Abstract RESEARCH ARTICLE

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1 Received: 12 October 2016 Revised: 13 January 2017 Accepted: 14 January 2017 DOI /ajh RESEARCH ARTICLE Addition of cladribine to the standard induction treatment improves outcomes in a subset of elderly acute myeloid leukemia patients. Results of a randomized Polish Adult Leukemia Group (PALG) phase II trial Agnieszka Pluta 1 Tadeusz Robak 1 Agata Wrzesien-Kus 1 Bozena Katarzyna Budziszewska 2 Kazimierz Sulek 3 Ewa Wawrzyniak 1 Magdalena Czemerska 1 Malgorzata Zwolinska 1 Aleksandra Golos 1 Aleksandra Holowiecka-Goral 4 Slawomira Kyrcz-Krzemien 5 Jaroslaw Piszcz 6 Janusz Kloczko 6 Monika Mordak-Domagala 7 Andrzej Lange 7 Małgorzata Razny 8 Krzysztof Madry 9 Wieslaw Wiktor-Jedrzejczak 9 Sebastian Grosicki 10 Aleksandra Butrym 11 Kazimierz Kuliczkowski 12 Krzysztof Warzocha 2 Jerzy Holowiecki 13 Sebastian Giebel 13 Richard Szydlo 14 Agnieszka Wierzbowska 1 1 Department of Hematology, Medical University of Lodz, Lodz, Poland; 2 Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland; 3 Department of Clinical Hematology, Military Medical Academy, Warsaw, Poland; 4 Department of Oncology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland; 5 University Department of Hematology and BMT, Silesian Medical University, Katowice, Poland; 6 Department of Hematology, Bialystok Medical Academy, Bialystok, Poland; 7 L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland and Lower Silesian Center for Cellular Transplantation & National Bone Marrow Donor Registry, Wrocław, Poland; 8 Hematology Department, Rydygier Memorial Hospital, Krakow, Poland; 9 Department of Hematology, Oncology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland; 10 Department of Cancer Prevention, Faculty of Public Health, Silesian Medical University, Katowice, Poland; 11 Department of Physiology, Wroclaw Medical University, Wroclaw, Poland; 12 Department of Hematology and Proliferative Diseases, Wroclaw Medical Academy, Wroclaw, Poland; 13 Department of Bone Marrow Transplantation, Comprehensive Cancer Center, M. Sklodowska-Curie Memorial Institute, Gliwice, Poland; 14 Hammersmith Hospital, Centre for Haematology, Imperial College London, London, United Kingdom Correspondence Agnieszka Wierzbowska, Department of Hematology, Medical University of Lodz, Ul. Ciolkowskiego 2, Lodz, Poland. agawierzbowska@wp.pl Funding Information Medical University of Lodz; Grant Number: 503/ / Abstract Intensive induction chemotherapy using anthracycline and cytarabine backbone is considered the most effective upfront therapy in physically fit older patients with acute myeloid leukemia (AML). However, outcomes of the standard induction in elderly AML are inferior to those observed in younger patients, and they are still unsatisfactory. As addition of cladribine to the standard induction therapy is known to improve outcome in younger AML patients. The present randomized phase II study compares efficacy and toxicity of the DAC (daunorubicin plus cytarabine plus cladribine) regimen with the standard DA (daunorubicin plus cytarabine) regimen in the newly diagnosed AML patients over 60 years of age. A total of 171 patients were enrolled in the study (DA, 86; DAC, 85). A trend toward higher complete remission (CR) was observed in the DAC arm compared to the DA arm (44% vs. 34%; P 5.19), which did not lead to improved median overall survival, which in the case of the DAC group was 8.6 months compared to in 9.1 months in the DA group (P 5.64). However, DAC appeared to be superior in the group of patients aged (CR rate: DAC 51% vs. DA 29%; P 5.02). What is more, a subgroup of patients, with good and intermediate karyotypes, benefited from addition of cladribine also in terms of overall survival (P 5.02). No differences in hematological and nonhematological toxicity between the DA and DAC regimens were observed. Am J Hematol. 2017;92: wileyonlinelibrary.com/journal/ajh VC 2017 Wiley Periodicals, Inc. 359

2 360 PLUTA ET AL. 1 INTRODUCTION Acute myeloid leukemia (AML) is a highly heterogeneous disease, mainly experienced by older adults. 1 age at a diagnosis is 67 and approximately 30% of the cases are diagnosed in patients older than 75 years. 2 4 Currently, treatment results of AML in patients aged 60 or older remain unsatisfactory. The treatment strategy for each patient is based on performance status, comorbidities, and diseaserelated prognostic factors. 5 Patient s survival depends on achieving complete remission (CR) and preventing a relapse. Recognition of AML in patients older than 60 years has resulted in a medical dilemma concerning finding the best possible implementation of a correct mode of the treatment, taking into account risk factors. The most commonly used standard of the induction treatment, that is, DA (3 1 7), consists of 3 days of daunorubicin (DNR) with 7 days of cytarabine (Ara-C). It is used in clinical practice in all age groups of AML patients. 6 A previous trial by the Polish Adult Leukemia Group (PALG) has demonstrated that a combination of cladribine (2-CdA) with DNR and Ara-C resulted in a significantly increased CR rate after the first induction treatment course in AML 60 years of age. Particularly patients older than 40 years benefited from addition of 2-CdA to the standard treatment (CR rate 45% vs. 60%; P <.05). 7 A combination of 2-CdA, Ara-C, and anthracycline has been tested in a study on untreated, elderly AML patients and has shown no additional toxicity. 8 Addition of 2-CdA to an intensive therapy has been also associated with a high response rate and good tolerance in relapse and refractory AML patients. 9,10 Such promising results, along with acceptable toxicity of the DAC regimen, prompted this study: a randomized multicenter phase II trial comparing the DAC with standard DA regimen in newly diagnosed, elderly AML patients eligible for intensive chemotherapy. 2 MATERIALS AND METHODS 2.1 Study group The patients were considered eligible if they fulfilled the following criteria: AML diagnosis established according to the WHO criterion, age over 60 but less than 80, Eastern Cooperative Oncology Group (ECOG) performance status 2, and lack of severe comorbidities (Charlson comorbidity index 0-2). 1,11 Patients with acute promyelocytic leukemia were excluded from the study. One hundred and seventy-one newly diagnosed de novo or secondary AML patients treated in 17 Hematology Departments in Poland between May 2004 and September 2010 were enrolled into the study. The primary end point was to achieve CR after the first induction course. Toxicity profile, overall survival (OS), and disease free survival (DFS) were secondary endpoints. Karyotypes were analyzed according to the International System for Human Cytogenetic Nomenclature (ISCN) criteria. The patients were divided into three risk groups according to the Southwest Oncology Group (SWOG) classification: favorable-risk with t(8,21), or inv (16), t(16;16); intermediate-risk with normal karyotype del Y, del 9q or 18, 111, 113, 121 and unfavorable-risk with complex karyotype (3 anomalies), del 5 or 5q, del 7 or 7q, 3q26, and 11q Based on a similar prognosis from earlier studies, a cytogenetic intermediate-risk group was formed from the patients with an insufficient number of metaphases. 13 The study was approved by the bioethical committees of the participating institutions and conducted in accordance with the Declaration of Helsinki. All the participants gave their written informed consent to take part in the study. 2.2 Treatment regimens The patients were screened at each PALG center. Following verification of eligibility criteria, they were centrally randomized to one of two induction regimens: DA (DNR 45 mg/m 2, i.v., days 1-3, Ara-C 100 mg/ m 2, 24-hours i.v. infusion, days 1-7) or DAC (DNR 45 mg/m 2,i.v.,days 1-3, Ara-C 100 mg/m 2, 24-hours i.v. infusion, 2 hours after 2-CdA infusion, days 1-7 and 2-CdA 5 mg/m 2, 2-hours i.v. infusion, days 1-5). Bone marrow (BM) aspiration to assess the treatment response was performed on days from 28 to 42 following the induction cycle. After achieving a CR, the patients of both arms underwent consolidation consisting of one cycle of Ara-C 100 mg/m 2,24-hoursi.v.infusion, days 1-5, Mitoxantron 6 mg/m 2, i.v., days 1-2. After consolidation, the patients proceeded to eight cycles of maintenance treatment consisting of two alternating cycles, DNR 30 mg/m 2, i.v., days 1-2 with Ara-C 100 mg/m 2 s.c. days 1-5, and tioguanine 100 mg/m 2,p.o.,BIDdays1-5 with Ara-C 100 mg/m 2 s.c. days 1-5. The maintenance treatment was given every 6 to 8 weeks. The moment partial remission (PR) was achieved, the same induction cycle was repeated. The lack of response or progression resulted in withdrawal from the trial. Response to the treatment was defined according to the 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. 14,15 In brief, CR was defined as the presence of less than 5% BM blasts with a neutrophil count higher than 1.0 g/l, a platelet count higher than 100 g/l, and no extramedullary disease. PR was established as either 5%-25% BM blasts, a 50% or more decrease in BM blasts, or BM blasts <5% but with the presence of Auer rods. No response (NR) was established in the case of patients who did not fulfill the above-mentioned criteria. Early death (ED) was defined as a death from any cause within 4 weeks after the induction therapy and was considered as the treatment failure. DFS was calculated from the first day of CR until the documentation of relapse. OS was calculated from the time of diagnosis until death. 2.3 Statistical analysis The size of the study was based on the power to detect an increase of the CR rate from 30% in the DA group to 45% for in the DAC group. Type I error was fixed at a With the power of 0.8 and expected 10% drop-out rate, the target number of 83 patients per study arm was required. Comparisons between the patients characteristics were performed by means of the Mann-Whitney U test for continuous variables and by

3 PLUTA ET AL. 361 the v 2 -statistics or Fisher s exact test for categorical variables. The Kaplan-Meier estimates of survival were calculated and compared using the log-rank test. The effect of the type of induction was analyzed in the whole group and in the subgroups stratified by age and karyotype. The subgroup analyses were predefined although the cut-off value for age was determined post hoc based on the patients characteristics. Effects heterogeneity was verified using the Cochrane Q test. P values <.05 were considered significant. 3 RESULTS 3.1 Patients characteristics A total of 171 patients were included in the study and were randomly assigned to one of the treatment arms (DA, 86; DAC, 85). One patient in the DA arm died before the treatment implementation due to hemorrhage to the central nervous system. In the DAC arm, three patients died due to influenza in epidemic time, one died due to gastrointestinal tract hemorrhage, and one patient withdrew his informed consent before the treatment implementation. The overall, 165 patients were available for the further analysis (DA, 85; DAC 80). Characteristic of the study patients is presented in Table I. The median age was 66 years (range years), and 52.1% of the patients were male. The median initial white blood cells (WBC) count was g/l (range, G/ L). In 23.9% of the patients, the diagnosis of AML was preceded by myelodysplasia or myeloprolifetetive disease or was secondary to previous treatment of solid tumors. Results of cytogenetic testing were obtained for 70.9% of the patients, of whom 5.3% had a karyotype that was classified as favorable, 73.7% as intermediate, and 21.1% as unfavorable. The two treatment groups did not differ with respect to clinical characteristics, except for the frequency of secondary AML, which was significantly higher in the DAC arm (P 5.024). 3.2 Response to induction treatment Of the whole group, a CR was achieved after a single course of induction in 64 patients (39%). Four of 19 patients (12%) with PR received the second repeated course of the induction, and all achieved CR, leading to an overall CR rate of 41%. Fifteen patients were excluded from the second induction course due to a severe infection or significant worsening of performance status. The CR rate after the first induction course in the DAC arm and the DA arm was 44% vs. 34%, respectively (P 5.19). DAC induction was associated with less frequent resistance to the treatment compared with the DA arm (23% vs. 36%). The incidence of early death in the DAC and DA arms was 23% vs. 17%, respectively (Table 2). The subgroup analysis revealed that the patients younger than 65 significantly benefited from addition of cladribine to the standard treatment (CR rate 51% vs. 29%; P 5.02; respectively); however, this observation did not affect the patients older than 65 years (Table 2). In the younger patients, even higher CR rates were observed in TABLE I Characteristic Age, years Sex Male Female AML de novo Secondary FAB subtypes M0 M1 M2 M4 M5 M6 M7 Karyotype Favorable Intermediate Unfavorable Patients characteristics WBC (G/L) at diagnosis the DAC arm in the good and intermediate cytogenetic risk groups (69% vs. 21% in the DA arm P , respectively) (Table 3). 3.3 Overall survival DA n=85 No % Hemoglobin (g%) at diagnosis Platelet (G/L) at diagnosis Serum LDH (U/L) Blasts in BM DAC n=80 No % p value Abbreviations: FAB, French American British classification; LDH, lactate dehydrogenase; BM, bone marrow The median time of follow-up was 6.4 ( ) months. The median OS time for the whole group was 8.6 months. No significant difference in OS was observed between the DA and DAC regimens. The median OS was 9.1 months (95% CI ) in the DA arm and 8.6 (95% CI ) months in the DAC arm (P 5.64) (Figure 1, Panel A). There was a trend toward longer OS in the DAC arm than in the DA arm in the patients with good- and intermediate-risk karyotypes (P 5.057) but not in the unfavorable-risk group (P 5.7) (Figure 1, Panel

4 362 TABE 2 Response rate after the first induction course All patients Patients 65 years Patients > 65 years DA DAC DA DAC DA DAC PLUTA ET AL. CR 29 (34) ( ) 35 (44) ( ) 10 (29) ( ) 23 (51) ( ) 17 (37) ( ) 9 (35) ( ) PR 11 (13) ( ) 8 (10) ( ) 7 (20) ( ) 3 (7) ( ) 4 (9) ( ) 3 (12) ( ) NR 31 (36) ( ) 18 (23) ( ) 14 (40) ( ) 9 (20) ( ) 15 (33) ( ) 7 (27) ( ) ED 14 (17) ( ) 18 (23) ( ) 4 (11) ( ) 10 (22) ( ) 10 (22) ( ) 7 (27) ( ) P value B). The difference was even higher in the patients 65 years of age. (P 5.024) (Figure 1, Panel C i), but nonsignificant in the AML patients >65 years of age. (P 5.43). In contrast, no benefit from addition of cladribine was observed in the poor-risk cytogenetic group (P 5.7) (Figure 1, Panel C ii). Hazard ratios were significantly different between the four subgroups: (i) the patients 65 with favorable/intermediate cytogenetics, (ii) the patients >65 with favorable/intermediate cytogenetics, (iii) the patients 65 with unfavorable cytogenetics; (iv) the patients >65 with unfavorable cytogenetics (P 5.02). In the whole group, there was no evidence of influence of the type of AML (de novo or secondary) on OS (P 5.6). No correlation was observed between OS and the patient s age, FAB classification and tumor burden (WBC, percentage of blast in bone marrow or peripheral blood and lactate dehydrogenase level). None of the patients underwent hematopoietic stem cell transplantation either allogeneic or autologous. One decade ago in Poland transplantation procedures were mostly performed in patients younger than 60 years of age due to a limited number of transplant centers. 3.4 Toxicity Duration of hospitalization was similar in the DA and DAC patient groups: 32 days (range: 7-74) vs. 33 days (range: 16-92), respectively (P 5.42). In all the patients, grade 4 neutropenia and thrombocytopenia were observed. Recovery from agranulocytosis took 19 days (range: 0-70) in the DA arm and 16 days (range: 0-42) in the DAC arm (P 5.54). The time for platelet recovery above 20 G/L did not differ between the groups: 18 days for DA (range: 0-34) vs. 17 days for DAC (range: 0-55) (P 5.67). Infection complications (grades II-IV) occurred in 80% of the patients in the DA arm and 88% of the patients in the DAC arm. Other nonhematological toxicities were infrequent and comparable in both study groups. Early death was observed in 14 (17%) patients in the DA arm and 18 (23%) patients in the DAC arm (P 5.19). In the DA regimen, seven patients died due to pneumonia, two due to fever of unknown origin (FUO), and five because of sepsis (Gram positive: 1 case, Gram negative: 4 cases). In the DAC arm, pneumonia was the cause of death in seven cases, seven patients died due to sepsis (Gram positive: 3 cases and Gram negative: 4 cases). The other causes of death were: FUO (n 5 2), urinary tract infection (n 5 1), and neutropenic colitis (n 5 1). 4 DISCUSSION AML is a heterogeneous disease progressing along with age, risk factors based on karyotype, molecular markers, and patient s characteristics. Several studies have attempted to determine which treatment strategy may improve outcomes in specific subgroups of patients. One of the modern options is supplementation of chemotherapy together with small active molecules for repairing single cell pathways. However, this strategy is based on detailed molecular diagnostics, which requires additional time before initiation of treatment and the use of an available molecular laboratory. Time before commencement of a therapy should be as short as possible, ideally less than 7 days after a diagnosis. 5 Therefore, targeted treatment may play a more important role during consolidation therapy, when a major reduction of leukemic burden is achieved. The search for the most suitable all-purpose induction TABLE 3 Response rate in the patients with good and intermediate karyotype risk groups Patients 65 years Patients > 65 years DA DAC DA DAC CR 4 (21) ( ) 13 (69) ( ) 8 (44) ( ) 2 (29) ( ) PR 4 (21) ( ) 2 (11) ( ) 1 (6) ( ) 0 (0) ( ) NR 9 (47) ( ) 3 (16) ( ) 4 (22) ( ) 2 (29) ( ) ED 2 (11) ( ) 1 (5) ( ) 5 (28) ( ) 3 (42) ( ) P value

5 PLUTA ET AL. 363 FIGURE 1 Survival probability. (Panel A): Probability of OS according to the induction treatment, Kaplan-Meier method. (Panel B) Probability of OS patients according to the induction treatment and the favorable, intermediate (i) and poor (ii) karyotype risk groups, Kaplan-Meier method. (Panel C) Probability of OS according to the induction treatment in the patients aged 65 with favorable, intermediate (i), and poor (ii) karyotype risk groups and the patients aged >65 with favorable, intermediate (iii), and poor (iv) karyotype risk groups; Kaplan- Meier method option for elderly AML patients who are fit for intensive chemotherapy has been a challenge for many hematologists. Our study was the first to compare effectiveness of a standard regimen based on the conventional induction treatment in AML patients above 60 years of age with the one supplemented with cladribine, a purine analog (DA vs. DAC). When the study started addition of small molecules to the therapy was not widely considered. The trial was based on a group of newly diagnosed AML patients with good

6 364 PLUTA ET AL. performance status and without severe comorbidities. The study enrollment was 6 years. The reason of such a long period was the poor performance status of AML patients over 60 years of age in Poland. The CR rate after the first course of induction in the DAC group was 44%, compared to 34% in the DA group. The further analysis revealed a higher CR rate in the DAC arm than in the DA arm among the patients aged (51% vs. 29%). This difference was even higher in the good and intermediate karyotype risk groups (69% vs. 21%). Addition of cladribine resulted in decreased leukemia resistance, while early mortality remained similar in both groups. In addition, both hematologic and nonhematologic toxicity was comparable among the treatment arms, indicating that addition of purine analogs did not impair tolerance of the treatment. 7,9,10,16 A previous PALG study performed on an AML population aged under 60 has examined addition of purine analogs to the standard induction treatment (3 1 7). 6,16 Patients in that study were randomized into three treatment arms: DA (DNR 60 mg/m 2 for 3 days, Ara-C 200 mg/m 2 for 7 days), DAC (DA plus cladribine 5 mg/m 2 for 5 days), and DAF (DA plus fludarabine 25 mg/m 2 for 5 days). The CR rate after the first induction was significantly increased by addition of cladribine (62%) compared to the standard DA therapy (51%; P 5.02). In phase II study efficacy and toxicity of cladribine combined with intermediate doses of Ara-C and idarubicin (cladribine 5 mg/m 2,days 1-5, Ara-C 1000 mg/m 2, days 1-5, and idarubicin 10 mg/m 2,days1-3) in AML patients <60 years of age were analyzed. CR rate after one induction cycle was 67%, and this regimen was also well tolerated. 17 Based on trials that covered younger AML patients, addition of cladribine as a third drug into the induction course is an effective option. Our present findings indicate that only younger (65 years of age) elderly patients with good- and intermediate-risk karyotypes benefited from addition of cladribine to the standard induction, both in terms of CR and OS. Our results do not indicate any advantage of DAC treatment in elderly AML patients with a poor-risk karyotype. This may be in part due to the different biology of AML in elderly patients. There is evidence that the frequency of a monosomal karyotype (MK), which defines a subset of AML patients with particularly unfavorable prognosis, increases significantly along with age. In the SWOG study MK has been identified in 20% of patients older than 60 but in only 4% of patients aged 30 or younger. 18 Results of PALG retrospective analysis regarding a population of AML patients with a complex karyotype have shown that addition of cladribine to the standard DA regimen improves OS only in MK 2 but not in MK 1 cytogenetic group. 19 Other explanation may be the fact that AML in the elderly exhibits several other biological features associated with chemoresistance, including frequent involvement of a more immature leukemic precursor clone or multidrug resistance mediated by MDR1/P-glycoprotein. 20 Lowenberg et al. have randomly compered two induction regimens with different doses of DNR (45 mg/m 2 vs. 90 mg/m 2 ) administered for 3 days with Ara-C 200 mg/m 2 for 7 days 21 in patients aged > 60, either with previously untreated AML or with refractory anemia with excess of blast and an international prognostic score of 1.5 or higher. 22 All patients were given a second cycle of Ara-C 1000 mg/m 2 twice a day for 6 days. The CR rate after the first cycle was 35% in the standard arm (DA-45), compared to 52% in the escalated-dose group (DA- 90). After the second cycle of Ara-C, the CR rate was 54% in the standard treatment group compared to 64% in the escalating group. In this study, the CR rate in the DA arm was comparable to that observed by Lowenberg in DA-45. However, in the escalated DA-90 arm, the CR rate was higher than in our DAC arm (52% vs. 44%, respectively). This observation could be attributed to the differences between the characteristics of the AML populations and the higher incidence of secondary AML in our DAC population (32% in DAC vs. 23% in DA-90). In the French ALFA-9803 randomized trial, newly diagnosed AML patients aged 65 have been treated with DNR 45 mg/m 2 for 3 days plus Ara-C 200 mg/m 2 for 7 days or with idarubicine (IDA) 9 mg/m 2 for 4 days plus Ara-C 200 mg/m 2 for 7 days. 23 The CR rate after a single course of chemotherapy was 57% in the whole cohort: 54% in DNR arm vs. 59% in IDA arm, differences were statistically insignificant. The CR rate in this trial was a little higher than that observed in our study. This difference could be related to the higher frequency of adverse risk factors (adverse cytogenetic, secondary AML) in our population and a lower dose of Ara-C used in our induction regimens (100 mg/m 2 vs. 200 mg/m 2 ) compared to the French study. Another French trial, ALFA-9801, has focused on newly diagnosed AML patients aged who were treated with a high dosage of 80 mg/m 2 DNR, day 1-3 with 200 mg/m 2 Ara-C, day 1-7 or IDA 12 mg/m 2 for 3 and 4 days with the same Ara-C doses. The CR rate after one induction cycle was 61% for DA, 70% for IDA3 and 67% for the IDA4 arm: the differences were not found to be statistically significant. Better results obtained in the Pautas et al. study are probably related to the AML patient population being younger (median age 60 years of age compared to 66 years of age in our cohort) and the treatment intensity being greater. The UK NCRI AML17 trial has randomly compared 90 mg/m 2 DNR and 60 mg/m 2 DNR given for 3 days with 100 mg/m 2 Ara-C administered for 10 days in newly diagnosed adult AML patients. No significant difference has been found between the groups with regard to the CR rate after a single induction course, those values being 66% in the DA60 group and 68% in the DA90 group (P 5.2). In the analysis of the subgroup aged 60-65, no difference in the CR rate or OS has been observed between the two arms. The detailed results were not presented. 3 Taking all these findings together, it appears that addition of cladribine to the standard treatment may be an interesting induction option in elderly AML patients. Importantly, other studies that have marked a significant role of other purine analog, in AML treatment were presented by Kantarjian and Faderl et al. These authors have demonstrated influence of clofarabine alone and with a low dose Ara-C on the CR rate and OS. 25,26 Nazha et al. have published II phase study in a younger than 60 years of age newly diagnosed AML cohort, where patients received clofarabine 20 mg/m 2, days 1-5, idarubicin 10 mg/m 2, days 1-3, and cytarabine 1 g/m 2, days 1-5. CR rate was 79%. 27 Addition of purine analog as a third drug to the standard treatment seems to be an interesting

7 PLUTA ET AL. 365 option for all AML patients improving response to the induction chemotherapy. In this study, OS was 9.1 months for the DA arm and 8.6 months for the DAC arm (P 5.64). Survival assessment in the subgroups according to a patient s age(65 and >65 years), cytogenetic risk and induction treatment indicated better OS scores in the DAC arm than in the DA arm for younger patients (<65 years) with good- and intermediate-risk karyotypes (P 5.02). As no difference could be demonstrated with respect to DFS, the observed survival advantage can probably be attributed to the improved CR rate. Our results suggest that DAC induction in AML patients over the age of 60 is an active treatment with standard toxicity and may be a bridge for transplantation and longer survival. In contrast, results of the induction treatment in the older than 65-year population, especially those with a poor-risk karyotype and with antecedent MDS or MPD, are still unsatisfactory. The results of the randomized AZA AML-001 trial found that treatment with azacitidine was associated with significant improvement of OS compared to the standard care, especially in the high-risk AML patients with a poor-risk karyotype or with myelodysplasia related changes. 28 These results suggest that AML patients who do not benefit from the standard induction therapy should be candidates for clinical trials with new drugs or could be transferred to the treatment with HMA. Finding the best treatment option for elderly AML patients remains a challenge. Nevertheless, addition of cladribine to the standard DA induction may improve outcomes in selected elderly AML patients, especially those under 65 years of age without a poor-risk karyotype. ACKNOWLEDGMENTS The authors thank mgr Edward Lowczowski, Foreign Language Teaching Center, Medical University of Lodz, for the review of the manuscript. This work was partly supported by a grant from the Medical University of Lodz (No. 503/ / ). 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