Cyclophosphamide Dose Intensification during Induction Therapy for Intermediate-Risk Pediatric Rhabdomyosarcoma Is Feasible but Does Not Improve Outcome

11501 Background: The role of dose intensification of chemotherapy in Ewing sarcoma (ES) is under evaluation in prospective trials. This is a controlled, randomized phase III study evaluating the impact on event-free survival (EFS) of two arms at different intensity of induction therapy in localized ES at onset. Methods: Newly diagnosed localized ES patients aged 2-40 were eligible. They were randomized to receive 4-courses induction therapy - 1 every 21 days - either with a standard arm (arm A) as per ISG/SSGIII protocol (Ferrari S, et at, Ann Oncol. 2011;22(5):1221) or with an intense arm B, consisting of vincristine 1,5mg/sqm+ doxorubicin 80mg/sqm+ifosfamide 9g/sqm for each course. After induction, patients underwent surgery and/or radiotherapy,followed by an adaptive treatment. Good responders received standard courses chemotherapy: arm A pts received 9 courses, while arm B pts received 5 courses. Poor responders in both arms received 4 courses followed by high-dose busulfan/melphalan+autologous stem cell rescue. The primary outcome measure was EFS for the 2 arms in the intention-to-treat population. Kaplan-Meier curves compared with log-rank test and Cox model were performed to assess differences between study arms. A secondary outcome was toxicity differences, assessed by means of the Fisher’s exact test. Initial sample size was 230 pts, type I error rate 5%, power 80%. Results: Between 2009 and 2019, 234 patients were randomized (arm A-115; arm B-119). M:F ratio was 1.8; median age 14 years (range 2-40); tumour site extremity in 55%, axial/pelvis in 45%; tumour volume < 200ml in 31% and ≥200ml in 69%. A good response was obtained in 56% in arm A and 60% in arm B. Median follow-up was 68 months. EFS was not significantly different between arms; HR: 0.85; 95% CI: 0,51-1,41, 5-year EFS (95% CI) was 73% (64-82%) in arm A and 75% (67-83%) in arm B ( p = 0.526). Good responders in arm A and in arm B and poor responders in arm B had comparable results: 5-year EFS (95% CI) was 80% (71-91%), 77% (67-88%), and 72% (59-86%), respectively, while poor responders in arm A showed a worse, not statistically significant (p = 0.164) performance (63%; 50-78%). Subgroup analyses showed similar outcome for age, tumour site and volume in both arms. Hematological, gastrointestinal, and cardiovascular grade ≥3 toxicities were more pronounced in arm B (p < 0.05). Conclusions: Intense induction therapy with arm B did not improve 5-year EFS when compared with the standard arm A. The higher toxicity observed in arm B than in arm A was counterbalanced, in good responders, by a similar outcome with a shorter treatment plan. For poor responders, with almost 30 patients per arm event-free and with < 48-month FUP, better 5-year EFS in arm B than in arm A was observed but needs further observation. Clinical trial information: NCT02063022.

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Cytogenetic Remission Status after Induction Chemotherapy for AML and High-Risk MDS Predicts Long-Term Outcome.

Blood ◽

10.1182/blood.v104.11.3009.3009 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3009-3009

Author(s):

Sebastian Balleisen ◽

Hildebrand Barbara ◽

Royer-Prokora Brigitte ◽

Kuendgen Andrea ◽

Gattermann Norbert ◽

...

Keyword(s):

High Risk ◽

Induction Chemotherapy ◽

Induction Therapy ◽

Intermediate Risk ◽

Abnormal Karyotype ◽

Term Outcome ◽

Long Term Outcome ◽

Remission Status ◽

Risk Patients ◽

Cytogenetic Remission

Abstract Cytogenetic findings at diagnosis have an important impact on prognosis in AML and MDS. Therefore, treatment is commonly stratified according to karyotype. Another important prognostic factor is remission status after induction chemotherapy. However, the diagnosis of remission, and the resulting treatment decisions, are usually not based on cytogenetic findings, but rely on peripheral blood counts and bone marrow blast cell counts. We analysed the prognostic impact of cytogenetic remission status in 115 patients with abnormal karyotype who received induction chemotherapy because of AML (n=102) or MDS (n=13). Initial karyotypes were as follows: 14x t(15;17), 9x t(8;21), 5x inv(16), 55 intermediate-risk, and 32 complex karyotypes. The following induction protocols were used: 38x TAD, 4x HAM, 25x Ida-Ara, 36x ICE, and 3x other protocols. Eleven patients received induction chemotherapy plus ATRA. 23 patients underwent allogeneic transplantation after induction therapy, either as late consolidation in cytologic remission (CR), or as standard treatment in high-risk patients. 78 patients achieved CR, 21 achieved partial remission (PR), and 16 patients were non-responders (NR). There were 26 patients who reached cytological CR but still showed an abnormal karyotype after induction. 17 of these 26 patients had been classified as standard-risk and therefore did not receive intensified consolidation. In 59 patients, a normal karyotype was found after induction therapy. 24 of 28 patients belonging to low-risk cytogenetics (t15;17, t8/21, or inv16) achieved cytogenetic complete remission (CCR). The CCR rate was much lower in patients with intermediate-risk cytogenetics (24/55) and patients with complex karyotypes (11/32). Median survival in the group achieving CCR was 40 months, as compared to 11 months in patients with persistence of abnormal karyotype after induction (p<0,00005). The difference remained highly significant when calculated only for patients with complex or intermediate-risk karyotypes (median survival 29 vs 11 months). Conclusions: Cytogenetic analysis after induction chemotherapy is useful to detect residual disease and therefore provides meaningful information in addition to cytology. Achieving cytogenetic remission after induction therapy is strongly correlated with a better long-term outcome. Patients with a persisting abnormal karyotype must be regarded as high-risk patients who should receive intensified treatment.

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Outcomes and Prognostic Scoring System for Elderly Patients with Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2020-139350 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 31-32

Author(s):

Fumi Nakamura ◽

Sachiko Seo ◽

Honoka Arai ◽

Yuka Nakamura ◽

Tomoyuki Handa ◽

...

Keyword(s):

Elderly Patients ◽

Induction Therapy ◽

Myeloid Leukemia ◽

Research Funding ◽

Performance Status ◽

Intermediate Risk ◽

Conventional Chemotherapy ◽

Factors Associated ◽

Induction Failure ◽

Acute Myeloid

Background: The prognosis of elderly patients with acute myeloid leukemia (AML) remains poor. Elderly patients are frequently intolerant to intensive chemotherapy due to poor performance status and co-morbidities. Moreover, considering the increase of genetic abnormalities, it is disputable whether conventional chemotherapy improves the prognosis of elderly AML patients. The purpose of this study is to identity patients who would benefit from conventional chemotherapy. Patients and Methods: We retrospectively analyzed the outcome of patients with AML aged over 65 years who received conventional chemotherapy based on the JALSG GML 200 protocol at our institution between December 2011 and January 2020. Patients with acute promyelocytic leukemia were excluded. No patients underwent hematopoietic cell transplantation (HCT). Dose reduction of each regimen was considered in patients over 70 years of age. MEC regimen was used for reinduction therapy in 70% of patients with induction failure. The primary end point was overall survival (OS) after induction therapy. Factors associated with the achievement of complete remission (CR) and overall mortality were analyzed using logistic regression and Cox proportional hazards models, respectively. Results: A total of 74 patients were analyzed. The median age was 72.8 years (range, 65-85). Nine patients (12%) had an ECOG performance status of 3-4. The most common AML subtype was AML with myelodysplasia-related changes (n=30, 41%) followed by AML with maturation (n=11, 15%). Twenty patients (27%) were previously diagnosed with myelodysplastic syndromes (MDS). According to the 2017 ELN stratification, 3 patients (4%) were classified as favorable-risk, 44 (60%) as intermediate-risk, and 27 (37%) as adverse-risk. Overall, 21 patients (28%) achieved CR after induction therapy. Among 53 patients with induction failure, 37 received reinduction therapy and 14 (38%) achieved CR. The ELN favorable- or intermediate-risk (OR, 23.2; 95% CI, 4.59-117.0, p<0.001) and age under 70 years (OR, 7.62; 95% CI, 1.54-37.8, p=0.013) were important factors associated with the achievement of CR. Median OS was 10.3 months for all patients and 19.3 months for patients who achieved CR after induction therapy. The probability of 3-year survival was 20.9% in the total patients. The day 100 and 1-year NRM incidences were 4% and 8%, respectively. In multivariate analysis, lower performance status (3-4) (HR, 3.93; 95% CI, 1.81-8.49, p<0.001), age 70 and older (HR, 3.38; 95% CI, 1.76-6.47, p<0.001), the ELN adverse-risk (HR, 3.16 95% CI, 1.83-5.47, p<0.001), and previous MDS diagnosis (HR=2.36, 95% CI=1.29-4.30, p<0.001) were the significant independent prognostic factors for poor OS. On the basis of the number of these four factors, the prognostic score was calculated for each patient and patients were categorized into five groups (score 0-4). The score was significantly correlated with OS (p<0.001, Figure). The probability of 1-year survival was 85.7% for score 0, 59.4% for score 1, and 5.9% for score 2. All patients for score 3 and 4 died within 1 year and their median OS was 2.8 months for score 3 and 0.4 months for score 4. Conclusions: Each two patient (age, performance status) and disease (ELN disease risk, history of MDS) factors were significantly associated with survival in elderly patients with AML. The prognostic scoring system based on the four factors clearly stratified survival, suggesting that it will be useful for making a treatment decision. Further large-scale studies are required to validate this system and a combination therapy with molecular targeted drugs should be established for patients with poor prognosis. Disclosures Seo: Janssen Pharmacuetical K.K.: Consultancy; Novartis: Speakers Bureau; Bristol Myers Squibb K.K.: Speakers Bureau; Meiji Seika Pharma.: Speakers Bureau. Ichikawa:Novartis, Takeda: Honoraria. Mitani:KYOWA KIRIN: Consultancy, Research Funding; CHUGAI: Research Funding; Takeda: Research Funding.

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Faculty Opinions recommendation of Addition of Vincristine and Irinotecan to Vincristine, Dactinomycin, and Cyclophosphamide Does Not Improve Outcome for Intermediate-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733793322.793575976 ◽

2020 ◽

Author(s):

Alberto Pappo

Keyword(s):

Intermediate Risk ◽

Oncology Group ◽

Improve Outcome

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Arsenic Trioxide (ATO) as Induction Therapy Achieves Early Complete Cytogenetic Remission In Acute Promyelocytic Leukemia (APL)

Blood ◽

10.1182/blood.v116.21.4350.4350 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4350-4350

Author(s):

Hari Menon ◽

Amol Akhade ◽

Manju Sengar ◽

Pratibha Amare ◽

P. Subramanian ◽

...

Keyword(s):

Hospital Stay ◽

Induction Therapy ◽

Risk Groups ◽

Cytogenetic Response ◽

Intermediate Risk ◽

Newly Diagnosed ◽

Transfusion Requirements ◽

Cytogenetic Remission ◽

The Impact

Abstract Abstract 4350 Introduction- All Trans Retinoic Acid (ATRA) with chemotherapy, though an effective induction therapy for newly diagnosed APL, is associated with significant morbidity and mortality in our population. In order to reduce toxicity without compromising efficacy, we treated 53 consecutive patients of newly diagnosed APL with single agent ATO as induction therapy. Minimum toxicity with excellent efficacy emerged from such an approach reiterating ATO's niche in frontline management of APL. Materials and methods- Newly diagnosed APL patients presenting to our centre were treated immediately at diagnosis with infusional ATO (10mg/day for 45 days). They were monitored for toxicity and evaluated for morphological and cytogenetic remission at the end of 45 days. This was followed by planned consolidation with ATRA (45mg/m2 × 60 days) plus Daunomycin (60mg/m2, 3 doses × 3 cycles) sequenced by standard maintenance with ATRA for 18 months. Results- Fifty three consecutive patients from May 2008 to May 2010 received induction with ATO. These included Low risk (n= 10), intermediate risk (N=18),and high risk (n=25). Four patients died within first week of diagnosis and were non evaluable. Amongst the 49 evaluable patients one died in induction phase due to neutropenic sepsis. No overt differentiation syndrome was encountered though 17 patients needed short course of steroids for weight gain. Twenty eight patients developed febrile neutropenia warranting antibiotics alone while 7 patients needed antifungals too. 2 patients had to be discontinued from ATO due to persistent QT prolongation on EKG. Median duration of hospital stay was 17 days (range 3 to 46 days). Response evaluation by cytogenetic remission status was not available in 5 patients. In the remaining (n=44), 43 achieved morphological and complete cytogenetic remission at the end of induction therapy while all were in cytogenetic remission after consolidation. One patient died in maintenance due to unrelated septic shock while still being in remission. All patients have either completed or are currently on maintenance phase at a median follow up of 17 months (range 2 to22 months). ATO was active across all risk groups with nearly all achieving complete cytogenetic response post induction treatment. Transfusion requirements, hospital stay and antibiotic use were modest as compared to our previous institutional data. Conclusion- ATO induction therapy is a suitable, effective and well tolerated regimen for newly diagnosed APL across all risk groups in our population. Complete cytogenetic remission with minimum toxicity was achieved in almost all patients after induction. However, longer follow up is required to gauge the impact of early cytogenetic response with regards to cure in APL.Future studies are aimed at decreasing doses of anthracyclines in low and intermediate risk groups. Disclosures: No relevant conflicts of interest to declare.

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The Expression of LEF1 Gene and its Clinical Significance in Chinese Patients with Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v120.21.4621.4621 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4621-4621 ◽

Cited By ~ 1

Author(s):

Yuan Fu ◽

Huayuan Zhu ◽

Wei Wu ◽

Jiadai Xu ◽

Wenyi Shen ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Wnt Signaling ◽

Clinical Significance ◽

Induction Therapy ◽

Myeloid Leukemia ◽

Expression Level ◽

Chinese Patients ◽

Intermediate Risk ◽

Normal Controls ◽

Acute Myeloid

Abstract Abstract 4621 Objective: Canonical Wnt signaling controls embryonic development, regulates cell growth, transference and differentiation, it also involves in the self-renewal process of normal tissue and multiplication of stem cell. Recently, the aberrant activation of the Wnt signaling pathway has been implicated in the pathogenesis of human neoplasm including leukemia. LEF1, as a major transcriptional factor of Wnt signaling, plays a pivotal role in lymphoid differentiation as well as in granulopoiesis. High expression of LEF1 has been proposed to be a novel favorable prognostic factor in cytogenetically normal acute myeloid leukemia (AML). In this study, we firstly investigated the expression level of LEF1 mRNA and its clinical significance in Chinese AML. Methods: 87 samples from 81 Chinese AML patients (81 primary untreated samples and 6 samples after induction therapy) and 14 healthy controls were collected in this study. The LEF1 mRNA expressions were measured by real-time PCR with fluorescent dye SYBR Green I, the GAPDH was used as internal control. The relative quantitative value of LEF1 expression was calculated by means of 2 (−ΔCt). We analyzed the results with established AML prognostic factors such as karyotype, gene mutations, fusion proteins, relapse-free survival (RFS) and overall survival (OS). Results: The expression level of LEF1 mRNA in 81 AML patients was significantly higher than 14 normal controls (p <0.001). LEF1 expression level was further analyzed in the subgroups distinguished by clinical characters. According to national comprehension cancer network (NCCN) guideline, we found that LEF1 was dramatically increased in patients with better risk karyotype group (n=18) than those with the intermediate risk karyotype group (n=51) (P=0.031); patients with PML-RARα positive (n=16) and AML1-ETO positive (n=5) have higher LEF1 level compared with those without PML-RARα or AML1-ETO (n=60). Among 70 patients who have received the induction therapy, we discovered that patients with relative higher LEF1 expression were more likely to achieve CR after first induction therapy (p= 0.031; CR: n=44, no CR: n=26); we further analyzed the samples before and after treatment from 6 patients who achieved CR, the results showed that the LEF1 level were dramatically decreased after first induction therapy (p=0.028). We can not find the differences in RFS and OS between low LEF1 expression group and high LEF1 expression group in total patients. However, among the AML patients with intermediate risk cytogenetic, the lower LEF1 expression was associated with worse RFS (median, 15.0 vs 31.7 months, P=0.044) and OS (median, 16.7 vs 33.7 months, P=0.046) compared with the higher LEF1 expression. Conclusion: These results showed the LEF1 expression in AML patients is markedly higher than normal controls, especially in patients with favorable risk karyotype and PML-RARα or AML1-ETO positive. Patients with higher LEF1 expression seems to more likely to achieve CR after induction therapy. Survival analysis revealed that the higher LEF1 expression patients have a significantly prolonged RFS and OS compared to the lower LEF1 expression patients in intermediate risk karyotype group of AML. Our results in Chinese patients verified that LEF1 can be a potential favorable marker in AML patients. Disclosures: No relevant conflicts of interest to declare.

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Residual Blast Cells in Bone Marrow on Day 15 Following Remission Induction Therapy for Acute Myeloid Leukemia Is Associated with Long-Term Prognosis: A Retrospective Analysis of the JALSG AML201 Study

Blood ◽

10.1182/blood.v128.22.2795.2795 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2795-2795

Author(s):

Maki Hagihara ◽

Shin Fujisawa ◽

Sumihisa Honda ◽

Shigeki Ohtake ◽

Shuichi Miyawaki ◽

...

Keyword(s):

Bone Marrow ◽

Induction Therapy ◽

Research Funding ◽

Remission Induction ◽

Intermediate Risk ◽

Chugai Pharmaceutical ◽

Significant Difference ◽

First Remission ◽

Long Term Prognosis

Abstract Background The percentage of blasts in the bone marrow in the early stage of remission induction therapy for acute myeloid leukemia (AML) has been reported to affect not only remission rate, but also long-term prognosis. If early post-treatment response to therapy was determined to affect prognosis, this finding could be a basis for selection of a proactive treatment such as hematopoietic stem cell transplantation; however, the proper assessment period and the percentage of blast cell survival vary among reports. Therefore, we retrospectively analyzed the relationship between prognosis and the percentage of blasts in the bone marrow in the early post-treatment stage in cases registered for the AML201 study conducted by the Japan Adult Leukemia Study Group (JALSG). Patients and Methods The JALSG AML201 study was a multicenter randomized study in which 1064 patients with newly diagnosed AML patients were registered between December 2001 and December 2005. For remission induction therapy, we compared standard-dose idarubicin or high-dose daunorubicin in combination with cytarabine. For consolidation therapy, we compared standard-dose multiagent chemotherapy or high-dose cytarabine alone, and no apparent differences were observed in overall survival (OS) between both treatment groups. The percentage of blasts in the bone marrow on day 15 was strongly associated with remission; using the receiver operating characteristic curve as a reference, we divided patients into a ≥5% and a <5% blasts group and compared their prognoses. For between-groups comparisons, we used Fisher's exact test. For comparison of survival curves, we employed the log-rank test. We conducted statistical analysis using the statistics program EZR. Results Among the 1064 patients registered for the JALSG AML201 study, 600 patients for whom bone marrow examination was performed on Day 15 were selected as subjects for the present study. The patients consisted of 375 men and 225 women with a median age of 47 years (15-64 years). A total of 377 patients (62.8%) had <5% blasts in their bone marrow on day 15 and their complete remission (CR) rate was 91.8%. On the other hand, 223 patients (37.2%) had ≥5% blasts and their CR rate was 58.3%. The 3-year overall survival rate (OS) in the <5% blasts group and the ≥5% blasts groups were 61.6% and 38.6%, respectively (p < 0.001) (Figure 1); while the 3-year relapse free survival rate (RFS) was 46.3% vs. 29.8%, respectively (p < 0.001). Thus, the group with <5% blasts in the bone marrow showed significantly more favorable results. The difference in outcomes was especially remarkable in the group with intermediate-risk cytogenetics (n = 397). These patients demonstrated significant differences in both OS (<5% blasts vs. ≥5% blasts = 59.3% vs. 34.0% p < 0.001) and RFS (<5% blasts vs. ≥5% blasts = 44.8% vs. 24.8%, p < 0.001). Among the patients with intermediate-risk cytogenetics, we analyzed 63 cases in which allogeneic stem cell transplantation was performed at the first remission. Patients with ≥5% blasts in the bone marrow demonstrated a significantly worse prognosis in terms of both OS and RFS, while no significant difference was observed in cumulative incidence rates (CIR) (2-year CIR 12.8% vs. 23.8%, p = 0.575). Among patients who required two courses of induction therapy at first remission (n = 24), non-relapse mortality occurred frequently. Furthermore, multivariate analysis of factors affecting OS and RFS revealed that <5% blasts in bone marrow was an independent prognostic factor (HR 1.92 [1.49-2.48]) p < 0.001, HR 1.66 [1.24-2.23] p < 0.001 respectively). Conclusion As an early assessment of bone marrow following remission induction therapy, having <5% of blasts in the bone marrow on day 15 was linked to not only a short-term remission rate, but also to long-term prognosis in terms of OS and RFS. A strong link to prognosis was observed particularly among patients with intermediate-risk cytogenetics; the group with ≥5% blasts had significantly worse outcomes even after allogeneic transplantation in the first remission. No significant difference in CIR was observed between the two groups following allogeneic transplantation during the first remission, but the non-relapse mortality rate was suggested to yield a difference in prognosis. Disclosures Fujita: Chugai Pharmaceutical CO.,LTD.: Honoraria. Kiyoi:Novartis Pharma K.K.: Research Funding; JCR Pharmaceutlcals Co.,Ltd.: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Phizer Japan Inc.: Research Funding; Toyama Chemikal Co.,Ltd.: Research Funding; AlexionpharmaLLC.: Research Funding; Celgene Corporation: Consultancy; Nippon Shinyaku Co., Ltd.: Research Funding; Alexion Pharmaceuticals: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; MSD K.K.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Mochida Pharmaceutical Co., Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Eisai Co., Ltd.: Research Funding; Yakult Honsha Co.,Ltd.: Research Funding. Naoe:Amgen Astellas BioPharma K.K.: Honoraria; Fujifilm Corporation: Honoraria, Patents & Royalties, Research Funding; Sumitomo Dainippon Pharma Co.,Ltd.: Honoraria, Research Funding; TOYAMA CHEMICAL CO.,LTD.: Research Funding; Pfizer Inc.: Research Funding; CMIC Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Honoraria, Research Funding; Celgene K.K.: Honoraria, Research Funding; Chugai Pharmaceutical Co.,LTD.: Honoraria, Patents & Royalties; Bristol-Myers Squibb: Honoraria; Kyowa-Hakko Kirin Co.,Ltd.: Honoraria, Patents & Royalties, Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding.

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Addition of Vincristine and Irinotecan to Vincristine, Dactinomycin, and Cyclophosphamide Does Not Improve Outcome for Intermediate-Risk Rhabdomyosarcoma: A Report From the Children’s Oncology Group

Journal of Clinical Oncology ◽

10.1200/jco.2018.77.9694 ◽

2018 ◽

Vol 36 (27) ◽

pp. 2770-2777 ◽

Cited By ~ 42

Author(s):

Douglas S. Hawkins ◽

Yueh-Yun Chi ◽

James R. Anderson ◽

Jing Tian ◽

Carola A.S. Arndt ◽

...

Keyword(s):

Radiation Therapy ◽

Primary Study ◽

Hematologic Toxicity ◽

Intermediate Risk ◽

Event Free Survival ◽

Free Survival ◽

Α Level ◽

Cyclophosphamide Dose

Purpose Intermediate-risk rhabdomyosarcoma (RMS) includes patients with either nonmetastatic, unresected embryonal RMS (ERMS) with an unfavorable primary site or nonmetastatic alveolar RMS (ARMS). The primary aim of this study was to improve the outcome of patients with intermediate-risk RMS by substituting vincristine and irinotecan (VI) for half of vincristine, dactinomycin, and cyclophosphamide (VAC) courses. All patients received a lower dose of cyclophosphamide and earlier radiation therapy than in previous trials. Patients and Methods Patients were randomly assigned at study entry to either VAC (cumulative cyclophosphamide dose, 16.8 g/m2) or VAC/VI (cumulative cyclophosphamide dose, 8.4 g/m2) for 42 weeks of therapy. Radiation therapy started at week 4, with individualized local control plans permitted for patients younger than 24 months. The primary study end point was event-free survival (EFS). The study design had an 80% power (5% one-sided α-level) to detect an improved long-term EFS from 65% (with VAC) to 76% (with VAC/VI). Results A total of 448 eligible patients were enrolled in the study. At a median follow-up of 4.8 years, the 4-year EFS was 63% with VAC and 59% with VAC/VI ( P = .51), and 4-year overall survival was 73% for VAC and 72% for VAC/VI ( P = .80). Within the ARMS and ERMS subgroups, no difference in outcome by treatment arm was found. Severe hematologic toxicity was less common with VAC/VI therapy. Conclusion The addition of VI to VAC did not improve EFS or OS for patients with intermediate-risk RMS. VAC/VI had less hematologic toxicity and a lower cumulative cyclophosphamide dose, making VAC/VI an alternative standard therapy for intermediate-risk RMS.

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Achieving Early Remission By Induction Therapy Predicts a Favorable Outcome in Patients with Acute Myeloid Leukemia and an Intermediate Risk Karyotype Undergoing Allogeneic Stem Cell Transplantation in First Complete Remission

Blood ◽

10.1182/blood.v124.21.2569.2569 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2569-2569

Author(s):

Philipp G. Hemmati ◽

Theis H. Terwey ◽

Il-Kang Na ◽

Philipp le Coutre ◽

Christian F. Jehn ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Stem Cell ◽

Complete Remission ◽

Stem Cell Transplantation ◽

Induction Therapy ◽

Myeloid Leukemia ◽

Intermediate Risk ◽

First Complete Remission ◽

Acute Myeloid

Abstract Purpose: Acute myeloid leukemia (AML) is a highly heterogeneous disease. In addition to patient-related factors (co-morbidities, age, physical performance) and disease-specific variables (genetic risk profile) response to treatment is an important prognostic factor. In particular, the rapid achievement of hematologic remission by induction therapy was shown to predict overall outcome irrespective of the type of post-remission therapy employed. Here, we specifically investigated the impact of achieving early remission (ER), i.e. absence of leukemic blasts in the bone marrow at the end of the first course of induction therapy, as compared to delayed remission (DR) on the outcome of patients with AML who underwent allogeneic stem cell transplantation (alloSCT) in first complete remission (CR1) at our center. Patients and Methods: We retrospectively analyzed 132 consecutive patients (ER: N=79, DR: N=53) with AML and an intermediate risk karyotype transplanted at our center between 1994 and 2013. Median age at alloSCT was 48 years. Before referral to transplantation, all patients were treated in a German multicenter AML trial. Patients aged <60 years were treated according to a double induction strategy, which consisted of one course of “7+3” followed by one course of high-dose cytarabine (HD-AraC) (3000 mg/m²). Patients aged ≥60 years were treated with a single course of “7+3”. In case of residual leukemic blasts, i.e. 5% or more in the bone marrow on day +16, first induction was followed by either one additional course of the same regimen or one course of HD-AraC (1000 mg/m2). Depending on the timing of alloSCT, one (N=78) or two (N=7) additional courses HD-AraC consolidation were given. For transplantation, myeloablative conditioning (MAC) (N=58) consisted of 12 Gy total body irradiation (TBI) and 120 mg/m2 cyclophosphamide (CY). Reduced-intensity conditioning (RIC) (N=74) consisted of fludarabine (FLU) 150 mg/m2, oral busulfan (BU) 8 mg/kg and anti-thymocyte globulin (ATG)(Fresenius®) 40 mg/kg. Transplants were from related (N=60) or unrelated (N=72) donors and were HLA-matched (10/10 antigens) (N=119) or HLA-mismatched (N=13) according to high-resolution molecular typing. Immunosuppression consisted of short course methotrexate (MTX) and cyclosporine in patients treated with MAC or cyclosporine and mycophenolate mofetil (MMF) in patients treated with RIC prior to alloSCT. Results: After a median follow-up of 56 (4-220) months for the surviving patients, 87 patients (66%) are alive and in CR. 26 patients (20%) relapsed after a median interval of 8 (1-133) months, whereas 19 patients (14%) died from NRM. Projected overall survival (OS) of the entire cohort after 1, 3, 5 and 10 years was 81%, 68%, 65%, and 61%. At the same time points the cumulative incidence of relapse (CI-R) or non-relapse mortality (CI-NRM) was 12%, 19%, 22%, and 22% or 13%, 13%, 13%, and 17%. In contrast to patients showing DR, patients achieving ER had a significantly higher 3-year OS and disease-free survival (DFS) of 76% versus 54% (p=0.03) and 76% versus 53% (p=0.03). Likewise, 3 years after alloSCT the CI-R was significantly lower in the ER subgroup as compared to patients achieving DR, i.e. 10% versus 35% (p=0.004). In contrast, NRM did not differ significantly between the ER and the DR subgroup. Multivariate analysis identified DR as an independent prognosticator for an inferior DFS (HR 3.37, p=0.002) and a higher CI-R (HR 3.55, p=0.002). Notably, there was no significant difference in OS, DFS, or CI-R between patients treated with MAC versus RIC in the ER or the DR subgroup. Conclusions: Taken together, these data indicate that rapid achievement of remission may predict a favorable outcome in patients with intermediate risk AML undergoing alloSCT in CR1. In turn, the adverse effect of DR may not be necessarily overcome by alloSCT. Disclosures No relevant conflicts of interest to declare.

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