:AraC10mg/m2,第1～14天,1次/12h,皮下注射;ACR8mg·m-2·d-1,第1～8天,静脉滴注;GCSF200μg·m-2·d-1,第1～14天,皮下注射,每次先于皮下注射AraC前1h开始。结果:9/18(50%)例AML接受1个AGA治疗即获完全缓解(CR),中位数缓解期4个月,其中6/10(60%)例M2获CR,22例治疗病例均无治疗相关死亡。20例接受传统标准剂量化疗对照组7例获得CR,4例死于化疗相关毒性。体外研究证实AGA方案明显提高新鲜白血病细胞凋亡率。结论:AGA方案对正常造血抑制较轻,非血液学不良反应小,外周血白细胞和血小板恢复较常规化疗组明显缩短。适于不能耐受常规治疗的、骨髓呈低增生的复发难治或老年AML患者,该药物协同诱导凋亡可能是该方案的治疗机制之一。     

A multicenter,open, non-comparative,phase II study of the combination of cladribine (2-chlorodeoxyadenosine), cytarabine,and G-CSF as induction therapy in refractory acute myeloid leukemia - a report of the Polish Adult Leukemia Group (PALG)

OBJECTIVES: To evaluate the efficacy and toxicity of cladribine (2-chlorodeoxyadenosine, 2-CdA), cytarabine (Ara-C), and granulocyte-colony stimulating factor (G-CSF) (CLAG) regimen in refractory acute myeloid leukemia (AML) in the multicenter phase II study. METHODS: The induction chemotherapy consisted of 2-CdA 5 mg/m2, Ara-C2 g/m2, and G-CSF. In the case of partial remission (PR), a second CLAG was administered. Patients in complete remission (CR) received two consolidation courses based on HD Ara-C, mitoxantrone or idarubicine, with or without 2-CdA. RESULTS: Fifty-eight patients from 11 centers were registered; 50 primary resistant and eight early relapsed (CR1 < 6 months). CR was achieved in 29 (50%) patients, 19 (33%) were refractory, and 10 (17%) died early. Forty of 50 primary resistant patients received daunorubicin (DNR) and Ara-C as the first-line induction therapy (DA-7), 10 received additional 2-CdA (DAC-7). The CR rates after CLAG were 58% and 10%, respectively in each group (P = 0.015). Five of six patients with myelodysplastic syndrome (MDS)/AML achieved CR. Hematologic toxicity was the most prominent toxicity of this regimen. The overall survival (OS, 1 yr) for the 58 patients as a whole, and the 29 patients in CR were 42% and 65%, respectively. Disease-free survival (DFS, 1 yr) was 29%. Only first-line induction treatment with DA-7 significantly influenced the probability of CR after CLAG. None of the analyzed factors significantly influenced DFS and OS. CONCLUSION: CLAG regimen has significant anti-leukemic activity and an acceptable toxicity in refractory AML. The addition of 2-CdA to the first-line induction treatment may worsen the results of salvage with CLAG. The high CR rate in patients with MDS preceding AML deserves further observation.     

Autologous blood stem cell transplantation for acute myeloblastic leukemia in first complete remission. Intensification therapy before transplantation does not prolong disease-free survival

BACKGROUND AND OBJECTIVE: To compare the clinical results of two consecutive therapeutic protocols including autologous blood stem cell transplantation (ABSCT) for patients with de novo acute myeloblastic leukemia (AML) in first complete remission (CR1). DESIGN AND METHODS: Between November 1989 and January 1997, 50 patients with AML in CR1 underwent ABSCT using two consecutive protocols. In the first one (Group A, 25 patients) peripheral blood stem cells (PBSC) were collected after induction and consolidation chemotherapy courses, and ABSCT was performed immediately thereafter. In the subsequent 25 patients (Group B), PBSC were collected after consolidation alone, and a further chemotherapy course with intermediate dose cytarabine (Ara-C 1 g/m2/12 h x3 days) and mitoxantrone (12 mg/m2/d x3 days) was administered as early intensification. The conditioning regimen consisted of busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg) in every case. RESULTS: Hematopoietic engraftment was slightly quicker in Group B, with median times to reach 0.5 x 10(9) neutrophils/L and 20 x 10(9) platelets/L being 13 and 12 days in Group A and 12 and 11 days in Group B, respectively. There were three graft failures (8%) (2 in Group A and 1 in Group B) and three transplant-related deaths (8%) (2 in Group A and 1 in Group B). No significant differences were observed between the groups in terms of relapse (64% at 4-years in Group A and 81% in Group B). Likewise, the actuarial 4-year disease-free survival (DFS) was not significantly different between the two groups (32% v 18%). INTERPRETATION AND CONCLUSIONS: Our study confirms that AML patients in CR1 receiving ABSCT have rapid engraftment with low mortality. However, autologous transplants with PBSC collected after consolidation chemotherapy were still associated with a high rate of relapse (RR). This RR was not apparently reduced by the administration of intermediate dose Ara-C before transplantation.     

Autologous transplantation gives encouraging results for young adults with favorable-risk acute myeloid leukemia, but is not improved with gemtuzumab ozogamicin

We report the results of a prospective, randomized phase 3 trial evaluating the use of gemtuzumab ozogamicin (GO) in an intensive consolidation approach in 657 patients 17-60 years of age. Patients in first complete remission (CR1) after cytarabine and standard- or high-dose daunorubicin induction received 2 cycles of consolidation with high-dose cytarabine followed by peripheral blood progenitor cell collection. The 352 patients who entered consolidation were randomized to receive GO (n = 132) or not (n = 138) and then proceeded to autologous hematopoietic cell transplantation (HCT). GO was given to 67 patients. Median follow-up was 50.9 months. Results of the intention-to-treat analysis demonstrated a 4-year disease-free survival (DFS) of 33.6% versus 35.9% (P = .54) and an overall survival (OS) of 41.3% versus 41.9% (P = .52) for those randomized to receive GO versus no GO, respectively. Patients with favorable- and intermediate-risk acute myeloid leukemia (AML) treated with high-dose daunorubicin and autologous HCT had 4-year DFS rates of 60% and 40% and OS rates of 80% and 49.3%, respectively. For younger AML patients in CR1, autologous HCT should be considered in favorable- and intermediate-cytogenetic risk patients who do not have an allogeneic donor. The addition of a single dose of GO in this setting did not improve outcomes.     

Combination chemotherapy with low-dose cytarabine, homoharringtonine, and granulocyte colony-stimulating factor priming in patients with relapsed or refractory acute myeloid leukemia

As sensitization of leukemic cells with granulocyte colony-stimulating factor (G-csf) can enhance the cytotoxicity of chemotherapy in acute myeloid leukemia (AML), a pilot study was conducted in order to evaluate the effect of G-csf priming combined with low-dose chemotherapy in patients with relapsed and refractory AML. The regimen, G-HA, consisted of cytarabine 7.5 mg/m2/12 hr by subcutaneous injection, days 1-14, homoharringtonine 1.5 mg/m2/day by intravenous continuous infusion, days 1-14, and G-csf 150 microg/m2/day by subcutaneous injection, days 0-14. Thirty-six AML patients were enrolled, 23 refractory and 13 relapsed. Eighteen patients (50%, 95% confidence interval: 33-67%) achieved complete remission (CR) with a median CR duration of 7.2 months, and two elderly patients continued a regimen of maintenance therapy and remained in remission for 26.3 and 14.1 months, respectively, as of last follow-up. Eight patients (22%) experienced neutropenia (median duration: 6 days; range: 2-22 days). Thirteen of the 36 (36%) developed severe infections. Grade 1-2 nonhematologic toxicities were documented, including nausea and vomiting (20%), liver function abnormality (6%), and heart function abnormality (6%). No central nervous system and kidney toxicity was observed. The G-HA regimen is effective in remission induction for refractory and relapsed AML patients and well tolerated in maintenance therapy in some subgroups of elderly patients. Further studies are necessary to elucidate optimum dose and schedule for this regimen to enhance the treatment efficacy of relapsed or refractory AML patients.     

Long-term results of the UHKT-911 study of adult patients under 65 years of age with de novo acute myeloid leukemias without favorable karyotypes

Between February 1991 and April 1994 induction chemotherapy of 32 adult consecutive patients under 65 years with de novo acute myeloid leukemias (AML) was started in the study UHKT-911. They were 19 women and 13 men, aged 18-63 (median 44) years. Their AML were classified according to the FAB classification: 3 M0, 3 M1, 9 M2, 14 M4, 3 M5. Induction chemotherapy consisted of 1-2 cycles with 3-4 doses of daunorubicin (DNR) 45 mg/m2/d i.v. and 14 doses of cytosine arabinoside (Ara-C) 200 mg/m2 per 3-h infusion every 12 hours. After the treatment patients, not being in complete remission, got the HD cycle with 10 high-doses of Ara-C 2000 mg/m2 per 3-h infusion every 12 hours i.v. and DNR 45 mg/m2/d i.v. on days 4 and 5, then the EMi cycle composed of etoposide 100 mg/m2/d i.v. for 5 days and mitozantrone 10-12 mg/m2/d i.v. on days 1, 3 and 5. Complete remission (CR) was achieved in 25 of 32 (78%) patients after 1-3 cycles. Five patients died between days 5 and 24 of treatment of infections, two patients were resistant to 4 cycles of induction therapy and survived 8.4 and 13.5 months. Three patients chose allogeneic bone marrow transplantation in their 1st CR from their relatives. Two of them have been living in CR for 115 a 110 months since diagnosis, the third died of sepsis on the day 52 after transplantation. Two patients in CR died of infections after their 2nd. consolidation cycle. Twenty patients in CR completed 2-4 consolidation cycles (1-3 HD, 1 EMi). Median of their CR duration was 17.8 (2-117) months. Relapse appeared in 12 cases after 4.4-34.8 (median 12.5) months, 8 patients (6 women and 2 men, aged 29-63 years) have remained longer than 5 years in their 1st. CR. Cytogenetic examination of their bone marrow showed a normal karyotype in 4 cases, 1x 46,XX,del(1)(p32p34), 1x 46,XX,16p+, 1x 47,XX,+mar, 1x 46,XX,del(5)(q22q33). After 62 months in CR a pancytopenia with dysplastic bone marrow changes developed in one of them, probably a secondary myelodysplastic syndrome, lasting for further 33 months. Event-free survival at 5 years was 27.5% (8/29 patients), significantly better (p = 0.046) against 7.5% (3/40) patients treated without HD cycles in the years 1982-1987. The same difference was observed in 7.5-year overall survival (p = 0.036) between the two studies, when 3 of 6 patients 60-64 years old remain in their 1. CR.     

Adding low-dose gemtuzumab ozogamicin to fludarabine, Ara-C and idarubicin (MY-FLAI) may improve disease-free and overall survival in elderly patients with non-M3 acute myeloid leukaemia: results of a prospective, pilot, multi-centre trial and comparison with a historical cohort of patients

We report the final results of a prospective multi-centre trial testing the combination of chemotherapy (fludarabine, cytosine arabinoside and idarubicin; FLAI) followed by low-dose gemtuzumab ozogamicin (GO), for induction treatment of patients with CD33+ acute myeloid leukaemia (AML). Forty-six consecutive patients were treated: the median age was 66 (range: 60-80) years; the karyotype was unfavourable in 12 patients (26%), intermediate in 33 (71%) and favourable in one (3%). Eleven major infectious complications were recorded. There was one early death. Of the 45 evaluable patients, 24 achieved a complete response (CR; 52%), 66% and 33% in good-intermediate/poor karyotype patients. Median duration of CR was 7 (3-24) months. The cumulative incidence of relapse was 37% with an actuarial 2-year survival of 54%. These results were compared with 47 patients matched for age and karyotype who received FLAI, without GO. The proportion of patients achieving CR was comparable. However, patients with de novo AML receiving GO (n = 26) had a significantly lower risk of relapse at 2 years when compared with patients not receiving GO (n = 35) (40% vs. 80%, P = 0.01) and significantly better overall 2-year survival (40% vs. 14%P = 0.02). Patients with secondary AML had comparable outcome whether or not they received GO. This GO-based induction chemotherapy has a good toxicity profile. In keeping with a recent prospective randomised trial, the addition of GO seems to prolong disease-free survival.     

Idarubicin, cytarabine, and topotecan in patients with refractory or relapsed acute myelogenous leukemia and high-risk myelodysplastic syndrome.

In an effort to develop more effective therapy for patients with refractory or relapsed acute myelogenous leukemia (AML) and high-risk myelodysplastic syndrome (MDS), we investigated the efficacy of a combination chemotherapy consisting of idarubicin, cytarabine, and topotecan. Twenty-seven patients were treated: four with primary refractory AML, nine with AML in first relapse, four with AML in second relapse, and 10 with MDS-RAEB/RAEBT. Patients received as salvage therapy a single course of idarubicin 12 mg/m(2) IV bolus on days 1-3, cytarabine 1 g/m(2) over two hours q 12 hr on days 1-5, and topotecan 1.25 mg/m(2) over 24 hr on days 1-5. Median age was 42 years (range 17-65 years). All patients were evaluable for response: 14 (51.9%) achieved complete remission, 10 with AML (59%) and four with MDS (40%), respectively. Thirteen AML patients (excluding four relapsed after autologous stem cell transplantation) were grouped into four categories to stratify the probability of achieving complete remission (CR): group 1, first CR duration > or = 2 years and receiving first salvage treatment (S1); group 2, first CR duration 1-2 years and receiving S1; group 3, first CR duration 0-1 years and receiving S1; and group 4, first CR duration 0-1 years and receiving S2, S3, or S4 after failing S1. The response rate of each group was as follows: group 1, one of two (50%); group 2, one of one (100%); group 3, four of four (100%); group 4, two of six (33.3%). The median remission duration and survival of patients with AML were six and 12 months, respectively. Median duration of survival in 10 MDS patients was 15 months, and all four MDS patients achieving a CR maintained continuous CR with a median follow-up of 11 months. Severe myelosuppression was observed in all patients, resulting in fever or documented infections in 89% of patients. Median time to recovery of neutrophils > or =0.5 x 10(9)/l was 22 days (11-34) and for platelets > 20 x 10(9)/l 35 days (11-58). Reversible grade 3-4 toxicities included diarrhea (two patients) and mucositis (seven patients). We conclude that combination chemotherapy with intermediate dose cytarabine, idarubicin, and topotecan has significant antileukemic activity and acceptable toxicity in salvage AML and high-risk MDS.     

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 < .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 < .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.     

Microtransplantation in older patients with AML: A pilot study of safety,efficacy and immunologic effects

Older AML patients have low remission rates and poor survival outcomes with standard chemotherapy. Microtransplantation (MST) refers to infusion of allogeneic hematopoietic stem cells without substantial engraftment. MST has been shown to improve clinical outcomes compared with chemotherapy alone. This is the first trial reporting on broad correlative studies to define immunologic mechanisms of action of MST in older AML patients. Older patients with newly diagnosed AML were eligible for enrollment, receiving induction chemotherapy with cytarabine (100 mg/m2) on days 1-7 and idarubicin (12 mg/m2) on days 1-3 (7 + 3). MST was administered 24 hours later. Patients with complete response (CR) were eligible for consolidation with high dose cytarabine (HiDAC) and a second cycle of MST. Responses were evaluated according to standard criteria per NCCN. Immune correlative studies were performed. Sixteen patients were enrolled and received 7 + 3 and MST (median age 73 years). Nine (56%) had high-risk and seven (44%) had standard-risk cytogenetics. Ten episodes of CRS were observed. No cases of GVHD or treatment-related mortality were reported. Event-free survival (EFS) was 50% at 6 months and 19% at 1 year. Overall survival (OS) was 63% at 6 months and 44% at 1 year. Donor microchimerism was not detected. Longitudinal changes were noted in NGS, TCR sequencing, and cytokine assays. Addition of MST to induction and consolidation chemotherapy was well tolerated in older AML patients. Inferior survival outcomes in our study may be attributed to a higher proportion of very elderly patients with high-risk features. Potential immunologic mechanisms of activity of MST include attenuation of inflammatory cytokines and emergence of tumor-specific T cell clones.     

Low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor (CAG regimen) for previously treated patients with relapsed or primary resistant acute myelogenous leukemia (AML) and previously untreated elderly patients with AML, secondary AML, and refractory anemia with excess blasts in transformation

We used the CAG regimen (low-dose cytarabine [10 mg/m2 per 12 hours, days 1-14], aclarubicin [14 mg/m2 per day, days 1-4], and granulocyte colony-stimulating factor [200 micrograms/m2 per day, days 1-14]) for the treatment of patients with primary resistant acute myelogenous leukemia (AML) and previously untreated elderly patients with AML, secondary AML, and refractory anemia with excess blasts in transformation (RAEB-T) in addition to relapsed AML. Forty-three of 69 (62%) patients achieved complete remission (CR), including 29 of 35 (83%) patients with relapsed AML, 1 of 8 patients with primary resistant AML, 5 of 8 elderly patients with previously untreated AML, and 8 of 18 patients with previously untreated secondary AML or RAEB-T. Ten of 22 (45%) patients > or = 65 years old achieved CR. The patients who achieved CR received at least 1 course of modified CAG therapy as the first consolidation therapy, followed by various second consolidation and intensification therapies. The median disease-free survival and overall survival were 8 and 15 months, respectively, for relapsed AML; 11 and 8 months for the elderly patients; and 8 and 17 months for secondary AML and RAEB-T. Myelosuppression was mild to moderate, and other than fever, severe nonhematologic toxicity was rare. CAG as the induction therapy seems promising for the treatment of various categories of poor-prognosis AML.     

High-dose melphalan with autologous hematopoietic stem cell transplantation for acute myeloid leukemia: results of a retrospective analysis of the Italian Pediatric Group for Bone Marrow Transplantation

This retrospective study from the Italian Association of Pediatric Hematology Oncology-Bone Marrow Transplant Group (AIEOP-TMO) reports the results of consolidation with high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with acute myeloid leukemia (AML) in first complete remission (CR1). From October 1994 to July 1999, 20 patients (median age 9.9 years, range 0.11-16.2) were treated in six centers. Eighteen had de novo AML and two had secondary AML. According to BFM criteria, 10 were classified as standard- and 10 as high-risk patients, respectively. The median time from diagnosis to CR1 and from diagnosis to Auto-HSCT were 1.1 months (range 0.8-1.6) and 4.3 months (range 3.1-6.2), respectively. Purging with either mafosfamide (three) or in vivo interleukin-2 (four) was performed in seven of 20 patients. Melphalan was administered at a dosage of 150-220 mg/m(2) (median 180). Median total number of nucleated cells infused was 2.5 x 10(8)/kg (range 1.1-8.9). The myeloablative regimen was well tolerated with no toxic death, veno-occlusive disease or life-threatening complications. All patients had hematopoietic recovery in a median time of 27 days for neutrophils and 44 days for platelets. Eight of 20 patients relapsed after a median time of 7.2 months from transplant (range 5.7-15.9). Six of them died (five of progression of disease and one of sepsis) while the remaining two patients are alive in CR2. The 3-year cumulative probability of survival and event-free-survival (EFS) is 62% and 56%, respectively. This study showed that in pediatric patients with AML consolidation of CR1 with high-dose melphalan allows survival and EFS to be obtained comparable to other auto-HSCT or chemotherapy published series with a potential sparing effect both on duration of treatment (with respect to chemotherapy) and on long-term side-effects (with respect to auto-HSCT with TBI or busulfan containing regimens).     

The role of gemtuzumab ozogamicin in acute leukaemia therapy

Gemtuzumab ozogamicin (GO) is an immunoconjugate that binds to CD33 on the surface of acute myeloid leukaemia (AML) blasts and, after internalisation, releases a cytotoxic drug, calicheamicin. GO is approved by the US Food and Drug Administration for the treatment of CD33-positive AML at first relapse in patients 60 years and older who are not candidates for other cytotoxic therapy. GO as a single agent has low antileukaemic activity. When given to patients meeting the criteria noted above, it produces a complete response (CR) rate of only 12%, with another 12% achieving CR with inadequate platelet recovery (CRp). The median survival of patients treated with GO monotherapy is 11.2 months. GO therapy at 9 mg/m(2) is complicated with hepatic veno-occlusive disease in 5-10% of patients, particularly prior to or following stem cell transplantation. GO at lower doses combined with chemotherapy as induction or postremission therapy is promising, however, and phase III trials are ongoing. GO is probably most active in acute promyelocytic leukaemia (APL). It is used for induction regimens in high-risk APL and for the elimination of minimal residual APL. Case reports suggest that GO also has activity in CD33-positive acute lymphoblastic leukaemia. In conclusion, single agent GO can induce responses in patients with CD33-positive AML in first recurrence. The future of GO is its use in combination with other cytotoxic agents. Ongoing clinical trials may better define the role of GO combinations, particularly in untreated AML.     

Consolidation treatment with autologous peripheral blood progenitor cell transplantation in acute myeloid leukemia: a single center experience

Several trials have suggested that intensive post-remission therapy may prolong the duration of complete remission (CR) in acute myeloid leukemia (AML). The purpose of this study was to evaluate the feasibility and the efficacy of high-dose cytarabine (HiDAC) consolidation chemotherapy followed by high-dose therapy and autologous infusion of peripheral blood progenitor cells (PBPC) mobilized by G-CSF in adult patients with AML in first CR. Fifteen consecutive AML patients underwent HiDAC consolidation chemotherapy, used as a method of in vivo purging, followed by G-CSF for the purpose of autologous PBPC collection. Eleven patients collected a median of 6.9x10(8)/kg peripheral blood mononuclear cells (MNC) (range 2.9-23) and a median of 6.67x10(6)/kg CD34+ cells (range 1.8-33.5) with a median of two aphereses (range 1-3). Two patients did not mobilize and two obtained an inadequate number of progenitor cells. The 11 patients with adequate collections received myeloablative chemotherapy followed by the infusion of PBPC. The median number of days to recover neutrophils and platelets was 12 and 13, respectively. After a median follow-up of 28.7 months (range 17.2-43.4), five out of 11 patients who underwent PBPC transplantation are still in CR, five have died in first relapse and one is alive in CR after relapse treated with salvage therapy and second PBPC infusion. These results demonstrate that HiDAC consolidation chemotherapy followed by autologous PBPC transplantation is a feasible procedure with minimal toxicity. Randomized studies should be performed to evaluate whether this form of consolidation may produce a significant improvement in leukemia-free survival.