AbstractOutcome of patients with primary refractory acute myeloid leukemia remains unsatisfactory. We conducted a prospective phase II clinical trial with gemtuzumab ozogamicin (3 mg/m2 intravenously on day 1), all-trans retinoic acid (45 mg/m2 orally on days 4–6 and 15 mg/m2 orally on days 7–28), high-dose cytarabine (3 g/m2/12 h intravenously on days 1–3) and mitoxantrone (12 mg/m2 intravenously on days 2–3) in 93 patients aged 18–60 years refractory to one cycle of induction therapy. Primary end point of the study was response to therapy; secondary end points included evaluation of toxicities, in particular, rate of sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation. Complete remission or complete remission with incomplete blood count recovery was achieved in 47 (51%) and partial remission in 10 (11%) patients resulting in an overall response rate of 61.5%; 33 (35.5%) patients had refractory disease and 3 patients (3%) died. Allogeneic hematopoietic cell transplantation was performed in 71 (76%) patients; 6 of the 71 (8.5%) patients developed moderate or severe sinusoidal obstruction syndrome after transplantation. Four-year overall survival rate was 32% (95% confidence interval 24%-43%). Patients responding to salvage therapy and undergoing allogeneic hematopoietic cell transplantation (n=51) had a 4-year survival rate of 49% (95% confidence intervaI 37%-64%). Patients with fms-like tyrosine kinase internal tandem duplication positive acute myeloid leukemia had a poor outcome despite transplantation. In conclusion, the described regimen is an effective and tolerable salvage therapy for patients who are primary refractory to one cycle of conventional intensive induction therapy. (clinicaltrials.gov identifier: 00143975)
The prognosis of patients with acute myeloid leukemia (AML) refractory to first induction chemotherapy is poor. About 15%–20% of younger patients (<61 years) are primary refractory to one cycle of standard 7+3 induction chemotherapy.31 Substantial long-term survival in this patient population has only been observed if allogeneic hematopoietic cell transplantation (HCT) was performed, resulting in overall survival (OS) rates of 10%-31% measured from date of HCT.94 Best outcome after allogeneic HCT is achieved when transplantation is performed in complete remission (CR) or partial remission (PR) after salvage therapy.986 Therefore, better response rates to salvage therapy are crucial to improve OS in these patients.
Different high-dose cytarabine-based salvage regimens, often used in combination with anthracyclins and epipodophyllotoxins, resulted in CR rates between 11% and 70%.3 In order to increase CR rates, high- or intermediate-dose cytarabine has been combined with a wide spectrum of different drugs such as idarubicin and fludarabine (FLAG-Ida), clofarabine, gemtuzumab ozogamicin (GO), and all-trans retinoic acid (ATRA).1310 The German-Austrian AML Study Group (AMLSG) evaluated the conventional (HAM) and a sequential (S-HAM) HAM regimen in patients with refractory disease. No beneficial effect could be shown with the dose-intense S-HAM regimen.14 In the subsequent trial, AML HD98A, ATRA was added to the HAM regimen (A-HAM) based on promising in vitro1615 and in vivo data.1817 The sequential administration of ATRA after HAM led to an overall response rate of 47% and was thus remarkably better than HAM alone.9 In line with our data, Montillo et al. reported a CR rate of 70% induced by a salvage therapy combining ATRA with fludarabine, cytarabine, idarubicin, and granulocyte-colony stimulating factor (G-CSF).10
Several phase I-II clinical trials evaluating GO in relapsed/refractory AML showed response rates up to 33% when used as single agent, and 12%–68% in combination with chemotherapy.201913 Based on these promising results, we combined GO with our previously established A-HAM regimen (GO-A-HAM) in patients refractory to one cycle of 3+7-based induction therapy. The main objectives of the study were to assess GO-A-HAM with regard to response rate, toxicity [including sinusoidal obstruction syndrome (SOS)] after allogeneic HCT, and survival.
Patients 18–60 years of age with AML defined by the 2001 World Health Organization Classification of Tumours21 who did not achieve a CR, CR with incomplete blood count recovery (CRi) or partial remission (PR) after one cycle of standard chemotherapy, and who had adequate organ function, were eligible for entry into the trial. Patients with acute promyelocytic leukemia and patients with a concomitant uncontrolled infection were not eligible. Written informed consent was obtained from all patients at study entry according to the Declaration of Helsinki. The study was approved by the local Ethics Review Committee and registered at clinicaltrials.gov identifier: 00143975.
The trial was a single-arm multi-center phase II trial. All patients received one cycle of GO-A-HAM consisting of GO 3 mg/m intravenously (IV max. 5 mg absolute) over two hours on day 1; cytarabine 3 g/m every 12 hours IV on days 1–3; mitoxantrone 12 mg/m IV days 2 and 3; oral all-trans retinoic acid 45 mg/m on days 4–6 and 15 mg/m on days 7–28. In all patients, allogeneic HCT from a matched related or matched unrelated or from a haploidentical family donor was intended irrespective of the remission status after GO-A-HAM.
Statistical analyses, efficacy and safety end points
The primary end point of the study was achievement of CR or CRi at a maximum of 30 days after start of therapy with GO-A-HAM defined by standard criteria.22 Beyond CR/CRi, partial remission (PR) defined according to standard criteria22 was documented and evaluated. A continuous safety assessment was performed during the study. Toxicities reported during therapy were evaluated according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC), v.3.0. The safety end points with corresponding maximally tolerated rates were: i) NCI-CTC grade 4+5 liver toxicity ≤ 10%; ii) rate of deaths within 30 days after start of GO-A-HAM 25% or under; and iii) rate of severe SOS after allogeneic HCT or under 20%. SOS was defined according to the Baltimore criteria23 and graded as described by Bearman.24 Management of SOS followed local standard operating procedures of the respective transplantation centers.
Univariable and multivariable logistic regression models were used to test the influence of covariates on response to induction therapy.
The Kaplan-Meier method was used to estimate the distribution of OS. Survival distributions were compared using the log rank test. To address the time dependence of the variable allogeneic HCT, a multivariable analysis based on an extended Cox regression model was used according to the method of Andersen and Gill.25 Missing data were replaced by 50 imputations using multivariate imputations by chained equations applying predictive mean matching.26 Backward selection applying a stopping rule based on P-values was used in multivariable regression models to exclude redundant or unnecessary variables.26 For all analyses, P<0.05 was considered statistically significant. All eligible patients who started with GO-A-HAM were included in the analysis. Statistical analyses were performed with the statistical software environment R v.3.2.1 using the R package cmprsk, survival, rms and Hmisc.27
From July 2004 to June 2007, 95 patients from 23 institutions fulfilled the eligibility criteria and were enrolled in the study. Two patients withdrew their consent before initiation of treatment; thus, a total of 93 patients are reported. Prior treatments of the patients were as follows: 29 patients received standard induction therapy with idarubicin, cytarabine, and etoposide (ICE), 26 patients ICE in combination with ATRA (A-ICE), 17 patients with valproic acid (V-ICE), and 12 patients with both ATRA and valproic acid (VA-ICE), according to the initial randomization of the AMLSG 07-04 protocol (clinicaltrials.gov identifier: 00151242);28 9 patients were treated in the German AML Intergroup trial29 and received standard induction therapy with daunorubicin and cytarabine (DA). Median age was 48 years (range 22–62 years); further demographics and baseline characteristics of the 93 patients are shown in Table 1. Eighteen of 83 (22%) patients had an fms-like tyrosine kinase internal tandem duplication (FLT3-ITD) mutation and 12 of 79 (15%) patients a nucleophosmin (NPM1) mutation at time of initial diagnosis. The surface marker CD33 was expressed in 87% of the patients with a 20% expression cut-off level.
Response rate and treatment outcome
Twenty-eight patients (30%) achieved CR, 19 patients (20%) CRi, and 10 patients PR (11%), resulting in an overall response rate of 61%; 33 patients (35%) were refractory and 3 patients (3%) died within 30 days (Table 2).
Multivariable analysis on the end point CR/CRi or overall response revealed no prognostic influence of the following variables assessed at diagnosis: age, sex, cytogenetics (according to European LeukemiaNet criteria),1 white cell count (WBC), bone marrow blast percentage, type of AML [de novo versus secondary AML evolving from myelodysplastic syndrome (AML) versus therapy-related AML (t-AML)], CD33 expression, mutated NPM1, FLT3-ITD and prior treatment with ATRA. Of note, patients with t-AML had a nearly equal CR/CRi rate of 50% compared to de novo AML with 53%, whereas none of the 4 patients with s-AML responded to GO-A-HAM.
Median times of WBC (>1×10/L), neutrophil (>0.5×10/L) and platelet (>20×10/L) recovery were 22, 25 and 21 days, respectively.
In 60 (65%) of the 93 patients, a total of 86 infections with a CTC grade 3 or over occurred. The most frequent infections were septicemia (n=43; 46%), pneumonia (n=20; 22%), and infections of the gastrointestinal tract (n=11; 12%). Other infection sites included skin and soft tissue (n=5; 5%), ear-nose-throat (n=3; 2%), urogenital tract (n=1; 1%), liver (n=1; 1%), and esophagus (n=1; 1%) (Table 3). Five patients died of severe infection, including 3 patients who died within 30 days after start of GO-A-HAM.
Other non-hematologic toxicities were seen in 30 patients, and 42 adverse events with a CTC grade 3 or more were reported (Table 4). The most common events were gastrointestinal toxicities (n=14) including diarrhea, nausea and mucositis, and neurological symptoms (n=10) with polyneuropathy, ataxia and hallucination. Cardiac events [tachyarrhythmia absoluta, left ventricular failure (n=2), pericardial effusion and pericarditis] occurred in 5 patients. A total of 4 episodes of hemorrhage CTC grade 3 were noted during treatment, two central nervous system bleedings, one vaginal bleeding, and one bleeding after central venous system installation. Four patients developed respiratory insufficiency. An additional 3 events of thrombosis were reported, two of them located in the internal jugular vein. One patient experienced renal failure. SOS was not observed during or after GO-A-HAM. Median duration of hospitalization was 27.5 days (range 8–96 days).
Consolidation therapy with allogeneic HCT was performed in 71 of 93 patients (76%); 51 patients achieved CR, CRi or PR after GO-A-HAM, and 20 patients had persistent refractory disease. Reasons for not proceeding to an allogeneic HCT were death after GO-A-HAM (n=3), comorbidities and bad performance status (n=12), no compatible donor (n=3) and patients’ wish (n=4). Of the 71 patients who received allogeneic HCT, 50 patients proceeded immediately to allogeneic HCT, 19 patients received one or two additional cycles of intensive chemotherapy [A-HAM, n=5; HAM/high-dose cytarabine, n=9; GO-A-HAM, n=3; high-dose cytarabine with mitoxantrone and topotecan (clinicaltrials.gov identifier: 00744081), n=1; fludarabine, cytarabine, G-CSF (FLAG),±idarubicin/mitoxantrone, n=1], one patient received GO as single agent, and one received low-dose cytarabine (Figure 1). Median time from start of therapy with GO-A-HAM to allogeneic HCT was 70 days; 16 patients were transplanted from matched related donors, 50 patients from matched unrelated donors, and 5 patients from haploidentical related donors. Myeloablative conditioning regimens (n=34) included cyclophosphamide (Cy) and total body irradiation (TBI-Cy) or busulfan and Cy (Bu-Cy) (n=26), Bu-Cy with radioimmunotherapy (RIT) (n=6),30 and fludarabine, melphalan and thiotepa (n=2). Dose-reduced conditioning regimens (n=37) included FLAMSA-based regimens (n=24),31 fludarabine plus total body irradiation (n=6), fludarabine plus busulfan (n=2), fludarabine plus melphalan+/−BCNU (n=3), and fludarabine plus or threosulfan (n=2). OS after allogeneic HCT with myeloablative and dose-reduced conditioning was comparable (P=0.54).
Of 19 patients not proceeding to allogeneic HCT, 7 received additional cycles of intensive therapy (HAM/high-dose cytarabine n=2, single agent GO, n=1; FLAG±idarubicin/mitoxantrone, n=4) followed by autologous HCT in 2 patients. Twelve patients received no further intensive treatment (Figure 1).
Sinusoidal obstruction syndrome after allogeneic HCT and safety analysis according to predefined safety end points
Nine patients developed SOS after allogeneic HCT; in 3 patients SOS was classified as mild, in 5 patients as moderate, and one patient died of severe SOS, leading to a rate of moderate/severe SOS of 8.5% (95%CI: 3.9%-17.2%). In 7 of 34 patients, SOS occurred after myeloablative conditioning, including the patient who died from SOS, whereas only 2 of 37 patients developed SOS after dose-reduced conditioning (P=0.08). Grade 4/5 liver toxicity was not observed. The rate of early and hypoplastic death within 30 days after start of GO-A-HAM was 3%. All rates were below the maximally tolerated death-rate predefined in the protocol.
Median follow up for survival was 48.8 months. In total, 62 of the 93 patients died; median OS was 16.0 months and the 4-year OS rate 32% (95%CI: 24%–43%) for the whole cohort. OS at four years after start of treatment was poor (7%, 95%CI: 1%-42%) in patients not proceeding to allogeneic HCT (n=22). In patients proceeding to allogeneic HCT (n=71), 4-year OS after transplant was 39% (95%CI: 29%-52%), with a significantly better OS (P=0.0006) (Figure 2) since the timepoint of allogeneic HCT in patients (n=51) responding to GO-A-HAM (49%, 95%CI: 37%-64%) compared to those (n=20) not responding (11%, 95%CI: 3%-41%); there was no difference in outcome in responding patients according to type of response (i.e. CR, CRi, PR; P=0.48). An Andersen Gill regression model (Table 5) on OS after GO-A-HAM with allogeneic HCT as a time-dependent co-variable after limited backward selection revealed allogeneic HCT (P=0.04) and response to GO-A-HAM (P<0.0001) as prognostic favorable variables, whereas adverse cytogenetics according to European LeukemiaNet1 criteria (P=0.09), older age (P=0.04), s-AML/t-AML (P=0.02) and FLT3-ITD (P=0.04) were unfavorable parameters. All 18 patients with FLT3-ITD positive AML proceeded to allogeneic HCT (n=13 responded to GO-A-HAM), but outcome was poor despite allogeneic HCT (Figure 3).
Here we report on the prospective phase II study evaluating the GO-A-HAM regimen consisting of gemtuzumab ozogamicin in combination with all-trans retinoic acid, high-dose cytarabine and mitoxantrone in patients with primary refractory disease. Primary refractory disease in this study was defined as AML not responding to one cycle of standard 3+7-based induction therapy with either CR, CRi or PR. Half of the patients achieved CR or CRi, and another 11% of patients achieved PR, leading to an overall response rate of 61% that compares favorably to those in previous AMLSG protocols which used the HAM and S-HAM14 as well as A-HAM regimens9 in this patient population.
Chevallier et al. reported on a similar salvage regimen combining intermediate-dose cytarabine with mitoxantrone and GO at a dosage of 9 mg/m given on day 4 in refractory or relapsed AML patients.13 Although a direct comparison is difficult, the authors reported a CR rate of 39% in the refractory patient cohort. Whether the somewhat superior CR/CRi rate in our trial was due to the addition of ATRA remains elusive. Of note, in a large randomized trial in refractory/relapsed AML conducted by the Medical Research Council, no significant impact of ATRA as adjunct to intensive chemotherapy could be shown.32 However, ATRA in this study was initiated at day 1 of chemotherapy raising the important issue of which is the best schedule with significant beneficial effects of ATRA when given after chemotherapy,33 as in the GO-A-HAM regimen. Several clinical trials353420 and a meta-analysis36 showed that GO given as adjunct to intensive induction chemotherapy improved several survival end points, in particular in patients with favorable or intermediate cytogenetic risk AML. Of note, GO was only effective if given early in the treatment course, i.e. in first induction therapy; however, there was no impact on the response rate.36 Interestingly, the addition of GO to induction therapy was particularly effective in AML with FLT3-ITD based on a subset analysis.34 However, this beneficial effect was based on a very small sample size and has not been confirmed by others.35
In our study, we were not able to identify prognostic factors for the response to GO-A-HAM. Compared to our historical controls,149 GO had a major impact in improving CR rates in primary refractory patients mainly with adverse or intermediate cytogenetic risk profile. In fact, in our multivariable analyses on OS, adverse cytogenetics represented the only trend associated with an inferior outcome, with a much weaker impact compared to type of AML, age, and presence of FLT3-ITD (Table 5). Thus, our results do not support a beneficial effect of GO in AML with FLT3-ITD, despite the fact that all patients in our study of this subgroup proceeded to allogeneic HCT (Figure 3). To improve outcome of patients with FLT3-ITD positive AML, the incorporation of FLT3 inhibitors before and after transplantation is currently being evaluated in clinical trials (clinicaltrials.gov identifers: 01477606, 01468467, and 02298166, and EudraCT 2010-018539-16).
The majority (76%) of enrolled patients could proceed to allogeneic HCT. Four-year OS since start of treatment of patients responding to GO-A-HAM and receiving allogeneic HCT was 49% compared to only 11% in patients who were refractory to salvage therapy. These results again underline the strong impact of the disease status at the time of transplantation on long-term survival, as has been previously reported.975 Thus, the two major prerequisites for long-term survival in primary refractory patients are chemo-sensitivity to salvage therapy followed by allogeneic HCT.
An important point to consider when GO is added to intensive chemotherapy is the dosage, especially if allogeneic HCT is planned. In most regimens conducted in Europe, doses lower than 9 mg/m (the dose originally approved by the US Food and Drug Administration in 2000 for single agent therapy) were applied. In our trial, a dosage of 3 mg/m had only a modest impact on toxicity, especially with regard to the development of SOS directly after salvage therapy as well as after transplantation, with a rate of moderate/severe SOS after transplantation of 8.5%, which is expected in this patient population.38373130 Thus, in contrast to previous data showing an enormously increased incidence of SOS (64%) by pre-treatment with GO (6 mg/m or 9 mg/m) in a 3.5-month period prior to transplant,39 we were able to show that salvage therapy including GO in a dosage of 3 mg/m is safe and can be followed by allogeneic HCT without increasing the rate of SOS. Whether an increment of the GO dosage by using fractionated administration,4140 comparable to successful attempts in first-line therapy,35 is safe in terms of SOS and even more effective compared to our GO-A-HAM regimens remains elusive.
In summary, the addition of GO in a dosage of 3 mg/m and of ATRA to intensive chemotherapy in patients with AML refractory to one cycle of induction therapy resulted in a high response rate and a high proportion of patients proceeding to allogeneic HCT with very limited additional toxicity. However, primary refractory AML with FLT3-ITD still had a very poor outcome despite allogeneic HCT.
We are also grateful to all members of the German-Austrian AML Study Group (AMLSG) for providing leukemia specimens and clinical data; a list of AMLSG institutions and investigators participating in this study appears in the Online Supplementary Appendix.
- Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/101/7/839
- FundingThis work was supported by grants 01GI9981 [Network of Competence Acute and Chronic Leukemias], and 01KG0605 [IPD-Meta-Analysis: A model-based hierarchical prognostic system for adult patients with acute myeloid leukemia (AML)] from the German Bundesministerium für Bildung und Forschung (BMBF), the German Research Foundation (DFG FI405/5-1, BU 1339/3-1 and BU 1339/5-1, SFB 1074 B3), the Deutsche José Carreras Leukämie-Stiftung (DJCLS H 05/02), and an unrestricted grant from Wyeth/Pfizer.
- Received December 27, 2015.
- Accepted March 24, 2016.
- Döhner H, Estey EH, Amadori S. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010; 115(3):453-474. PubMedhttps://doi.org/10.1182/blood-2009-07-235358Google Scholar
- Schlenk RF, Döhner H. Genomic applications in the clinic: use in treatment paradigm of acute myeloid leukemia. Hematology Am Soc Hematol Educ Program. 2013; 2013:324-330. PubMedhttps://doi.org/10.1182/asheducation-2013.1.324Google Scholar
- Thol F, Schlenk RF, Heuser M, Ganser A. How I treat refractory and early relapsed acute myeloid leukemia. Blood. 2015; 26(3):319-327. Google Scholar
- Biggs JC, Horowitz MM, Gale RP. Bone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy. Blood. 1992; 80(4):1090-1093. PubMedGoogle Scholar
- Craddock C, Labopin M, Pillai S. Factors predicting outcome after unrelated donor stem cell transplantation in primary refractory acute myeloid leukaemia. Leukemia. 2011; 5(5):808-813. Google Scholar
- Michallet M, Thomas X, Vernant JP. Long-term outcome after allogeneic hematopoietic stem cell transplantation for advanced stage acute myeloblastic leukemia: a retrospective study of 379 patients reported to the Société Française de Greffe de Moelle (SFGM). Bone Marrow Transplant. 2000; 26(11):1157-1163. PubMedhttps://doi.org/10.1038/sj.bmt.1702690Google Scholar
- Duval M, Klein JP, He W. Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. J Clin Oncol. 2010; 28(23):3730-3738. PubMedhttps://doi.org/10.1200/JCO.2010.28.8852Google Scholar
- Aoudjhane M, Labopin M, Gorin NC. Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: a retrospective survey from the Acute Leukemia Working Party (ALWP) of the European group for Blood and Marrow Transplantation (EBMT). Leukemia. 2005; 19(12):2304-2312. PubMedhttps://doi.org/10.1038/sj.leu.2403967Google Scholar
- Schlenk RF, Döhner K, Mack S. Prospective evaluation of allogeneic hematopoietic stem-cell transplantation from matched related and matched unrelated donors in younger adults with high-risk acute myeloid leukemia: German-Austrian trial AMLHD98A. J Clin Oncol. 2010; 28(30):4642-4648. PubMedhttps://doi.org/10.1200/JCO.2010.28.6856Google Scholar
- Montillo M, Ricci F, Tedeschi A. Twice daily fludarabine/Ara-C associated to idarubicin, G-CSF and ATRA is an effective salvage regimen in non-promyelocytic acute myeloid leukemia. Leuk Res. 2009; 33(8):1072-1078. PubMedhttps://doi.org/10.1016/j.leukres.2008.12.014Google Scholar
- Pastore D, Specchia G, Carluccio P. FLAG-IDA in the treatment of refractory/relapsed acute myeloid leukemia: single-center experience. Ann Hematol. 2003; 82(4):231-235. PubMedGoogle Scholar
- Becker PS, Kantarjian HM, Appelbaum FR. Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapsed and refractory acute myeloid leukaemia. Br J Haematol. 2011; 155(2):182-189. PubMedhttps://doi.org/10.1111/j.1365-2141.2011.08831.xGoogle Scholar
- Chevallier P, Delaunay J, Turlure P. Long-term disease-free survival after gemtuzumab, intermediate-dose cytarabine, and mitoxantrone in patients with CD33(+) primary resistant or relapsed acute myeloid leukemia. J Clin Oncol. 2008; 26(32):5192-5197. PubMedhttps://doi.org/10.1200/JCO.2007.15.9764Google Scholar
- Schlenk RF, Benner A, Hartmann F. Risk-adapted postremission therapy in acute myeloid leukemia: results of the German multicenter AML HD93 treatment trial. Leukemia. 2003; 17(8):1521-1528. PubMedhttps://doi.org/10.1038/sj.leu.2403009Google Scholar
- Hu ZB, Minden MD, McCulloch EA. Direct evidence for the participation of bcl-2 in the regulation by retinoic acid of the Ara-C sensitivity of leukemic stem cells. Leukemia. 1995; 9(10):1667-1673. PubMedGoogle Scholar
- Andreeff M, Jiang S, Zhang X. Expression of Bcl-2-related genes in normal and AML progenitors: changes induced by chemotherapy and retinoic acid. Leukemia. 1999; 13(11):1881-1892. PubMedhttps://doi.org/10.1038/sj/leu/2401573Google Scholar
- Venditti A, Stasi R, Del Poeta G. All-trans retinoic acid and low-dose cytosine arabinoside for the treatment of ‘poor prognosis’ acute myeloid leukemia. Leukemia. 1995; 9(7):1121-1125. PubMedGoogle Scholar
- Schlenk RF, Fröhling S, Hartmann F. AML Study Group Ulm. Phase III study of all-trans retinoic acid in previously untreated patients 61 years or older with acute myeloid leukemia. Leukemia. 2004; 18(11):1798-1803. PubMedhttps://doi.org/10.1038/sj.leu.2403528Google Scholar
- Prebet T, Etienne A, Devillier R. Improved outcome of patients with low- and intermediate-risk cytogenetics acute myeloid leukemia (AML) in first relapse with gemtuzumab and cytarabine versus cytarabine: results of a retrospective comparative study. Cancer. 2011; 117(5):974-981. PubMedhttps://doi.org/10.1002/cncr.25554Google Scholar
- Thol F, Schlenk RF. Gemtuzumab ozogamicin in acute myeloid leukemia revisited. Expert Opin Biol Ther. 2014; 14(8):1185-1195. PubMedhttps://doi.org/10.1517/14712598.2014.922534Google Scholar
- World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon, France; 2001. Google Scholar
- Cheson BD, Bennett JM, Kopecky KJ. Revised recommendations of the international working group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2003; 21(24):4642-4649. PubMedhttps://doi.org/10.1200/JCO.2003.04.036Google Scholar
- Jones RJ, Lee KS, Beschorner WE. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation. 1987; 44(6):778-783. PubMedhttps://doi.org/10.1097/00007890-198712000-00011Google Scholar
- Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood. 1995; 85(11):3005-3020. PubMedGoogle Scholar
- Andersen P, Gill RD. Cox’s regression model for counting processes: A large sample study. Ann Stat. 1982; 10:1100-1120. https://doi.org/10.1214/aos/1176345976Google Scholar
- Harrell FE. Regression Modeling Strategies: With Applications to Linear Models, Logistic Regression, and Survival Analysis. Springer: New York, NY; 2001. Google Scholar
- R. A language and environment for statistical computing. R Foundation for Statistical Computing: Vienna, Austria; 2007. Google Scholar
- Schlenk RF, Döhner K, Krauter J. All-trans retinoic acid improves outcome in younger adult patients with nucleophos-min-1 mutated acute myeloid leukemia: results of the AMLSG 07-04 randomized treatment trial. Blood. 2011; 118(21):80a. https://doi.org/10.1182/blood-2010-12-322339Google Scholar
- Büchner T, Schlenk RF, Schaich M. Acute Myeloid Leukemia (AML): different treatment strategies versus a common standard arm–combined prospective analysis by the German AML Intergroup. J Clin Oncol. 2012; 30(29):3604-3610. PubMedhttps://doi.org/10.1200/JCO.2012.42.2907Google Scholar
- Bunjes D, Buchmann I, Duncker C. Rhenium 188-labeled anti-CD66 (a, b, c, e) monoclonal antibody to intensify the conditioning regimen prior to stem cell transplantation for patients with high-risk acute myeloid leukemia or myelodysplastic syndrome: results of a phase I-II study. Blood. 2001; 98(3):565-572. PubMedhttps://doi.org/10.1182/blood.V98.3.565Google Scholar
- Schmid C, Schleuning M, Schwerdtfeger R. Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Blood. 2006; 108(3):1092-1099. PubMedhttps://doi.org/10.1182/blood-2005-10-4165Google Scholar
- Milligan DW, Wheatley K, Littlewood T, Craig JIO, Burnett AK. Fludarabine and cytosine are less effective than standard ADE chemotherapy in high-risk acute myeloid leukemia, and addition of G-CSF and ATRA are not beneficial: results of the MRC AML-HR randomized trial. Blood. 2006; 107(12):4614-4622. PubMedhttps://doi.org/10.1182/blood-2005-10-4202Google Scholar
- Schlenk RF, Fröhling S, Hartmann F. Phase III study of all-trans retinoic acid in previously untreated patients 61 years or older with acute myeloid leukemia. Leukemia. 2004; 18(11):1798-1803. PubMedhttps://doi.org/10.1038/sj.leu.2403528Google Scholar
- Castaigne S, Pautas C, Terré C. Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012; 379(9825):1508-1516. PubMedhttps://doi.org/10.1016/S0140-6736(12)60485-1Google Scholar
- Burnett AK, Hills RK, Milligan D. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011; 29(4):369-377. PubMedhttps://doi.org/10.1200/JCO.2010.31.4310Google Scholar
- Hills RK, Castaigne S, Appelbaum FR. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol. 2014; 15(9):986-996. PubMedhttps://doi.org/10.1016/S1470-2045(14)70281-5Google Scholar
- Tsirigotis PD, Resnick IB, Avni B. Incidence and risk factors for moderate-to-severe veno-occlusive disease of the liver after allogeneic stem cell transplantation using a reduced intensity conditioning regimen. Bone Marrow Transplant. 2014; 49(11):1389-1392. PubMedhttps://doi.org/10.1038/bmt.2014.168Google Scholar
- Carreras E, Díaz-Beyá M, Rosiñol L, Martínez C, Fernández-Avilés F, Rovira M. The incidence of veno-occlusive disease following allogeneic hematopoietic stem cell transplantation has diminished and the outcome improved over the last decade. Biol Blood Marrow Transplant. 2011; 17(11):1713-1720. PubMedhttps://doi.org/10.1016/j.bbmt.2011.06.006Google Scholar
- Wadleigh M, Richardson PG, Zahrieh D. Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation. Blood. 2003; 102(5):1578-1582. PubMedhttps://doi.org/10.1182/blood-2003-01-0255Google Scholar
- Pilorge S, Rigaudeau S, Rabian F. 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. Am J Hematol. 2014; 89(4):399-403. PubMedhttps://doi.org/10.1002/ajh.23653Google Scholar
- Walter RB, Medeiros BC, Gardner KM. Gemtuzumab ozogamicin in combination with vorinostat and azacitidine in older patients with relapsed or refractory acute myeloid leukemia: a phase I/II study. Haematologica. 2014; 99(1):54-59. PubMedhttps://doi.org/10.3324/haematol.2013.096545Google Scholar