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.     

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.     

CAG预激方案联合伊马替尼治疗复发/难治性Ph+急性淋巴细胞白血病首例报道

目的:寻找有效治疗复发/难治性Ph染色体阳性急性淋巴细胞白血病(Ph ALL)的疗法。方法:以CAG预激方案联合伊马替尼诱导治疗复发/难治性Ph ALL病例1例。结果:该复发/难治Ph ALL患者经CAG方案联合伊马替尼诱导治疗后达缓解。结论:对于复发/难治性Ph ALL,CAG联合伊马替尼是一个值得尝试的方案。     

Cytarabine and clofarabine after high‐dose cytarabine in relapsed or refractory AML patients

Clofarabine has been shown to be effective in AML patients, either as single agent or, mainly, in association with intermediate dose cytarabine. Based on these reports, we conducted a preliminary study combining clofarabine and intermediate dose cytarabine in AML patients who relapsed or failed to respond to at least two induction therapies. We treated 47 patients affected by relapsed/refractory AML with a regimen including clofarabine at 22.5 mg/m² daily on days 1–5, followed after 3 hr by cytarabine at 1 g/m² daily on days 1–5. Ten patients received a further consolidation cycle with clofarabine at 22.5 mg/m² and cytarabine at 1 g/m² day 1–4. Among the 47 patients, 24/47 (51%) achieved a complete remission, 5/47 (10.5%) a partial response, 10/47 (21%) had a resistant disease, and 6/47 (13%) died of complications during the aplastic phase. The most frequent nonhematologic adverse events were vomiting, diarrhea, transient liver toxicity, febrile neutropenia, and infections microbiologically documented. Among the 24 patients who obtained a CR 13 underwent allogeneic bone marrow transplantation. In 14 patients, complete remission duration was shorter than 12 months, whereas 10 patients experienced longer complete remission duration. These very preliminary results suggest that clofarabine‐cytarabine regimen is effective in this particularly poor prognosis category of patients, representing a potential “bridge” toward bone marrow transplant procedures. Safety data were consistent with previously reported salvage therapies. Further studies and a longer follow up are warranted. Am. J. Hematol., 2012. © 2012 Wiley Periodicals, Inc.     

Fludarabine and cytarabine in patients with relapsed acute myeloid leukemia refractory to initial salvage therapy

The most effective regimen for relapsed acute myeloid leukemia (AML) patients who do not achieve complete remission (CR) after a course of salvage therapy has not been established. We evaluated the efficacy and toxicity of fludarabine and cytarabine in patients with AML in first relapse who did not respond to a course of salvage chemotherapy with mitoxantrone and etoposide. CR was achieved in 39 % of treated patients, and in 47 % of patients with a favorable/intermediate-risk karyotype. The median overall survival was 4.75 months. The median survival for patients achieving CR with fludarabine–cytarabine was significantly higher than for those who did not respond to therapy (9.6 vs. 4.5 months, P = 0.04). Our data suggest that the fludarabine–cytarabine regimen merits further investigation in relapsed AML patients with favorable or intermediate-risk karyotype with persistent leukemia after a course of salvage therapy.     

Aclarubicin and Low-Dose Cytosine Arabinoside in Combination with Granulocyte Colony-Stimulating Factor in Treating Acute Myeloid Leukemia Patients with Relapsed or Refractory Disease and Myelodysplastic Syndrome: A Multicenter Study of 112 Chinese Patients

One hundred twelve patients with geriatric acute myeloid leukemia (AML), refractory or relapsed AML, or myelodysplastic syndrome and refractory anemia with excess of blasts in transformation (MDS-RAEBt) were entered into this study to receive CAG (aclarubicin and low-dose cytosine arabinoside [Ara-C]in combination with granulocyte colony-stimulating factor [G-CSF]) with the objective of evaluating the efficacy and tolerance of this regimen. Low-dose Ara-C was given subcutaneously at a dosage of 10 mg/m2 every 12 hours on days 1 to 14. Aclarubicin was administered intravenously at a dosage of 14 mg/m2 per day on days 1 to 4 (CAG regimen A) or 7 mg/m2 on days 1 to 8 (CAG regimen B). Recombinant G-CSF was given subcutaneously at a dosage of 200 3g/m2 per day on days 1 to 14. We demonstrated comparable overall complete remission rates for the 4 groups of patients: 30.8% (8/26) in the elderly patients, 48.4% (30/62) in the refractory AML patients, 44.4% (8/18) in the relapsed AML patients, and 38.5% (5/13) in the MDS-RAEBt patients. Of the 52 patients followed up, the 12-month progression-free survival (PFS) and overall survival (OS) rates estimated by the Kaplan-Meier method were 40.73% 3 8.15% and 42.85% 3 8.23%, respectively. The median PFS and OS times were 9.0 3 2.2 months and 11.0 3 1.6 months, respectively. Toxic effects were very rare and mainly consisted of neutropenia and thrombocytopenia due to myelosuppression; approximately 70% to 80% of patients had neutropenia or thrombocytopenia that exceeded National Cancer Institute grade II. Nonhematologic toxicities were not observed in this study.The CAG regimen seems promising, with acceptable toxicity, for the treatment of various categories of poor-prognosis AML and MDS-RAEBt.     

Efficacy and feasibility of cyclophosphamide combined with intermediate- dose or high-dose cytarabine for relapsed and refractory acute myeloid leukemia (AML)

Background

Approximately, 70 % of adult patients with de novo acute myeloid leukemia (AML) achieve a complete remission (CR) while 10–20 % of AML are refractory to induction chemotherapy. Furthermore, a significant proportion of AML patients in CR will relapse during or after consolidation treatment. There is no evidence for a standard salvage regimen and most centers use a combination of an anthracycline and cytarabine (AraC). The aim of this study was to investigate the impact of two age-adjusted regimens containing AraC and cyclophosphamide applied for the treatment of relapsed or refractory AML.

Patients and methods

We retrospectively analyzed 60 patients (24 male, 36 female; median age 56 years) with relapsed or refractory AML who were treated with a combination of AraC and cyclophosphamide monocentrically between October 2000 and January 2013. Two different protocols containing either high-dose (hAC) or intermediate-dose cytarabin (iAC) have been applied dependent on age and performance status.

Results

We demonstrate an overall response rate (CR + PR) induced by hAC and iAC of 56.7 %. Importantly, a complete remission rate (CR + CRp) of 52.2 % was found in patients who received the hAC regimen while only 8.8 % of patients achieved a CR following the iAC protocol (p < 0.001). The rate of refractory disease was 26.1 and 47.1 %, respectively. High-risk cytogenetics, i.e., a complex aberrant or monosomal karyotype had no effect on achievement of CR after hAC. In addition, there was no impact of activating FLT3 mutations on response to treatment according to the hAC regimen. In the cohort of patients treated with the iAC protocol, treatment-related mortality of 11.8 % within 60 days was observed but none of the patients who received the hAC regimen died within the first 2 months following chemotherapy. The toxicity profile was acceptable at both cytarabine dose levels. Importantly, 19 patients (82.6 %) of the hAC cohort underwent allogeneic hematopoietic stem cell transplantation (HSCT) as consecutive treatment.

Conclusion

The hAC regimen represents a promising therapeutic approach to induce a second CR in younger patients with relapsed or refractory AML prior to HSCT without using anthracyclines.     

Successful Cytoreduction with CAG (cytarabine,Aclarubicin and G-CSF) Therapy in Refractory Acute Myelogenous Leukemia before Allogeneic Stem Cell Transplantation

Refractory acute myelogenous leukemia (AML) has a poor prognosis, and a long-term survival cannot be expected in most patients even if allogeneic bone marrow transplantation (allo-BMT) or allogeneic peripheral blood stem cell transplantation (allo-PBSCT) is performed. An abundance of residual leukemic cells and poor performance status of patients before allo-BMT are often associated with a high relapse rate and high transplant-related mortality. Thus, to improve the prognosis of patients with refractory AML undergoing allo-BMT, it is necessary to reduce the leukemic cell volume as low as possible without severe complications. In this report, we used CAG (cytarabine, aclarubicin and granulocyte colony-stimulating factor (G-CSF)) therapy for cytoreduction before allo-BMT or allo-PBSCT in five patients with refractory AML. One of them achieved complete remission (CR) by CAG therapy alone and others achieved major tumor reduction prior to BMT and PBSCT. All patients achieved CR after allo-BMT and allo-PBSCT without severe complications. Three of them have remained CR for 9, 21 and 30 months, respectively. Although the results of this feasibility study are preliminary, the pre-transplant CAG therapy for refractory AML deserves further evaluation.     

G‐CSF Priming,clofarabine, and high dose cytarabine (GCLAC) for upfront treatment of acute myeloid leukemia,advanced myelodysplastic syndrome or advanced myeloproliferative neoplasm

Prior study of the combination of clofarabine and high dose cytarabine with granulocyte colony‐stimulating factor (G‐CSF) priming (GCLAC) in relapsed or refractory acute myeloid leukemia resulted in a 46% rate of complete remission despite unfavorable risk cytogenetics. A multivariate analysis demonstrated that the remission rate and survival with GCLAC were superior to FLAG (fludarabine, cytarabine, G‐CSF) in the relapsed setting. We therefore initiated a study of the GCLAC regimen in the upfront setting in a multicenter trial. The objectives were to evaluate the rates of complete remission (CR), overall and relapse‐free survival (OS and RFS), and toxicity of GCLAC. Clofarabine was administered at 30 mg m^?2 day^?1 × 5 and cytarabine at 2 g m^?2 day^?1 × 5 after G‐CSF priming in 50 newly‐diagnosed patients ages 18–64 with AML or advanced myelodysplastic syndrome (MDS) or advanced myeloproliferative neoplasm (MPN). Responses were assessed in the different cytogenetic risk groups and in patients with antecedent hematologic disorder. The overall CR rate was 76% (95% confidence interval [CI] 64–88%) and the CR + CRp (CR with incomplete platelet count recovery) was 82% (95% CI 71–93%). The CR rate was 100% for patients with favorable, 84% for those with intermediate, and 62% for those with unfavorable risk cytogenetics. For patients with an antecedent hematologic disorder (AHD), the CR rate was 65%, compared to 85% for those without an AHD. The 60 day mortality was 2%. Thus, front line GCLAC is a well‐tolerated, effective induction regimen for AML and advanced myelodysplastic or myeloproliferative disorders. Am. J. Hematol. 90:295–300, 2015. © 2014 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 phase I–II study of plerixafor in combination with fludarabine,idarubicin, cytarabine,and G-CSF (PLERIFLAG regimen) for the treatment of patients with the first early-relapsed or refractory acute myeloid leukemia

Clinical outcomes of patients with acute myeloid leukemia (AML) showing the first primary refractory or early-relapsed disease remain very poor. The Programa Español de Tratamientos en Hematología (PETHEMA) group designed a phase I–II trial using FLAG-Ida (fludarabine, idarubicin, cytarabine, and G-CSF) plus high-dose intravenous plerixafor, a molecule inducing mobilization of blasts through the SDF-1α-CXCR4 axis blockade and potentially leading to chemosensitization of the leukemic cells. We aimed to establish a recommended phase 2 dose (RP2D) of plerixafor plus FLAG-Ida, as well as the efficacy and safety of this combination for early-relapsed (first complete remission (CR/CRi)?<?12 months) or primary refractory AML. Between 2012 and 2015, 57 patients were enrolled, and 41 received the RP2D (median age 52 years [range, 18–64]). Among these patients, 20 (49%) achieved CR/CRi, and 3 (7%) died during induction. CR/CRi rate was 50% (13/26) among primary refractory and 47% (7/15) among early relapse. Overall, 25 patients (61%) were allografted. Median overall and disease-free survivals were 9.9 and 13 months, respectively. In summary, the combination of plerixafor plus FLAG-Ida resulted in a relatively high CR/CRi rate in adult patients with primary refractory or early relapsed AML, with an acceptable toxicity profile and induction mortality rate, bridging the majority of patients to allogeneic stem cell transplantation. ClinicalTrials.gov Identifier: NCT01435343     

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.     

Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapsed and refractory acute myeloid leukaemia

This phase I/II study was conducted to determine the maximum tolerated dose, toxicity, and efficacy of clofarabine in combination with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming (GCLAC), in the treatment of patients with relapsed or refractory acute myeloid leukaemia (AML). Dose escalation of clofarabine occurred without dose-limiting toxicity, so most patients were treated at the maximum dose, 25 mg/m(2) per day with cytarabine 2 g/m(2) per day, each for 5 d, and G-CSF 5 μg/kg, beginning the day before chemotherapy and continuing daily until neutrophil recovery. The complete remission (CR) rate among the 46 evaluable patients was 46% (95% confidence interval [CI] 31-61%) and the CR + CR but with a platelet count <100 × 10(9)/l rate was 61% (95% CI 45-75%). Multivariate analysis showed that responses to GCLAC were independent of age, cytogenetic risk category, and number of prior salvage regimens. GCLAC is highly active in relapsed and refractory AML and warrants prospective comparison to other regimens, as well as study in untreated patients.     

Successful treatment with G-CSF and continuous infusion of low-dose cytarabine and etoposide for therapy-related acute myeloid leukemia developed during chemotherapy for malignant lymphoma

In March 2000, a 30-year-old Chinese male was initially diagnosed as having non-Hodgkin's lymphoma because of right cervical lymphadenopathy. He had received 8 cycles of chemotherapy including doxorubicin in China. As of February 2001, he was treated in our hospital with the CEPP regimen including etoposide, and was admitted in June 2001 because of leukopenia and thrombocytopenia. Peripheral blood showed hemoglobin 12.7 g/dl, platelets 4.1 x 10(4)/microliter and white blood cells 2300/microliter with 15% blasts. Bone marrow was hypocellular with 48% blasts, which were positive for myeloperoxidase, CD13 and CD33. Chromosome analysis showed 46,XY, t(9;11) (p21;q23) in all 20 metaphase spreads. He was diagnosed as having therapy-related acute myeloblastic leukemia (AML). Because of hypoplastic bone marrow, induction therapy with the CAG regimen including cytarabine, aclarubicin and granulocyte-colony stimulating factor (G-CSF) was started, but no apparent effect was observed. The patient was then treated with the AVG regimen comprising 250 micrograms of G-CSF and continuous infusion with 20 mg of cytarabine and 50 mg of etoposide for 14 days. Complete hematological and cytogenetic remission was achieved after two courses of the AVG regimen. Although it has been shown that the CAG regimen is effective for refractory and/or secondary AML, our results indicate that the AVG regimen should be tried for cases of AML resistant to the CAG regimen.     

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.     

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 %.     

Maintenance with low-dose cytarabine for acute myeloid leukemia in complete remission

Summary Thirty-four patients with acute myeloid leukemia (AML) in complete remission (CR), 30 of them aged over 60, received maintenance therapy scheduling four courses of low-dose cytarabine (LDA) 20 mg/m²/day in two subcutaneous injections for 3 weeks every 6 weeks. Each course was stopped when hematologic toxicity occurred, and doses of LDA were subsequently reduced by 50% for the following courses. During the first course of LDA, 15 patients needed blood and four patients platelet transfusions. Overall, 28 patients received four courses of LDA: 11 did not require any dose reduction, while 14 required one dose reduction and three neeeded two successive dose reductions. Two patients were hospitalized during maintenance. Median disease-free survival (DFS) is 308 days, with 16% of patients surviving at 5 years. Seven patients relapsed during the 168 days of maintenance, while ten of the 27 patients remaining at risk on day 169 relapsed during the 168 days following maintenance. We conclude that in AML in CR, the maximal dose of LDA tolerated by ambulatory patients is 10 mg/m²/day for 3 weeks. LDA seemed to delay relapse; however, precise assessment of the efficacy of this approach would require a randomized trial.     

Idarubicin,cytarabine, and pravastatin as induction therapy for untreated acute myeloid leukemia and high‐risk myelodysplastic syndrome

Previous studies suggest that idarubicin/cytarabine(ara‐C)/pravastatin (IAP) is an active salvage regimen for patients with AML. We therefore investigated this regimen in patients with newly‐diagnosed AML or MDS (≥10% blasts). Patients were eligible if the anticipated treatment‐related mortality (TRM) was <10%. Patients received pravastatin (1,280 mg/day po; days 1–8), cytarabine (1.5 g/m²/day; days 4–7), and idarubicin (12 mg/m²/day, days 4–6). Up to 3 cycles of consolidation with a shortened course was permitted. The primary endpoints were “good CR” rate (CR on day 35 without minimal residual disease) and TRM in the first 28 days. The study was to stop if after each cohort of 5 patients (a) the Bayesian posterior probability was < 5% that the true “good CR rate” was ≥ 70% or (b) the posterior probability was >25% that the TRM rate was ≥5%. Twenty‐four patients were included. Conventional CR was achieved in 15 (63%) patients but only 12 (50%) achieved “good CR”. 4 of 12 (33%) patients with “good CR” relapsed at median of 16 weeks (10.5–19). Five (21%) patients had refractory disease. Survival probability at 1 year was 72% (48.7–64). Two (8.3%) patients died within 28 days from multiorgan failure. The most common grade 3–4 adverse effects were febrile neutropenia (75%) and diarrhea (25%). Based on the stopping rules accrual ceased after entry of these 24 patients. IAP did not meet the predefined efficacy criteria for success. Therefore, we would not recommend this regimen for phase three testing in this patient subset. Am. J. Hematol. 90:483–486, 2015. © 2015 Wiley Periodicals, Inc.     

CAG-GO therapy for patients with relapsed or primary refractory CD33-positive acute myelogenous leukemia

We previously tested a less toxic CAG regimen consisting of low-dose cytarabine, aclarubicin and granulocyte-colony stimulating factor for the treatment of patients with relapsed or refractory myeloid malignancies or elderly patients with untreated ones, obtaining a satisfactory complete remission rate of 62%. Gemtuzumab ozogamicin, an anti-CD33 monoclonal antibody conjugated to calicheamicin, has recently been approved as a single agent in Japan for the treatment of relapsed/refractory CD33-positive acute myelogenous leukemia (9 mg/m(2) on days1 and 15). Complete remission rate was reported as 30% in a phase 2 trial in Japan. In this study, effectiveness and safety of combining dose-attenuated gemtuzumab ozogamicin (3 mg/m(2) on day5) and original CAG regimen were assessed in nine patients with relapsed/refractory CD33-positive acute myelogenous leukemia and a median age of 70 years. Rate of complete remission with or without platelet recovery was 44% (4/9). The median duration of complete remission and overall survival were 5.5 and 16 months, respectively. Reversible myelosuppression and liver toxicity were the main adverse events, but no regimen-related death was recorded. Although only a small number of cases were included in this preliminary study, this CAG-GO regimen was found to be feasible and useful even in high-risk relapsed or refractory patients.