Course Of Induction Treatment Research Articles

Efficacy and Safety of Venetoclax-Based Induction Therapy in Acute Myeloid Leukemia

The clinical data of 51 newly diagnosed patients ineligible for intensive therapy and patients with R/R AML treated in the Department of Hematology of Xijing Hospital from February 1, 2021 to April 30, 2022 were retrospectively analyzed. The incidence of complete remission (CR)/CR with incomplete hematological recovery (CRi), objective remission rate (ORR), minimal residual disease (MRD) status, advense events (AE), overall survival (OS) and progression-free survival (PFS) were analyzed. Among 51 patients, 32 patients were newly diagnosed patients unfit for intensive therapy, with a median age of 60 (29-88) years, and 19 patients were R/R patients, with a median age of 49 (22-92) years. The median cycles of VEN-based treatment in the two groups were both 2. The CR/CRi rates in the ND-AML and R/R-AML group after one course of induction treatment were 65.6% and 36.9%, respectively, and the ORR were 81.3% and 42.1%, respectively. The cumulative CR/CRi rates after 1-3 courses of VEN-based treatment were 71.9% and 47.4%, respectively. The MRD negativity rates of patients achieving CR/CRi were 69.6% and 33.3%, respectively. In the ND-AML and R/R-AML group, the median PFS were 8(5-11) and 3(1-5) months, and the median OS were 13 (6-20) and 5 (3-7) months, respectively. The median OS of patients achieving CR/CRi in both groups was significantly better than that of patients not achieving CR/CRi (13 months vs 4 months; OS not reached vs 4 months). During the first induction cycle, the incidence of grade 3 or higher granulocytopenia, anemia and thrombocytopenia was 96%, 90.2% and 84.3%, respectively. 30 patients (58.8%) had granulocytopenia with fever. The most common non-hematological AE was infection (12/51, 23.5%), followed by gastrointestinal symptoms (6/51, 11.8%). The VEN-based strategy has good treatment response and tolerance in newly diagnosed patients unfit for intensive therapy and R/R AML. The most common AEs are hematological toxicities and infection.

The Vitamin D Status in Children With Newly Diagnosed Acute Lymphoblastic Leukemia and Its Potential Impact on the Primary Symptoms of Leukemia and Course of Induction Treatment.

Vitamin D deficiency is ubiquitous within the population of children. A similar problem is recognized among pediatric patients with acute lymphoblastic leukemia. The purpose of this study was to analyze the prevalence of vitamin D deficiency and to investigate the connection between vitamin D status and the course of induction treatment of ALL. A cross-sectional study including 59 patients with newly diagnosed ALL from May 2017 until November 2020. Vitamin D deficiency was found in 39% of the patients. There were no seasonal differences in vitamin D status. Patients with optimal 25(OH)D concentration presented more profound thrombocytopenia (P=0.015) and required more frequent platelet transfusions (P=0.018). Good prognosis factors such as B phenotype and hyperdiploidy were also more frequent among children with higher 25(OH)D concentration (P=0.01 and 0.014, respectively). The study showed that patients with a higher serum concentration of 25(OH)D presented deeper thrombocytopenia and needed more frequent transfusions. Moreover, those patients showed higher rates of B-cell leukemia and hyperdiploid karyotype. We did not find any influence of the possible exposure to sunlight (defined as the season of the year on admission) on serum 25(OH)D concentration, which supports the argument for supplementing vitamin D all year round. Moreover, the supplementing of vitamin D seems to be safe and does not cause any renal complications connected to calcium and phosphorus imbalance as no correlation between their levels and 25(OH)D concentration was found.

Analysis of Gene Mutation Characteristics and Prognosis of Elderly Patients with Acute Myeloid Leukemia

To investigate the characteristics of gene mutation in elderly patients with acute myeloid leukemia (AML) and its effect on prognosis. The clinical and laboratorial characteristics of 54 AML patients (≥60 years old) in Department of Hematology, Tangdu Hospital were analyzed retrospectively during April 2016 to October 2019. Thirty-four AML/myelodysplastic syndrome/myeloproliferative neoplasm related mutant genes were detected by second-generation sequencing technology, and their clinical characteristics, treatment effect, and influence on prognosis were analyzed. All the patients received DAC+CAG induction treatment, after 1-2 couses of treatment, 36 cases (66.7%) achieved complete response, with a total effective rate of 75.9%, and the median survival time was 17 months. The most frequent mutant genes were TET2 (33.3%), CEBPA (31.5%), DNMT3A (18.5%), ASXL1 (16.7%), NRAS (14.8%), RUNX1 (14.8%), FLT3-ITD (12.9%), TP53 (12.9%), NPM1 (12.9%), and IDH2 (12.9%). Among 7 patients with TP53 mutation, 6 cases obtained complete response after 1-2 courses of induction treatment, but there was no statistically significant difference in the effect on prognosis. Patients with FLT3-ITD and NRAS mutations had shorter overall survival time compared with who had no mutation (P=0.47, P=0.48). Multivariate analysis showed that FLT3-ITD and NRAS mutations were poor prognostic factors. The incidence of TET2 gene mutation is high in elderly AML patients. AML patients with TET2 and TP53 mutations may benefit from Decitabine-based chemotherapy. However, patients with FLT3-ITD and NRAS mutations have a short survival time, and may have a poor prognosis.

Clinical features and treatment outcomes of pediatric Langerhans cell histiocytosis with macrophage activation syndrome-hemophagocytic lymphohistiocytosis

BackgroundLangerhans cell histiocytosis (LCH) is a rare myeloid neoplasm. A few LCH patients had Macrophage activation syndrome-hemophagocytic lymphohistiocytosis (MAS-HLH), a life-threatening, hyper-inflammatory syndrome. We retrospectively described the clinical-biological characteristics of a series of 28 pediatric LCH patients with MAS-HLH in a single center. We further analyzed the difference in treatment outcomes between second-line chemotherapy (cytarabine and cladribine) and targeted therapy (dabrafenib) for BRAF-V600E-positive patients.ResultsLCH patients with MAS-HLH were aged < 2 years, harbored high frequencies of risk organ, skin, or lymph nodes involvement, and most of them carried BRAF-V600E mutation in lesions (88.0%) or plasma (90.5%). Patients were firstly treated with the initial induction first-line therapy (vindesine-steroid combination), and most of them (26/28) failed to control the active MAS-HLH after one six-week course of induction treatment. Then they were shifted to second-line chemotherapy or targeted therapy dabrafenib. BRAF-V600E-mutant patients treated with dabrafenib had prompt resolution of MAS-HLH signs and symptoms with less toxicity than second-line chemotherapy. Moreover, the progression-free survival (PFS) rate for patients given dabrafenib was much higher than those treated with chemotherapy (4 year-PFS: 75% vs. 14.6%, P = 0.034).ConclusionsLCH patients with MAS-HLH harbored specific clinical-biology characteristics compared to the multisystem LCH without MAS-HLH. The BRAF inhibitor dabrafenib provides a promising treatment option for LCH with MAS-HLH.

P497 Early improvement in bowel wall thickness on transperineal ultrasonography predicts treatment success in active ulcerative colitis

Abstract Background Bowel ultrasonography is a non-invasive imaging tool that can repeatedly monitor the activity of ulcerative colitis (UC). This study aimed to determine whether early changes in bowel ultrasonographic findings could predict subsequent clinical response to induction treatment in patients with ulcerative colitis. Methods This single-center prospective study compared ultrasonographic findings with fecal calprotectin, and C-reactive protein (measured at baseline, week 1, and week 8) in predicting remission (patient-reported outcome-2 ≤ 1 with no rectal bleeding subscore) at week 8 in active UC patients who initiated the remission-induction treatments. Predictive factors were assessed using multivariate regression models and a receiver operating curve analysis. Results A total of 100 patients were analysed, of which 54 achieved remission at week 8. Baseline values of biomarkers, and ultrasonographic parameters were not predictive of remission. Bowel wall thickness and bowel wall flow at baseline and week 1 were also not sufficiently predictive. By contrast, changes from baseline to week 1 in bowel wall thickness in the rectum measured by transperineal ultrasonography was an independent predictor of remission by week 8 (adjusted odds ratio associated with 1 mm decrease: 1.90 (95% confidence interval 1.22–2.95)). Predictive value of changes in rectal bowel wall thickness remained high for clinical improvement even among patients who did not achieve remission in 1 week. Conclusion Improvement in rectal bowel wall thickness measured by transperineal ultrasonography at week 1 predicts treatment success and thus would help decision making during the early course of induction treatment in UC.

A Multicenter Nonrandom Clinical Study of Induction Regimen of FLAG-ID and Dae in the Treatment of Childhood De Novo Acute Myeloid Leukemia in South of China:the Early Report of Efficacy and Safety

Objective: Complete remission (CR) after induction chemotherapy was one of the important prognostic factors in the treatment of acute myeloid leukemia(AML). Intensive induction regimen have potential of increasing the CR rate, but also followed high risk of treatment related mortality (TRM). This multicenter nonrandom clinical study is to evaluate the early efficacy and safety of induction regimen of FLAG-IDA and DAE in the treatment of childhood de novo acute myeloid leukemia in south of China.Methods: Total of 135 newly diagnosed childhood AML patients come from 8 centers of south of China involved in the clinical study from November 2014 to January 2017.Eighty-three boys and 52 girls, median age 6 (1-14) year old were included. Patients with Down syndrome and acute promyelocytic leukemia were excluded. The median follow-up period was 12 (4 to 33) months till to June 2017.Thirty-seven patients (27.4%)had favorable cytogenetic karyotypes including t(8;21) and inv(16) but without FLT3-ITD, and c-KIT mutations. Sixty-one patients had unfavorable cytogenetic karyotypes including 11q23/MLL(non MLL-MLLT3) , FLT3-ITD, ASXL1 and c-KIT. Double FLAG-IDA courses(n=77) or DAE(3+5+10) followed DAE(3+5+8) course(n=58) by non random scheme admitted to patients for induction chemotherapy. The similarity of clinical data between two groups was analyzed by the chi square test. Complete remission (CR) rate, serious adverse event(SAE) and treatment related mortality (TRM) were studied by Log-Rank chi square test.Results:The FLAG-IDA and DAE group in gender, age, initial WBC count, morphological classification, risk classification,cytogenetics and molecular genes(favorable and unfavorable ) had no significant difference.The overall CR rates was 80.0% and 91.1% after 1st course and 2nd course respectively. CR rates of FLAG-IDA group is 83.1% and 96.1% after 1st and 2nd course.CR rates of DAE group is 75.8% and 84.5% after 1st course of DAE(3+5+10) and 2nd course of DAE(3+5+8).The remission rates of FLAG-IDA group was significantly superior than that of DAE group after 2 courses of induction treatment(P=0.03).The CR rates of patients with favorable cytogenetic karyotypes was significantly higher than patients with unfavorable cytogenetic karyotypes (100% vs 84.3%,P=0.012) after the first course. The SAE during induction chemotherapy included : 44 cases of sepsis (32.59%), 34 cases of invasive fungal disease (25.18%), 32 cases of abdominal infection (23.70%), 22 cases of severe pneumonia (16.30%),4 cases of heart failure (2.96%). Nine cases died (6.67% ) during induction chemotherapy.Moreover, the TRM in FLAG-IDA group were not different from DAE group in induction treatment.FLAG-IDA is an effective induction regimen with high CR rates after 2 courses of treatment and can be used as first line induction chemotherapy in childhood de novo acute myeloid leukemia in south of China. Severe infection and drug toxicity will be needed more strategies of prophylaxis and treatment. DisclosuresNo relevant conflicts of interest to declare.

Gene mutations in acute promyelocytic leukemia early death in patients treated with arsenic trioxide alone

APL patients have recurrent alterations in FLT3, WT1, NRAS and KRAS. Gene mutations have a strong potential for involvement in pathogenesis and may have potential effects on the clinical manifestations. Gene mutations may even be associated with early death (ED) in APL patients. However, there is little published information on mutations in APL patients and whether they are attributed to early death. In this study, we retrospectively analyzed the clinical data and gene mutations of 134 de novo APL patients. We detected the gene mutations by next-generation sequencing (NGS) to investigate the genetic predictors of early death in APL patients. According to the number of gene mutations per patient, the 134 APL patients were divided into three groups. All patients received arsenic trioxide (ATO) alone as induction therapy. The clinical data and gene mutations were compared and analyzed. A total of 134 APL patients were involved in the study. The clinical data of sex, WBC, PT, and DD, UA, and LDH level were significantly different between the three groups (P = 0.000, P = 0.000, P = 0.009, P = 0.020, P = 0.030, P = 0.001 and P = 0.014, respectively). Meanwhile, among them, the Sanz risk stratification and early death rate were significantly different (P = 0.001). The early death rate was 10.4%, and the median time to early death was 6.6days (range 2-15days). For the next-generation sequencing, a mean of 1.28 ± 1.06 mutations per patient was detected (range: 0-5). The univariate and the multivariate regression analysis showed that age > 50[HR = 1.666, CI (1.027-2.702), P = 0.039], high WBC count [HR = 4.702, CI (1.026-21.543), P = 0.046] and low ALB levels [HR = 4.547, CI (1.088-18.995), P = 0.038] were independent risk factors for early death in APL patients. Furthermore, Kaplan-Meier survival analysis, univariate analysis, and the multivariate regression analysis showed that patients with multiple gene mutations [HR = 2.258, CI (1.115-4.571), P = 0.024], KRAS [HR = 5.136, CI (1.356-19.455), P = 0.016] and/or GATA2 [HR = 4.070, CI (1.287-12.877), P = 0.017] have a significantly higher early death rate. The results of this investigation show that both molecular markers and clinical variables should be used as potential predictors for early death in APL patients. Our results suggested that age > 50, high WBC count, low ALB levels, and the presence of multiple gene mutations, KRAS and/or GATA2 at the time of diagnosis were independent risk factors for early death in APL patients. For these patients, clinicians should be more cautious during the course of induction treatment.

Quantitative changes in selected bacteria in the stool during the treatment of Crohn's disease

PurposeThe aim of this study was to determine quantitative changes in selected species of bacteria (Bacteroides fragilis, Lactobacillus fermentum, Lactobacillus rhamnosus, Serratia marcescens) in the stool of patients with Crohn's disease (CD) in the course of induction treatment with exclusive enteral nutrition (EEN) or anti-tumor necrosis factor alpha (Infliximab, IFX) vs. healthy controls (HC). Materials/methodsDNA was isolated from stool samples of CD (n = 122) and HC (n = 17), and quantitative real-time Polymerase Chain Reaction (qPCR) was applied. In both treatment groups, the first stool sample was taken before the start of treatment, and the second 4 weeks after its end: in EEN (n = 48; age (mean; SD) 13.35 ± 3.09 years) and IFX groups (n = 13; age (mean; SD) 13.09 ± 3.76 years). ResultsThe only species that showed a statistically significant difference between the two groups of patients before any therapeutic intervention was L. fermentum. Moreover, its number increased after completion of EEN and differed significantly when compared with the HC. In the IFX group the number of L. fermentum decreased during the therapy but was significantly higher than in the HC. The number of S. marcescens in the EEN group was significantly lower than in the controls both before and after EEN. ConclusionThe implemented treatment (EEN or IFX) modifies the microbiome in CD patients, but does not make it become the same as in HC.

Maintenance Therapy With Interleukin-2 for Childhood AML: Results of ELAM02 Phase III Randomized Trial.

Despite significant progress in the treatment of pediatric acute myeloblastic leukemia (AML), relapse remains the commonest cause of death. Randomized ELAM02 trial questioned if maintenance therapy with interleukin-2 (IL2), for 1 year, improves disease-free survival (DFS). Patients aged 0 to 18 years, with newly diagnosed AML (excluding patients with acute promyelocytic leukemia or down syndrome AML) were enrolled. They received 1 course of induction treatment (cytarabine and mitoxantrone) and 3 courses of consolidation treatment (high-dose cytarabine in courses 1 and 3). According to the cytogenetics risk, patients not undergoing hematopoietic stem cell transplantation, still in complete remission (CR) after the third course of consolidation treatment, were eligible for randomization to 1 year of maintenance therapy with monthly courses of IL2 or no maintenance treatment. There were 438 evaluable patients, 154 of whom were randomized to the IL2/no maintenance groups. Relapse occurred in 28 patients from the IL2+ group and 29 patients in the IL2- group. Survival was similar in the 2 groups, with a 4-year DFS of 62% without IL2 and 66% with IL2 (P = 0.75). In the CBF population, 4-year DFS was 55% without IL2 and 78% with IL2 (P = 0.07). No deaths from toxicity or excess of serious adverse events related to IL2 treatment were recorded. Prolonged IL2 for maintenance therapy after intensive chemotherapy is feasible and safe in pediatric AML patients in their first CR. Such treatment did not improve DFS in this study, but a positive trend was observed in favor of IL2 maintenance therapy among core binding factor acute myeloblastic leukemia.

A survey on hematology-oncology pediatric AIEOP centres: The challenge of posterior reversible encephalopathy syndrome.

Posterior reversible encephalopathy syndrome (PRES) is one of the most common neurological complications in hematology-oncology pediatric patients. Despite an increasingly recognized occurrence, no clear consensus exists regarding how best to manage the syndrome, because most cases of PRES have reported in single-case reports or small series. Aim of this paper is to identify incidence, clinical features, management, and outcome of PRES in a large series of hematology-oncology pediatric patients. The cases of PRES occurred in twelve centers of the Italian Association of Pediatric Hematology and Oncology were reported. One hundred and twenty-four cases of PRES in 112 pediatric patients were recorded with an incidence of 2.1% and 4.7%, respectively, in acute lymphoblastic leukemia in first complete remission and hematopoietic stem cell transplantation (HSCT). The majority of cases occurred after a cycle of chemotherapy rather than after stem cell transplant. PRES after chemotherapy significantly differs from that after HSCT for diagnosis, time of presentation, risk factors, management, and outcome. This study demonstrates that PRES is a common neurological complication and occurring preferentially in course of induction treatment of some hematologic malignancies, as ALL and after HSCT. It also highlights great clinical differences in the management and outcome in patients with PRES occurring after chemotherapy or after HSCT.

Analysis of the safety and efficacy of 60 mg·m-2·d-1daunorubicin combined with standard dose of cytarabine as induction therapy in acute myeloid leukemia patients under 65 years old

目的观察60 mg·m−2·d−1柔红霉素(DNR)联合标准剂量阿糖胞苷(DA)方案诱导治疗≤ 65岁初治急性髓系白血病(AML)的长期疗效和安全性。方法回顾性分析116例2012年7月至2016年2月接受基于DNR 60 mg·m−2·d−1的DA诱导方案治疗且≤65岁初治非急性早幼粒细胞白血病的AML患者的临床资料，包括治疗后完全缓解(CR)率、总生存(OS)时间、无病生存(DFS)时间以及近期和远期的不良反应。结果116例患者中，DA方案诱导治疗1个疗程后CR 78例(67.2%)，≤2个疗程CR共94例(81.0%)。第1疗程诱导治疗中仅3例(2.6%)发生早期死亡。有1例患者在诱导化疗后6个月时发现无症状性心脏射血分数减低。89例患者接受了1~4个疗程巩固治疗。在中位随访24(1~46)个月后，中位DFS时间为25个月，中位OS时间未到达。Cox多因素分析显示，遗传学危险分层是影响DFS的独立预后因素(HR=0.258, 95% CI 0.100~0.664，P=0.005)，遗传学危险分层(HR=0.309, 95% CI 0.126~0.756，P=0.010)以及是否接受大于1个疗程大剂量阿糖胞苷巩固治疗(HR=0.370, 95% CI 0.179~0.765，P=0.007)是影响OS的独立预后因素。结论含DNR 60 mg·m−2·d−1的DA方案诱导治疗≤65岁初治AML患者可获得较高CR率，且不良反应无明显增加。

Effect observation of low-dose idarubicin or reduced homoharringtonine combined with cytarabine for the treatment of de novo patients with acute myeloid leukemia

Objective To compare the efficacy and adverse effects of low-dose idarubicin (IDA) or low-dose homoharringtonine (HHT) combined with cytarabine (Ara-C) for the treatment of de novo patients with acute myeloid leukemia (AML). Methods De novo AML patients (except for the acute promyelocytic leukemia) treated with low-dose IDA combined with Ara-C (low-dose IA group) or low-dose HHT combined with Ara-C (low-dose HA group) as initial induction from 1st, January, 2013 to 30th, June, 2015 were retrospectively analyzed, and their efficacy and adverse reactions were compared. Results 46 of 67 patients in the low-dose IA group reached complete remission (CR), meanwhile there were 8 of 20 patients in the low-dose HA group reached CR after two courses of induction treatment. The CR rate of IA regimen was 68.7 % , which was significantly higher than that of HA regimen (40.0 %) (χ2= 5.372, P= 0.020). The overall response rates of low-dose IA group and HA group were 77.6 % (52/67) and 60.0 % (12/20) respectively, and there was no significant difference between the two groups (P > 0.05). Both the hematological and non-hematological adverse effects were observed and no difference was found in the two groups, neither in myelosuppression,the major hematological adverse effects, nor in non-hematological adverse effects (all P > 0.05), except for the median duration of absolute neutrophil count < 1×109/L (Z=-3.023, P= 0.003). Conclusion With more serious adverse effects, the CR rate after two induction chemotherapy courses of low-dose IA regimen is higher than that of low-dose HA regimen in de novo AML patients. Key words: Leukemia, myeloid, acute; Idarubicin; Homoharringtonine; Cytarabine

Primary Plasma Cell Leukemia: Identity Card 2016.

Primary plasma cell leukemia (PPCL) is an aggressive and rare variant of multiple myeloma (MM), characterized by peculiar adverse clinical and biological features. Though the poor outcome of PPCL has been slightly improved by novel treatments during the last 10 years, due to the limited number of available studies in this uncommon disease, optimal therapy remains a classic unmet clinical need. Anyway, in the real-life practice, induction with a bortezomib-based three-drug combination, including dexamethasone and, possibly, lenalidomide, or, alternatively, thalidomide, cyclophosphamide, or doxorubicin, is a reasonable first-line option. This approach may be particularly advisable for patients with adverse cytogenetics, hyperleucocytosis, and rapidly progressive disease, in whom a fast response is required, or for those with suboptimal renal function, where, however, lenalidomide should be used with caution until renal activity is restored. In younger subjects, leukemia/lymphoma-like more intensive regimens, including hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone or continue-infusion cisplatin, doxorubicin, cyclophosphamide, and etoposide, may be also combined with bortezomib +/- thalidomide. Treatment must be started immediately after a diagnosis of PPCL is made to avoid the risk of irreversible disease complications and, in such a context, the prevention of tumor lysis syndrome is mandatory. In patients eligible for autologous stem cell transplantation (AuSCT), other alkylating agents, in particular melphalan, should be initially avoided in order to allow adequate collections of CD34+ peripheral blood stem cells (PBSC). A combination of lenalidomide and dexamethasone may be a valuable alternative option to manage older or unfit patients or those with slower disease evolution or with signs of neuropathy, contraindicating the use of bortezomib. Patients not suitable for transplant procedures should continue the treatment, if a response occurs and if tolerated, considering the possibility of a prolonged maintenance therapy. AuSCT should be pursued in all eligible patients less than 65 years old who achieve a significant response after a short course of induction treatment. PBSC collection should reach a threshold of at least 5 × 10(6) CD34+ PBSC/kg using cyclophosphamide plus G-CSF and adding the mobilizing agent plerixafor, if necessary. High-dose melphalan (HDM) (200 or 140 mg/m(2), according to age and renal function) remains the preferable conditioning regimen. A second AuSCT should be always considered, even in patients achieving complete response (CR) after the first AuSCT, as the short progression-free survival (PFS) generally seen in PPCL suggests the persistence of a relevant burden of residual disease; this provides a strong rationale for the use of post-transplantation therapies in PPCL to improve depth of response, to maintain remission, and, possibly, to increase survival, though consolidation and/or maintenance strategies with novel agents, whose efficacy has been well demonstrated in MM, have not been still extensively evaluated in PPCL. The search of a suitable donor should start as soon as possible and an allogeneic stem cell transplant (AlloSCT) with a myeloablative conditioning (MAC) regimen discussed with younger patients responsive to induction therapy and with poor prognostic parameters at diagnosis. A sequence of AuSCT followed by reduced intensity conditioning (RIC) or non-myeloablative (NMA) AlloSCT may be considered in selected cases. Salvage therapies for relapsed/refractory disease, especially using new drugs not employed at diagnosis, are sometimes effective in the short term, but a rapid relapse is still generally the rule; AlloSCT in relapsed and eligible patients with sensitive disease after salvage treatments is, therefore, recommended.

Treatment of Ph-adult acute lymphoblastic leukemia patients with Tongji-96 regimen

目的探讨Ph染色体阴性成人急性淋巴细胞白血病（Ph−aALL）的系统序贯治疗方案（同济96方案）的疗效。方法回顾性分析2004年1月至2012年12月收治的95例初治Ph−aALL患者的临床资料，并随访生存期。结果95例Ph−aALL患者总的完全缓解（CR）率为92.6%，7年总体生存(OS）率为（39.3±5.9)%，7年无事件生存（EFS）率为（31.5±5.3) %，中位生存期28个月；多因素COX比例风险回归模型分析，预后差核型组患者的死亡风险是预后良好组的3.380倍（95%CI 1.530~7.463，P=0.003)，≥2个疗程获得CR者是单疗程获得CR者的3.005倍（95%CI 1.522~5.933，P=0.002)；Kaplan-Meier法及Log-rank检验分析，<60岁患者的7年OS率和EFS率明显高于≥60岁患者；单疗程获得CR者的7年OS率和EFS率明显高于≥2个疗程获得CR者；正常核型组和超二倍体核型组患者的2年OS率和EFS率明显高于复杂核型组、t(4; 11)组和其他核型组。结论年龄（60岁为界点）、获得CR的疗程数和细胞遗传学成为影响Ph−aALL患者生存的相关因素。同济96方案系统序贯治疗Ph−aALL, CR率达到发达国家水平，远期疗效令人满意，可以实现部分Ph−aALL患者的长期生存，减少其复发，改善预后。

Prognostic significance of interim PET/CT based on visual, SUV-based, and MTV-based assessment in the treatment of peripheral T-cell lymphoma.

BackgroundsThe role of interim PET/CT in peripheral T-cell lymphoma (PTCL) is less identified compared to other subtype of lymphoma. This study prospectively investigated the prognostic accuracy of sequential interim PET/CT using visual and quantitative assessment to determine whether it provided prognostic information for the treatment of PTCL.MethodsSixty-three patients with newly diagnosed PTCL were enrolled, and 59 patients underwent interim PET/CT after three or four courses of induction treatment. The response of interim PET/CT was assessed by three parameters: the Deauville five-point scale (5-PS), ΔSUVmax, and ΔMTV2.5.ResultsOver a median follow up of 40.3 months, each assessment of interim PET/CT using the 5-PS, ΔSUVmax, and ΔMTV2.5 had predictive value for progression-free survival. To increase the predictive accuracy of interim PET/CT, we divided patients into three groups according to the sum of scores for three adverse responses based on the visual, SUV-based and MTV-based assessment: favorable, intermediate, and poor responder. The clinical outcome of patients in the favorable group was significantly superior to patients in the poor or intermediate group.ConclusionVisual, quantitative SUV-based, and MTV-based assessment in interim PET/CT are valuable for early treatment response assessment in patients with PTCL, and the combined approach using the three parameters was more efficient in discriminating between patients with different survival outcomes compared with single-parameter assessment.Trial registrationNCT01470066.

Utility Of D-Dimer As a Marker For Differentiation Syndrome and Infections In Acute Promyelocytic Leukemia (APL)

BackgroundAcute Promyelocytic Leukemia is a highly curable malignancy with cure rates of greater than 90% in most co-operative group trials. However, population based studies indicate that the survival is much lower with up to 30% early deaths. The most common causes of early deaths are bleeding, differentiation syndrome and infection. Early identification and management of these three complications is essential if the outcomes are to be improved further. Bleeding in APL is secondary to disseminated intravascular coagulation (DIC) a peculiar complication of the disease and coagulation panel including d-dimer, fibrinogen levels, prothrombin time, activated partial thromboplastin time are commonly used as markers of DIC. There are presently no available tests to identify DS or infection early and are entirely clinical diagnoses. Here we report the importance of d-dimer levels as probable markers of DS or infection during induction treatment for APL. MethodsWe performed a retrospective chart review on forty one patients diagnosed with Acute Promyelocytic Leukemia and treated with ATRA from September 2005 – June 2013 from Georgia Regents University and those referred here from surrounding treatment centers. Data obtained included D-Dimer levels at diagnosis, daily d-dimer levels when available, dates of differentiation syndrome from start of treatment and dates of infectious complications when available which was obtained from progress notes and microbiology lab and radiology reports. Results41 consecutive APL patients were evaluated for this study. One patient refused treatment and 15 patients did not have coagulation labs (specifically d-dimer) done throughout the course of induction treatment and had to be excluded. Age range of all the patients treated was 21-75 years. There were seven deaths overall and 21 patients had some evidence of DS. The diagnosis of DS was made clinically as per standard guidelines. We included 25 patients in whom there were d-dimer levels done throughout the hospitalization in this study. In these 25 patients, all had an increase in d-dimer levels after an initial drop as the DIC is corrected. 6 patients did not have any complications. In 4 patients the rise in d-dimer was followed by infectious complications. In the other 15 patients, their hospitalization was complicated by DS. In these 15 patients, 6 had elevation in d-dimer prior (0-5 days) to development of DS. In 3 patients the DS developed followed shortly by an elevation in d-dimer. The correlation between d-dimer elevation and DS could not be clearly ascertained from the available documentation in the other 6 patients. ConclusionsAPL is a curable malignancy but early deaths leads to poor outcomes outside of clinical trials. Early identification of the complications of the disease and treatment will allow us to further improve the outcomes in the community. D-dimer is an acute phase reactant and is elevated in any inflammatory state. From our data, the elevation in d-dimers following an initial decrease after correction of coagulopathy secondary to DIC might be marker of differentiation syndrome and or infection. These two conditions are pro-inflammatory states and might explain the increase in d-dimers observed. A larger scale validation is essential to confirm this observation which then might lead to more prompt identification of the complications and ultimately improved outcomes. Disclosures:No relevant conflicts of interest to declare.

Lenalidomide and Low Dose Dexamethasone As First Line Therapy for Newly Diagnosed Patients with Primary Plasma Cell Leukemia

AbstractAbstract 729 Introduction:The prognosis of primary plasma cell leukemia (PPCL) remains poor. The “novel agents” have recently shown promising results in PPCL patients in case reports or small retrospective series. Here we describe the first prospective, multicenter, phase II clinical trial of PPCL, where lenalidomide in combination with low dose dexamethasone (Ld) was tested as initial therapy in newly diagnosed patients fulfilling the IMWG diagnostic criteria of PPCL. Patients and methods:Ld regimen consisted of lenalidomide 25 mg/d for 21 days and oral dexamethasone 40 mg on days 1, 8, 15, and 22 for each 28-day cycle. After 4 cycles, responding patients not eligible for stem cell transplantation (SCT) continued until 8 cycles of full-dose Ld, followed by a maintenance dose of single agent lenalidomide equal to 10 mg/d on days 1–21 of each 28-day cycle. Patients responding after 4 cycles and eligible for SCT proceeded according to the treatment centre’s transplant policy. Patients not responding after 4 cycles or progressing during this treatment were considered off-study. Appropriate dose reductions (in particular for patients with reduced renal function at baseline), double contraception methods and anti-thrombotic/anti-infective prophylaxis were recommended. The primary end-point was early response rate according to IMWG uniform response criteria. Secondary end-points were PFS, OS, feasibility and efficacy of SCT, safety. Results:According to the Simon optimal two-stage adaptive design, twenty-three patients were enrolled in between March 2009 and May 2011. The male/female ratio was 1.1, and median age was 60 years (range 44–80). The median absolute number and percentage of circulating plasma cells were 4.280/μl (range 1.500–114.660) and 34% (range 21–90) respectively. Fifteen patients (65.2%) had abnormal renal function at presentation. Twenty-one patients (91.3%) were tested by FISH analysis and cytogenetic abnormalities were detected in all of them, del13q being the most frequently found (16 patients). Seventeen patients showed multiple chromosomal lesions. Involvement of chromosome 14 was observed in 18 patients, three of whom showed t(4;14). Chromosome 1q gain and del17p were detected in 10 and 7 patients, respectively. In the intention-to-treat (ITT) population, overall response rate (ORR) after at least one Ld cycle was 73.9% (17/23), with 8 patients (34.7%) achieving partial remission (PR), 5 (21.7%) very good PR (VGPR), 3 (13%) complete response (CR), and 1(4.3%) near CR (nCR) (VGPR or better: 39%). In the efficacy-evaluable (EE) population, 14 out of 15 patients who received the initially planned 4 Ld cycles (65.2% of the ITT population) responded (ORR 93.3%), achieving 5 PR (33.3%), 5 VGPR (33.3%), 1 near-CR (6.6%) and 3 CR (20%) (VGPR or better: 59.9%). The maintenance phase was reached and safely performed in 4 responding patients not eligible for SCT, 3 of whom relapsed after 2, 8 and 22 months, respectively. After Ld induction therapy, 8 patients received single (n. 4) or double (n. 4) autologous SCT (ASCT); another patient underwent a sequence of ASCT followed by non-myeloablative allogeneic SCT (AlloSCT). Six eligible patients did not receive ASCT frontline, due to initial Ld failure or adverse events; three of them underwent single ASCT (n. 2) or tandem ASCT/non-myeloablative AlloSCT (n. 1) after a bortezomib-based salvage therapy, achieving 2 CR and 1 PR. After a median follow-up of 23 months, median OS and PFS in ITT population were not reached and 22 months, respectively. All transplanted patients remained alive, although three of them relapsed and started salvage treatments; OS was 12 months in the 11 patients who did not receive ASCT (p < 0.001). The correspondent figures for PFS were 29 and 16 months, respectively (p < 0.01). Considering ITT population, multivariate analyses showed that SCT was positively correlated to both OS and PFS. There were 17 episodes of grade 3/4 non hematological toxicity, which occurred in 13 patients (5 infections, 3 renal, 3 metabolic, 2 gastro-intestinal, 2 skin, 1 fatigue, 1 thromboembolic), causing early interruption of Ld treatment in 4 patients. Grade 3/4 hematological toxicity (mainly neutropenia) occurred in 11 patients (47.8%). Conclusions:Ld may be a feasible and effective initial therapeutic option for PPCL, particularly in patients who receive ASCT after a short course of induction treatment. Disclosures:Musto:Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide as first line therapy of plasma cell leukemia. Petrucci:Celgene: Honoraria. Cascavilla:Celgene: Honoraria. Di Raimondo:Celgene: Honoraria. Caravita:Celgene: Honoraria. Morabito:Celgene: Honoraria. Offidani:Celgene: Honoraria. Bringhen:Celgene: Honoraria. Boccadoro:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Palumbo:Celgene: Consultancy, Honoraria.

Comparison of Autologous Hematopoietic Cell Transplantation and Chemotherapy as Postremission Treatment in Non-M3 Acute Myeloid Leukemia in First Complete Remission

Randomized trials of acute myeloid leukemia (AML) in first complete remission (CR1) showed that autologous hematopoietic cell transplantation (auto-HCT) improves relapse-free survival (RFS) but not overall survival (OS), compared with chemotherapy. Using a database of 2518 adult patients with AML in CR1, we conducted a 5-month landmark analysis and found that auto-HCT improves 3-year RFS but not OS compared with chemotherapy. A number of randomized trials in patients with AML in CR1 have been conducted and they showed that auto-HCT improves RFS but not OS, compared with chemotherapy. However, because these trials have had compliance problems, the value of auto-HCT still has not been clearly established. Using a database of 2518 adult patients with AML in CR1, we retrospectively analyzed the outcome of auto-HCT and compared it with intensive nonmyeloablative chemotherapy using landmark analyses. In 103 auto-HCT recipients, OS and RFS at 3 years from treatment were 65% and 57%, respectively. Multivariate analysis showed that unfavorable risk cytogenetics and entry into CR1 after 2 courses of induction treatment predicted a poor outcome. Because the median time interval between CR1 and auto-HCT was 153 days, landmark analyses at 5 months after CR1 were performed to compare 1290 patients who received chemotherapy alone (median age, 52 years; range, 16-70) with 103 who received auto-HCT (median age, 48 years; range, 16-67). Auto-HCT improves 3-year RFS (58% vs. 37%; P < .001) but not OS compared with chemotherapy alone. Among patients with unfavorable risk cytogenetics or those who required 2 courses to reach CR1, there was no significant difference in RFS between the 2 groups. Auto-HCT can be considered as a postremission therapy for AML patients with favorable or intermediate risk cytogenetics who achieve CR1 after a single course of induction treatment.

Final Results of a Phase II Study Evaluating Lenalidomide in Combination with Low Dose Dexamethasone As First Line Therapy for Primary Plasma Cell Leukemia

Abstract 2925Primary plasma cell leukemia (PPCL) is an aggressive variant of multiple myeloma, accounting for 0.5–4% of all newly diagnosed myeloma cases and characterized by a short survival (generally less than 1 year), which is only moderately improved by transplant procedures. Novel agents seem to be able to ameliorate the poor clinical outcome of both primary and secondary leukemic phases of myeloma; however, no data are currently available on the use of lenalidomide as first line therapy in PPCL.On March, 2009, we started a multicenter, phase II trial aiming to evaluate safety and antitumor activity of lenalidomide in combination with dexamethasone (LD) in previously untreated PPCL. Here we report the final results of this study. Newly diagnosed PPCL patients received lenalidomide at a dose of 25 mg/d for 21 days and oral dexamethasone at a dose of 40 mg on days 1, 8, 15, and 22 for each 28-day cycle. After 4 cycles, responding patients not eligible for stem cell transplantation (SCT) continued until 8 cycles of full-dose LD, if tolerated, followed by a maintenance dose of single agent lenalidomide equal to 10 mg/d on days 1–21 of each 28-day cycle. Patients responding after 4 cycles and eligible for SCT proceeded according to single Centre transplant policy. Patients not responding after 4 cycles or progressing during this treatment were considered off-study. The primary endpoint was early response rate according to International Uniform Criteria. The secondary endpoints were PFS, OS, safety and percentage of eligible patients able to undergo autologous or allogeneic SCT. Appropriate dose reductions, contraception methods and anti-thrombotic prophylaxis were applied.Twenty-three patients, as requested by the Simon Optimal Two-Stage Adaptive Design adopted, were enrolled. The trial was therefore closed on May, 31, 2011. M/F ratio was 0.7, mean age was 62 years (range 44–80). Circulating plasma cells ranged from 2.1 to 115 × 10e9/l. Moderate renal failure, increased LDH and extramedullary disease occurred in 39.1%, 43.5% and 13 % of patients, respectively. Hb was < 10 g/dl in 19 patients (82.6%), while platelet count was < 50 × 10e9/l in 5 patients (21.7%). Karyotype abnormalities were detected by FISH in 21 out of 22 tested patients; in particular, 1p loss was found in 9 patients, 1q gain in 10 patients, del(13q) in 16 patients, del(17p13) in 7 patients, t(11;14) in 7 patients, t(4;14) in 3 patients and MAF translocations, including t(14;20) and t(14;16), in 8 patients. Seventeen patients had a combination of two (n. 5) or more (n. 12) cytogenetic lesions.On intention-to-treat analysis, 14 patients completed the initial four planned cycles and all of them responded. In particular, 6 PR (26.1%), 4 VGPR (17.4%), 1 near-CR (4.3%) and 3 CR (13%) were achieved (ORR 60.8%, VGPR or better 34.7%). Causes of early treatment discontinuation were: a) progressive disease (4 patients, after an initial, brief response in 2 cases); b) severe adverse events (4 patients: one acute renal failure, one Stevens-Johnson’s syndrome, one pneumonia suspected for Pneumocystis carinii etiology, one multi-organ failure); c) death in PR due to causes unrelated to treatment or disease (one patient). Other relevant non-hematological toxicities included four episodes of pneumonia and one case of DVT. Grade 3–4 hematological toxicities occurred in about half of cases, requiring Lenalidomide dose adjustments. So far, among subjects achieving a response after 4 LD cycles, 8 eligible patients have successfully collected peripheral blood stem cells: 5 of them have completed single or double autologous SCT, one patient received tandem autologous-allogeneic non myeloablative SCT from a MUD donor. All patients transplanted after LD are currently alive and in remission phase. The maintenance phase has been reached in 3 responding patients not eligible for SCT, 2 of whom have relapsed after 2 and 8 months, respectively. With a mean follow-up of 15 months, OS and PFS are 65.2% and 52.1%, respectively.LD is a possible initial therapeutic option for PPCL, particularly in patients who receive SCT after a short course of induction treatment. Caution is required to prevent and to manage renal and hematological toxicities, as well as infectious complications. Considering some previous results obtained with other novel agents, the combination of lenalidomide and bortezomib might be an appealing approach to investigate prospectively in PPCL patients. Disclosures:Musto:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Petrucci:Celgene: Honoraria. Cascavilla:Celgene: Honoraria. Di Raimondo:Celgene: Honoraria. Caravita:Celgene: Honoraria. Morabito:Celgene: Honoraria. Offidani:Celgene: Honoraria. Bringhen:Celgene: Honoraria. Boccadoro:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Palumbo:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Induction Therapy by Ara-C Plus Daunorubicin Versus Ara-C Plus Gemtuzumab Ozogamicin: Interim Analysis of a Randomized Phase II Trial of the SAL In Elderly Patients with Acute Myeloid Leukemia

AbstractAbstract 335 Purpose.Standard chemotherapy for elderly patients with acute myeloid leukemia (AML) results in a median overall survival of only </= 1 year. Considerable numbers of elderly patients with AML present with cardiac comorbidity rendering the use of daunorubicin (DNR) containing chemotherapy regimens hazardous. Gemtuzumab ozogamicin (GO) is active in elderly (=/> 60 years) patients with relapsed AML and shows low cardiac toxicity. The purpose of the randomized phase II study reported here was to compare the antileukemic activity of a standard combination of ara-C (100 mg/m2/day c.i., days 1–7) and DNR (60 mg/m2 i.v., on days 3–5) (7+3) versus ara-C plus GO (6 mg/m2 i.v. on days 1 and 8) (7+GO) as the first course of induction therapy in AML patients at the age of 60 years and older. Patients and Methods.On the basis of the data from the AMLCG (JCO 27: 61–69, 2009) the study was powered to detect an increase of median event free survival (EFS) from 90 to 160 days and a prolongation of the median overall survival (OS) from 9 to >16 months with a power of 80% (alpha= .05), in order to obtain information as a basis for potential further phase III randomized studies. Primary objectives of the study were the achievement of blast clearance (< 5%) on day 16 after induction therapy onset and EFS. OS, complete response (CR) and tolerability were among the secondary objectives. 112 pts. entered the study, suffering from de novo AML, treatment-related secondary AML, AML with a history of MDS, and high-risk MDS. Median age of the patients was 69 years (range 60–83). Study protocol outlined a second induction course 7+3 in those pts. without blast clearance on day 16 and 2 courses of consolidation therapy with high-dose ara-C (1 g/m2 q 12 hours i.v., days 1, 3, 5) for patients in CR. We looked for balance of AML standard risk factors between both arms of the study. Results.The study was approved by the Ethical Board of the University of Muenster and the other participating institutions and written informed consent was obligatory by every pt. prior to entry on study. 58 pts. were randomized to induction therapy with 7+3 as the first course, whereas 54 pts. were randomized to receive 7+GO. All parameters evaluated are for the intent-to-treat population. There were no statistically significant differences between treatment arms in blast clearance (< 5%) on day 16 after treatment onset (7+3: 18 pts., 7+GO: 19 pts.), complete response (CR) rate (7+3: 53.5%, 7+GO: 61.1%), EFS (median for 7+3: 67 days, median for 7+GO: 172 days), or OS (median for 7+3: 9 months, median for 7+GO: 15 months). Toxicity profiles of the protocols were different with 4 pts. developing severe veno-occlusive disease in the 7+GO group. Conclusion.The study did not show a significant advantage of 7+GO over 7+3 as the first course of induction treatment in elderly pts. with AML. Ara-C and GO and ara-C and DNR have comparable antileukemic activity as the first course of induction. Ara-C and GO may represent an alternative, replacing non-targeted anthracyclines for induction therapy of elderly AML patients e.g. with significant cardiac comorbidities. Disclosures:Berdel:Wyeth: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Mylotarg as first-line treatment in AML.