Intensive Chemotherapy Group Research Articles

Higher average chemotherapy dose intensity improves prognosis in patients with aggressive adult T‐cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T-cell lymphoma with poor prognosis. We retrospectively reviewed the medical records of 312 patients with aggressive ATL and analyzed the effect of chemotherapy dose intensity on prognosis in clinical practice. As first-line therapy, 62 patients underwent best supportive care (BSC) or single-agent chemotherapy, and 235 underwent intensive chemotherapy. The median survival time (MST) was 0.58years in the 312 total patients, and 0.13years and 0.75years in the BSC/single-agent chemotherapy group and intensive chemotherapy group, respectively. The median average relative dose intensity (ARDI) of patients who received intensive chemotherapy was 60%. We divided patients into 3 groups according to ARDI. Those in the top tertile of ARDI (ARDI≥75%, n=82) had better overall survival compared with those in the intermediate tertile (45%≤ARDI<75%, n=79) (P<.0001), with MSTs of 4.69 and 0.75years, respectively. The occurrence of organ dysfunction and infectious complications was comparable between the two ARDI groups. Higher ARDI improves prognosis in patients with aggressive ATL in clinical practice.

Ten-Day Decitabine with Venetoclax Versus Intensive Chemotherapy in Relapsed or Refractory Acute Myeloid Leukemia: A Propensity Score Matched Analysis

Ten-Day Decitabine with Venetoclax Versus Intensive Chemotherapy in Relapsed or Refractory Acute Myeloid Leukemia: A Propensity Score Matched Analysis

CD34+CD38-CD123+ Leukemic Stem Cell Frequency Predicts Outcome in Older Acute Myeloid Leukemia Patients Treated by Intensive Chemotherapy but Not Hypomethylating Agents.

The prognostic impact of immunophenotypic CD34+CD38−CD123+ leukemic stem cell (iLSC) frequency at diagnosis has been demonstrated in younger patients treated by intensive chemotherapy, however, this is less clear in older patients. Furthermore, the impact of iLSC in patients treated by hypomethylating agents is unknown. In this single-center study, we prospectively assessed the CD34+CD38−CD123+ iLSC frequency at diagnosis in acute myeloid leukemia (AML) patients aged 60 years or older. In a cohort of 444 patients, the median percentage of iLSC at diagnosis was 4.3%. Significant differences were found between treatment groups with a lower median in the intensive chemotherapy group (0.6%) compared to hypomethylating agents (8.0%) or supportive care (11.1%) (p <0.0001). In the intensive chemotherapy group, the median overall survival was 34.5 months in patients with iLSC ≤0.10% and 14.6 months in patients with >0.10% (p = 0.031). In the multivariate analyses of this group, iLSC frequency was significantly and independently associated with the incidence of relapse, event-free, relapse-free, and overall survival. However, iLSC frequency had no prognostic impact on patients treated by hypomethylating agents. Thus, the iLSC frequency at diagnosis is an independent prognostic factor in older acute myeloid patients treated by intensive chemotherapy but not hypomethylating agents.

Validation of SIE, Sies, GITMO Operational Criteria for the Definition of Fitness in Elderly Patients Affected with Acute Myeloid Leukemia: A Six-Years Retrospective Real-Life Experience

Introduction:Acute Myeloid Leukemia (AML) predominantly affects the older population, with a median age at diagnosis of 67 years (yrs). In the last decades, Overall Survival (OS) has not changed meaningfully for these patients (pts). This worse outcome is explained by the poor-risk biological profile of the disease but also by the scarce propensity in administering curative treatments in this age category. Despite this general attitude, there is consensus that age alone should not be representative of the functional profile of older pts and that making decisions based on the sole age parameter can compromise possible therapeutic attempts. Therefore, a panel of experts from SIE (Italian Society of Hematology),SIES (Italian Society of Experimental Hematology) and GITMO (Italian Group for Bone Marrow Transplantation) summarized a list of operational criteria to be used in the process of treatment allocation, identifying 3 fitness categories of patients to address to differentiated strategies: 1)Fit pts (FP), eligible to intensive chemotherapy (IC) with the aim to achieve complete remission (CR); 2)Unfit pts (UP), eligible to non-intensive chemotherapy (NIC) with the aim to prolong survival; 3)Frail pts (FP) for whom, since the natural course of disease cannot be altered, supportive therapy (ST) is the best option in the attempt to preserve an acceptable quality of life (Ferrara et. al, Leukemia 2013). Aim: We retrospectively applied the operational SIE, SIES, GITMO criteria to a series of 180 consecutive non-APL AML pts diagnosed at our institution from 2013 to 2018 to investigate (1) the degree of concordance between the "operational criteria derived categories" and the actual treatment received; (2) the impact of this evaluation on long-term OS. Methods: We analyzed 180 consecutive pts with AML (median age 66 yrs, range 21-91) diagnosed at our institution from January 2013 to December 2018. We mainly focused on 125 pts older than 60 yrs (median 70 yrs, range 61-91). For the purpose of comparison, 55 younger pts, submitted to IC (51/55, 93%), were also analyzed. Results: SIE, SIES, GITMO operational criteria were retrospectively applied through medical files backtracking. One-hundred-48 out of 181 pts were stratified according to ELN 2010 as follow: 24 (16%) low risk, 59 (40%) intermediate-I, 25 (17%) intermediate-II and 40 (27%) high risk. This risk stratification did not differ between younger and older pts, suggesting that risk distribution may not be always an age-related factor. Overall, according to physician choice, 98 pts were submitted to IC, 40 to NIC, 42 to ST (54%, 22%, 24%, respectively). When focusing on pts older than 60 yrs, 47/125 were submitted to IC, 39/125 to NIC, 39/125 to ST (38% vs. 31% vs. 31%, respectively). A high concordance between treatment actually given and the one derived from the application of the "operational criteria" (165/180, 92%) was observed. The highest concordance was observed for the association of ST with FrP (39/40, 98%), whereas the associations IC with FP (96/107, 90%) and NIC with UP (30/33, 91%) showed a lower level of concordance. Overall, by applying the "operational criteria" the 3 categories differed significantly in terms of OS: 15,3 mos (range 0,4-78) for FP, 8,6 mos (range 2,2-47,9) for UP and 1 mos (range 0,1-29,9) for FrP, respectively (p&lt;0.001). For pts older than 60 yrs, OS was 9,1 mos (range 0,4-78), 9,2 mos (range 2,2-47,9) and 1 mos (range 0,1-29,9) for FP, UP and FrP, respectively (p&lt;0.001) (Fig. 1A). According to the treatment actually received, OS of pts older than 60 yrs was 6,9 mos (range 0,4-78) for IC, 11.0 mos (range 2,2-47,9) for NIC and 1 mos (range 0,1-29,9) for ST, respectively (p&lt;0.001) (Fig. 1B). Conclusions: In our real-life analysis, we confirmed that SIE, SIES, GITMO "operational criteria" represent a powerful tool to discriminate categories of older pts with different outcome.In pts older than 60 years, it was observed a high degree of concordance (&gt;90%) between the "operational criteria" and the actual treatment delivered. However, long-term OS was longer when plotted according to the 3 fitness categories rather than to treatment intensity stratification (Fig.1 A and B). Such a discrepancy can be explained by a higher incidence of toxicity/early mortality in the IC group and also by a suboptimal application of treatment selection criteria. Reproducibility of operational criteria applications in a prospective fashion is currently underway. Disclosures Venditti: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy. Buccisano:Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Decitabine Versus Intensive Chemotherapy for Elderly Patients With Newly Diagnosed Acute Myeloid Leukemia

BackgroundElderly patients with acute myeloid leukemia (AML) have generally had a poor prognosis with unfavorable clinical and biologic disease features. Hypomethylating agents have shown potential for treating medically unfit and elderly patients with AML. Patients and MethodsWe compared the outcomes of elderly patients with AML treated with decitabine and intensive chemotherapy (IC). ResultsThe data from 107 patients with newly diagnosed AML aged ≥ 65 years were analyzed. The overall response rate was 38.6% and was significantly greater in the IC group than in the decitabine group (65.6% vs. 26.1%; P < .001). With a median follow-up duration of survivors of 14.8 months, the median overall survival (OS) and event-free survival were 12.3 months (95% confidence interval [CI], 10.0-14.7) and 2.0 months (95% CI, 2.0-2.0), respectively, which were not different between the 2 treatment groups. The FLT3-internal tandem duplication mutation (hazard ratio [HR], 2.637; 95% CI, 1.379-5.043; P = .003), complex karyotype (HR, 2.513; 95% CI, 1.258-5.020; P = .009), and peripheral blood blast percentage at diagnosis (HR, 1.983; 95% CI, 1.148-3.422; P = .014) were analyzed as independent prognostic factors for OS. A subgroup analysis for OS showed that IC was superior to decitabine for patients with the FLT3-internal tandem duplication mutation (P = .025) and poor risk cytogenetics, except for −7/del(7q) (P = .005), and decitabine was associated with longer OS for patients with −7/del(7q) (P = .077). ConclusionDecitabine showed a similar OS to IC, despite the lower response rate in patients. The clinical outcomes of specific subgroups seemed to differ with different treatment options. Optimal therapeutic approaches for elderly patients with AML should be further examined.

Hypomethylating Agents Versus Intensive Chemotherapy in Older Patients (Age ≥ 70) with Acute Myeloid Leukemia with High White Blood Cell Count

Abstract Background Acute myeloid leukemia (AML) is primarily a disease of older adults, with 40-50% of patients ≥ 70 years old at diagnosis. Optimal frontline therapy for elderly AML patients remains controversial. Intensive chemotherapy (IC) is often favored in those AML patients who present with leukocytosis (P-AML), yet the evidence to support this practice as opposed to lower intensity therapy is scarce. We aimed to investigate the outcomes of older patients with P-AML based on treatment choice of intensive chemotherapy (IC) vs hypomethylating agents (HMA). Methods We retrospectively analyzed 983 elderly AML patients (age ≥ 70 years) treated at Moffitt Cancer Center between 1995 and 2016. Patients with prior exposure to HMA for non-AML diagnoses were excluded. We focused on P-AML patients, defined as baseline WBC ≥ 10x109/L, who received initial therapy with either: intensive chemotherapy (IC) (defined as daunorubicin/cytarabine or equivalent) or hypomethylating agents (HMA) (azacitidine (AZA) or decitabine (DEC)). Age, type of AML, history of antecedent hematologic disease, cytogenetics (per European LeukemiaNet (ELN) criteria), Eastern Cooperative Oncology Group (ECOG) performance status, Charlson comorbidity Index (CCI), complete blood counts and myeloblast percentage at time of diagnosis were obtained for each patient. Kaplan-Meier analysis was performed to calculate overall survival (OS) and the log-rank test was used to determine significance where a p-value of 0.05 was defined as significant. Fisher's exact t-test, hazard ratios (HR) and confidence interval (CI) were calculated using GraphPad Prism v7.03. Univariate and multivariate analysis for the baseline characteristics and type of therapy were performed using SPSS v24.0 to determine prognostic impact. Results Within the entire cohort of older AML patients, we identified 156 who were treated with either HMA (n=41) or IC (n=115). Baseline characteristics of these patients are described in Figure 1A. Significant baseline differences in age, hemoglobin, WBC, ELN cytogenetic category, marrow blast %, and CCI score were observed between the HMA and IC groups. Most notably, the HMA group were older (median age 77 yrs vs 74 yrs, p=0.0037), had a higher incidence of poor-risk cytogenetics (36.6% vs 7%), and were more likely to have CCI score ≥ 3 (29.3% vs 8.7%). Median time of initial treatment was 4.3 months (range: 0.10-70.0 months) in the HMA group compared to 0.5 months (range: 0.33-1.90months) in the IC group. Median OS of the entire group was 7.85 mo. Median OS in the HMA-treated patients was superior to IC treated patients (13.7 mo vs. 5.1 mo, HR 0.63, 95% CI 0.443 - 0.886, p=0.0082) (Figure 1B). The 12 month survival rate was 55.0% in the HMA group and 31.0% in the IC group (p=0.0082). Fifty-two (33%) patients achieved CR/CRi. There was no difference in CR/CRi rates between HMA or IC treated cohorts (30.0% vs. 34.8%, p=0.6983). Rate of relapse upon achievement of CR/CRi was not statistically significant between HMA and IC cohort (41.7% vs. 62.5%, p=0.3181). The 30-day mortality rate was lower in the HMA group compared to the IC group (7.3% vs 24.4%, p=0.0217). Univariate analysis identified treatment type (p Conclusions Elderly patients (age ≥ 70) with proliferative AML appear to achieve a survival advantage with HMA-based frontline therapy compared to IC, despite a disproportionately higher incidence of traditionally adverse prognostic features (poor-risk cytogenetics, high CCI score) in the HMA group. The reasons for this observation are unclear, but could relate to a higher early death rate with IC or biologic/molecular features that induce greater sensitivity to HMAs, which should be studied in future analyses. Although this study was limited by small size and retrospective nature, our findings cast doubt on the notion that intensive therapy should be the standard frontline approach in elderly patients proliferative/high WBC AML. Download : Download high-res image (266KB) Download : Download full-size image Disclosures Sallman: Celgene: Research Funding. Padron: Incyte: Honoraria, Research Funding. Komrokji: Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria. Lancet: Biopath, Biosight, Boehringer Ingelheim, Celator/Jazz, Celgene, Janssen, Karyopharm Therapeutics, and Novartis: Consultancy; Pfizer: Other: Institutional research funding.

Analysis of the Clinicopathological Characteristics, Treatment and Prognosis of Unclassifiable B-Cell Lymphoma Intermediated between DLCBL and BL

To analyze the clinicopathological characteristics, treatment and prognosis of patients with unclassifiable B-cell lymphoma intermediated between DLCBL and BL. A total of 16 patients with DLBCL/BL in our hospital were included in this study between July 2014 and June 2016. The clinical and pathological data of 16 patients were collected. Kaplan-Meier method was used to estimate and compare overall survival (OS) and progression-free survival (PFS). The log-rank test was used to analyze the influence of age, sex, B symptoms, LDH level, lymyhoma staging, KPS score, Ki-67(%), extranodal sites, IPI score, β2 microglobulin level, DPLs, tumour cell origin and treatment etc. Results: Fifty out of 16 patients showed extra-nodal involvement among the 16 patients with DLBCL/BL. The median OS and PFS times were 11 and 7 months respectively. The one year OS and PFS rates were 50.0% and 43.8% respectively. The borderline difference between the CHOP, CHOP-like, and intensive chemotherapy groups is statistically significant(P=0.067). Univariate analysis showed that IPI score and LDH were significant prognostic factors for the overall survival of the patients with DLBCL/BL. DLBCL/BL is a highly aggressive B-cell lymphoma with a short survival time. DLBCL/BL responded better to intensive chemotherapy than CHOP or CHOP-like regimen. IPI score and LDH level are significant prognostic factors for the overall survival of the patients with DLBCL/BL.

Characteristics and outcomes of older patients with secondary acute myeloid leukemia according to treatment approach.

The development of newer strategies to improve outcomes for older patients with secondary acute myeloid leukemia (s-AML) is a critical unmet need. Establishing baseline metrics for evaluating newer approaches is important. s-AML was defined as 1 or more of the following: a history of an antecedent hematologic disorder (AHD), a diagnosis of therapy-related acute myeloid leukemia (AML), and AML with karyotype abnormalities characteristic of myelodysplastic syndrome. Newly diagnosed s-AML patients aged 60 to 75 years were grouped into 5 treatment cohorts: 1) patients receiving high- or intermediate-dose cytarabine-based intensive chemotherapy (IC), 2) patients receiving a hypomethylating agent (HMA) or HMA combinations, 3) patients receiving low-dose cytarabine (LDAC) combinations, 4) patients receiving CPX-351, and 5) patients receiving investigational (INV) agents. Nine hundred thirty-one patients met the age and s-AML criteria. Complete remission rates were statistically lower in the HMA group (36%) versus the IC (46%), CPX-351 (45%), and LDAC groups (43%). Patients receiving less intensive regimens (the HMA and LDAC groups combined) had superior overall survival (OS) in comparison with patients receiving IC-based regimens (median 6.9 vs 5.4 months; P = .048). Only 4.3% of the IC patients proceeded to transplantation, whereas 10.3% of the patients on lower intensity regimens did (P = .001). There was no difference in median survival between patients treated with CPX-351 and patients treated with conventional lower intensity approaches (P = .75). Age > 70 years, an adverse karyotype, and a prior AHD were associated with decreased OS in a multivariate analysis. Lower intensity approaches are associated with lower early mortality rates and improved OS in comparison with intensive regimens. OS is poor with currently available therapies with a median OS of 6 months (5.4-7.6 months across regimens). Unsatisfactory outcomes with other INV agents underscore the need for more effective therapies. Cancer 2017;123:3050-60. © 2017 American Cancer Society.

Effect of Age on Treatment Decision-Making in Elderly Patients With Acute Myeloid Leukemia.

Patients aged ≥ 70 years with acute myeloid leukemia (AML) have a poorer prognosis than those aged 60 to 69 years. We retrospectively analyzed the cases of 183 patients aged ≥ 70 years with a performance status of ≤ 2 treated at our institution from 2000 to 2014. Treatment consisted of anthracycline- and cytarabine-based chemotherapy for 93 patients and lower intensity therapy with low-dose cytarabine or hypomethylating agent cycles for 90 patients. A total of 57 patients (61%) achieved complete remission in the intensive chemotherapy group versus only 11 (12%) in the lower intensity treatment group (P < .0001). The median overall survival (OS) was 14.5 months and 11.7 months with a 3-year OS rate of 34% and 18% (P = .005) for the intensive and lower intensity groups, respectively. The difference remained significant when considering patients aged ≤ 75 years, but not for patients aged > 75 years. Similarly, a significant difference was only observed when considering favorable and intermediate cytogenetic factors (P = .007) but not unfavorable karyotypes. On multivariate analysis, age did not appear as an independent prognostic factor. With intensive chemotherapy, the median OS significantly increased after the introduction of an improved supportive care policy compared with historical controls (14 vs. 5.4 months, with a 3-year OS rate of 33% vs. 8%). After 2006, a more "personalized" therapeutic approach tended to erase the difference in terms of OS, especially in patients aged > 75 years.

Comparison Of Epigenetic Versus Intensive Chemotherapy For Newly Diagnosed Acute Myeloid Leukemia Patients ≥60 Years Old: The Roswell Park Experience

Abstract Background Epigenetic therapy (Epi) with the hypomethylating agents, azacitidine (Aza) and decitabine (Dec), is increasingly being utilized for induction treatment of older AML patients (pts) based on studies demonstrating both tolerability and prolonged survival. By contrast, standard “7+3” intensive chemotherapy (IC) effectively induces remission in many individuals but is associated with significant toxicity and higher mortality. We compared our institute's experience with Epi vs. IC for the upfront treatment of newly diagnosed AML pts ≥60 years old. Methods We performed a retrospective chart review of 164 pts ≥ 60 yrs old with newly diagnosed AML who underwent initial therapy at our center between 3/2008-2/2013. Half (n=84; 51%) received IC with regimens containing cytarabine 100 mg/m2 IV for 7 days and daunorubicin 60 mg/m2 IV for 3 days. Half were treated with Epi (n=82; 49%) regimens containing either Dec (20 mg/m2 IV daily for 5 or 10 days) or Aza (75 mg/m2 sq daily for 7 days). Kaplan Meier method, log rank test, and univariate cox proportional hazard models were used to assess overall survival (OS) and correlation with covariates of interest. Results Baseline pt characteristics demonstrated a difference in the median age of pts in each group (IC 67 vs. Epi 75 yrs; p &lt;0.01). All other factors were comparable: ECOG status 0-2 (96% vs. 96%, p=1.0), WBC (12.0 x 109/dL vs. 4.5 x 109/dL; p=0.08), hemoglobin (9.2g/dL vs. 9.4g/dL; p=0.39), platelets (69 x 109/dL vs. 54 x109/dL; p=0.99), marrow blasts (53% vs. 45%; p=0.10), peripheral blasts (21% vs. 9%; p=0.14), poor-risk cytogenetics (56% vs. 66%; p=0.21). At our center, older AML pts receiving IC had superior complete response at any time point (CRatp)(43% vs. 21%; p&lt; 0.01) and higher overall response rates (ORR=CR+CRp) (50% vs. 28%; p&lt;0.01) versus Epi-treated pts. IC also resulted in a longer median OS as compared to Epi (10.6 vs. 7.9 mos; p=0.01). Thirty-day mortality and leukemia-free survival (LFS) were similar across the two groups (IC 10% vs. Epi 11%; p=0.8; 11.2 vs. 9.3 mos; p=0.47 respectively). Interestingly, in pts with AML characterized by poor-risk cytogenetics (n=77; 46%), the choice of induction (IC vs. Epi) did not impact outcome and yielded similar CRatp (39% vs. 27%; p= 0.4) and OS (10.3 vs. 7.8 months; p=0.4). Choice of Epi drug (Aza vs. Dec) did not impact results. Thirty-three percent of pts (n=55; IC 38% vs. Epi 28%) had refractory or relapsed disease (RR-AML) after induction, requiring ≥1 salvage treatment. We found that selection of either IC or Epi as prior treatment had no effect on CR or ORR in RR-AML pts receiving salvage. In multivariate Cox regression analysis, older age, higher ECOG score, increased peripheral blasts, and poor-risk cytogenetics were independently associated with inferior survival. By comparison, marrow blast percentage, hemoglobin, and choice of induction therapy did not impact OS (IC vs. Epi: HR 0.79; CI 0.508-1.237, p= 0.31). Conclusions Our results suggest that IC and Epi represent clinically equivalent approaches for the upfront treatment of older AML pts. In spite of significantly higher CR and ORR in the IC group, our finding of improved OS following IC vs. Epi was not substantiated in multivariate analysis, suggesting that this difference may be explained by the comparatively younger age of pts in the IC group. Leukemia-free survival and 30-day mortality were the same for IC vs. Epi-treated pts, as were all response and survival outcomes in the poor-risk cytogenetics subgroup. These data highlight the growing need for prospective clinical trials to conclusively determine the respective roles of IC vs. Epi therapy in older AML pts. Disclosures: No relevant conflicts of interest to declare.

Geriatric Assessment Driven Treatment In 149 AML Elderly Patients

In elderly AML the prognosis still remains poor and unchanged in the last decades, with only 10% long term OS. Aging is often synonymous of frailty, traducing in difficulties of enrolment of older patients in experimental study. We explored feasibility and efficacy of an high dose Cytarabine regimen, the so called ‘Memorial', including Idarubicin plus Amifostine, in a cohort of 149 AML patients older than 59 years and prospectively evaluated by Multidimensional Geriatric Assessment, between 1999 and 2010. We estimated comorbidities by CIRSG, presence of geriatric syndromes and autonomy in daily life activities (ADL) score as described by Balducci et al, frail patients, candidate to best supportive care (BSC), have been identified as those with 1 grade III or more than 2 grade II comorbidities or a geriatric syndrome or ADL score<6. Ninetyone patients (61%) resulted fully fit or partially fit but with adequate cardiac function (50% EF by echocardiography) and therefore eligible to receive a Memorial based induction and consolidation. The 58 patients of the BSC group, compared with intensive chemotherapy group, had a higher incidence of unfavourable karyotype (64.5% vs 40.7%, p= 0.05), secondary AML (53.4% vs 39.6%, p=0.005), WHO PS>1 (44.4% vs 12.1%, p=0.003), age>69 years (82.7% vs 42.9%, p<0.001).In the 91 patients we observed 5 induction deaths (5.5%) and 76% CR rate (67/88, 3 too early) with 67 grade III-IV febrile episodes, 13% and 9% grade III-IV mucositis and liver toxicity. Neutrophils (>1,500/ml) and platelets (>20,000/ml) recovery was achieved on days +15 and +16 respectively, with a median duration of hospitalization of 30 days (range: 15-69). Sixty-one patients achieving CR received a consolidation, followed by Allogeneic Transplant in 4, Autologous Transplant in 22 and Gemtuzumab Ozogamycin in 23, according to the mobilization results and donor availability. The remaining patients went off the study because of early leukemia recurrence or poor tolerance.With a median follow-up of 70 months we observed a 20.4% 8 years OS with a median duration of 11.4 months. The 58 BSC patients had a significantly lower OS since all died within 18 months with a median OS of 1.5 months (p<0.001).The presence of poor risk cytogenetic was confirmed as the only factor significantly predictive of refractory disease with a RR of 3.26 (95% CI: 1.18-9.53) p=0.03. By the way we observed a 63,6% CR rate in this unfavourable setting, unusually high if compared to the results reported by the literature.Eight years OS was significantly reduced at univariate analysis in patients with secondary disease vs those with de novo AML (10.4% vs 27.1%; p= 0.04); in those with unfavourable cytogenetic risk vs other risk groups (11.4% vs 30.3% p= 0.01) and in those with WBC count> 50,000/ml vs < 50,000/ml (0% at 33 months vs 23.4%, p= 0.009). Multivariate Analysis selected only cytogenetic risk and hyperleukocytosis as predictors of Overall Survival. Patients with poor karyotype had a 2.1 relative risk to die and a 1.89 relative risk to die or relapse when compared with patients with other cytogenetic risk (p=0.005, 0.012), those with hyperleukocytosis ≥50,000/ml showed lower OS and EFS in comparison with patients with a WBC count <50,000/ml, with relative risks respectively of 3.53 and 3.45 (p=0.001).In conclusion Multidimensional Geriatric assessment allows a reproducible and accurated selection of AML elderly patients eligible for intensive chemotherapy treatment.Memorial plus Amifostine represents an intriguing approach in elderly AML patients with an acceptable haematological and extra-haematological tolerance, a transplant feasibility comparable to other studies; finally 8 yrs OS doubled than that reported by the literature. Disclosures:Off Label Use: Gemtuzumab Ozogamycin was administered as post consolidation treatment after September 2010 (when it has lost indication for AML elderly treatment after SWOG phase III study results) only after AIFA permission and approval by IRB. A written informed consent indicating the reasons for the withdrawal of Gemtuzumab from the market, was signed by patients receiving Gemtuzumab after that date.

Long-Term Outcome Of Acute Promyelocytic Leukemia (APL) With Lower Initial Leukocyte Counts By Using All-Trans Retinoic Acid (ATRA) Alone For Remission Induction Therapy: Japan Adult Leukemia Study Group (JALSG) APL97 Study

BackgroundATRA and anthracycline-based chemotherapy is a standard remission induction therapy for APL, leading to complete remission (CR) rate of 90% or more. (Asou et al, 2007; Ades et al, 2010; Avvisati et al, 2011). As reported in many APL studies including the JALSG study, risk adopted strategy according to initial leukocyte counts has demonstrated successful results. However, the long-term outcome of the patients with initial leukocyte counts < 3,000/µl received ATRA alone in the induction therapy and followed by post remission chemotherapies, remains to be elucidated. Furthermore, it is controversial whether concomitant chemotherapy is needed for such a very low risk group. In the JALSG-APL97 study, patients with initial leukocyte counts < 3,000/µl received ATRA alone until remission (Group AA), except for patients with leukocytosis during the ATRA therapy who received additional chemotherapy (Group AD). Here, we reported the long-term outcome of this study based on risk adopted therapy, particularly, focusing on the outcome of the very low risk group. MethodsThe treatment schedule of JALSG-APL97 study was initially reported by Asou et al. in 2007. In brief, patient groups were defined as: leukocytes < 3000/µl (Group A: ATRA alone), 3000/µl ≤ leukocytes < 10,000/µl (Group B: ATRA plus IDA/Ara-C: 2+5), and leukocytes ≥ 10,000/µl (Group C: ATRA plus IDA/Ara-C: 3+5). Patients who experienced leukocytosis received additional chemotherapy (Group D). After 3 courses of consolidation chemotherapy, patients achieved molecular CR were allocated to an intensive chemotherapy group or observation. The CR rate, overall survival (OS), event-free survival (EFS), and cumulative incidence of relapse (CIR) were analyzed for each group. ResultsTwo hundred and seventy-one newly diagnosed APL patients, ranging from 15 to 70 years of age, were evaluable. The number of patients in each group was 150 (A), 69 (B), 52 (C) and 70 (D), respectively. Of 150 patients in Group A, 83 achieved CR with ATRA alone (AA), and 67 were added chemotherapy due to leukocytosis during ATRA therapy (AD). In Group A, B, C and D, CR rates were 95.2%, 97.0%, 90.4% and 97.1%, respectively (P = 0.30); OS (Figure 1) 90.1%, 77.3%, 73.1% and 71.4%, respectively (P = 0.02); EFS (Figure 2) 71.1%, 63.6%, 55.7% and 64.3%, respectively (P = 0.26); CIR 23.5%, 27.6%, 34.5% and 20.4% (P = 0.51), respectively. Initial leukocyte counts in Group AA were significantly lower compared to those in Group AD (median leukocyte counts; 900/µl vs. 1,100/µl, P = 0.03). The median administration period of ATRA was similar between Group AA and AD (46 days vs. 43 days, P = 0.57). Differentiation syndrome was more frequent in Group AA (28.0% vs. 14.9%, P = 0.04). The CR rate and early death rate were not different between two groups (95.2% vs. 95.5%, P = 0.92 and 3.6% vs. 4.5%, P = 0.79, respectively). OS was significantly inferior (90.1% vs. 73.1%, P = 0.005) and non-relapse mortality after post-remission therapy was significantly higher in Group AD (5% vs. 16%, P = 0.04), compared to Group AA, while EFS was not different between two groups (71.1% vs. 65.7%, P = 0.33). The cumulative incidence of late relapse occurred more than 2 years after CR was significantly higher in Group AA compared to Group AD (17.5% vs. 3.9%, P = 0.04). [Display omitted] [Display omitted] ConclusionsRisk adopted therapy according to initial leukocyte counts is totally useful in this study as well as previous reports including us. OS was favorable in APL patients with initial leukocyte counts < 3,000/µl, achieved CR by using ATRA alone for remission induction therapy, whereas EFS in this group was still unsatisfactory in the long-term follow up. It could be explained by the high frequency of late relapse. Ades et al reported better long-term outcomes in patients concomitantly treated with ATRA and chemotherapy rather than in those treated with ATRA followed by chemotherapy in their APL patients with initial leukocyte counts < 5000/µL. However, very low risk patients (Group AA) could be put into the separate category, and therapeutic approaches to reduce the late relapse in this group should be discussed. Additionally, the genetic profile studies will provide us informative data in relation to initial leukocyte counts and leukocytosis during ATRA therapy. Disclosures:Kiyoi: Bristol-Myers Squibb: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Novartis Pharma: Research Funding; Kyowa Hakko Kirin Co. Ltd.: Research Funding.

Peripherally Inserted Central Catheters (PICCs) Can Be Successfully Utilized in Haematological Patients: Efficacy of an Educational Program.

AbstractAbstract 3161 Purpose:Patients with haematological disorders frequently require the insertion of medium or long-term central venous catheters (CVCs) for stem-cell transplantation, the administration of chemotherapy, or transfusions. Although peripherally inserted central catheters (PICCs) have been in use for many years, little data exist on their use in patients receiving intensive chemotherapy and blood progenitor cell transplantation. Methods:Evidence-based interventions were implemented in our department from November 2009 to July 2012, and include: 1.An high level nurse education program for correct practices and prevention of catheter-associated complications. was developed for PICC nursing team; 2) The use of ultrasound guide for the insertion of the tip of PICCs, thanks to a special operator training; 3) Bedside placement and confirmed PICC tip placement by chest radiography after removal of the guidewire and before the securing of the catheter; 4) Maintenance of maximum sterile barrier precautions during PICC insertion and aftercare; 5) chlorhexidine preparation, replace 10% povidone iodine for skin antisepsis; 6) adoption of PICC patient nurse archive, including the information of weekly PICC line review at our department for each patient. Aim:Here, we carried out a clinical prospective investigation to determine the efficacy of these interventions in reducing the rate of PICC-related complications (thrombotic events, exit site infection and other complications requiring early removal of PICCs); the studied population included hematology patients receiving intensive chemotherapy compared to allogeneic/autologous stem cell transplant recipients. Results:Three hundred sixty-four (364) PICCs were in place in 299 patients for a total of 41.111 PICC days ( range, 1–482 days; mean 112,94 days); 292 were inserted in patients receiving conventional chemotherapies, and 72 in patients undergoing allogeneic or autologous hematopoietic stem cell transplantation (SCT). Sixty-six (60) PICCs were inserted during severe thrombocytopenia (platelets < 50 × 10(9)/L), seventy (70) during severe neutropenia (neutrophils < 0.5 × 10(9)/L) and thirty-eight (38) during antithrombotic prophylaxis. Predominantly, patients had Lymphoma (50%). The rate of major complication was very low: 15 thrombotic complications PICC-related (4%; 0.36 per 1,000 CVC days), and 3 CRBSI (0,8%; 0.07 per 1,000 CVC days) during neutropenia. Mechanical complications occurred in 52 catheters, and were accidental dislodgement (30), catheter break (3), catheter inadequate (19); other reasons for catheter removal were completion of therapy (137), lumen occlusion (19) and death (58). Interesting, taking in account the underlying disease, lymphoma and leukemia patients have, respectively, an increased risk of developing a CRBSI and a thrombotic PICCs-complication when submitted to hematopoietic stem cell transplantation (SCT) (see table 1). However, compared with allogeneic/autologous stem cell transplant group, the intensive chemotherapy group was associated with a marginally lower incidence of CRBSI complication rate (0.6 % vs 1.0 %, 0.10 vs 0.60 per 1,000 CVC days) [odds ratio (OR) 2,042]; no relevant differences in terms of thrombotic complications between the two cohorts (4.11 % vs 4.17%), 0.29 vs 0.39 per 1,000 CVC days) [odds ratio (OR) 1.014]. Conclusions:Our findings suggest, therefore, PICC devices are a viable and safe option for management of the haematology patients receiving intensive chemotherapy and even in patients particularly prone to infective and thrombotic complications such as patients receiving blood stem cell transplantation.Table 1Outcomes according to underlying disease and relative adhibitionDiagnosisChemotherapyASCTStatisticsOdds Ratio% Definite CRBSI% Thrombosis% Definite CRBSI% ThrombosisDefinite CRBSI (%)Definite CRBSI per 1000 PICC daysTrombosis (%)Trombosis per 1000 PICC daysRange (days)Means (days)OR CRBSIOR ThrombosisLymphoma (n. 182)0.694.162.632.631.100.103.850.344–336146.33.860.62Acute Leukemia (n 120))0.954.76013.330.830.075.830.4699–432213.803.07Others (n. 62)02.32000.0001.610.196-28779.200Overall0.684.111.394.170.820.074.120.360–482112.942.0421.014CRBSI catheter-related bloodstream infection. PICC peripherally inserted CVC. ASCT allogeneic/autologous stem cell transplant Disclosures:No relevant conflicts of interest to declare.

Intensive chemotherapy for elderly patients with acute myelogeneous leukemia: a propensity score analysis by the Japan Hematology and Oncology Clinical Study Group (J-HOCS)

The prognosis of acute myelogenous leukemia (AML) in the elderly patients is extremely poor. Although several previous studies have suggested that intensive chemotherapy is associated with a better prognosis, there may have been a selection bias. Therefore, we retrospectively evaluated the impact of intensive chemotherapy for AML in the elderly by stratifying patients according to a propensity score. Eighty-one AML patients aged 70 years or more were included in this study. Patients with acute promyelocytic leukemia were not included. A propensity score for the use of intensive chemotherapy was calculated from four factors at diagnosis. Forty-five patients received intensive chemotherapy, whereas 36 received low-dose or no chemotherapy. We stratified the patients into quartiles based on the propensity score. The numbers of patients in the first, second, third, and forth quartiles who received intensive chemotherapy were 5 of 21, 10 of 20, 12 of 20, and 18 of 20, respectively. A stratified log-rank test showed significantly better overall survival in the intensive chemotherapy group (P = 0.0088). Especially, in the combined second and third quartiles, which showed an equal tendency for intensive and non-intensive strategies; overall survival at 3 years was 37.5 % for the intensive chemotherapy group and 13.0 % for the non-intensive chemotherapy group (P = 0.0022). A conventional multivariate analysis confirmed that intensive chemotherapy was beneficial (hazard ratio 0.50, 95 % confidence interval 0.27-0.93, P = 0.028). In conclusion, intensive chemotherapy may prolong overall survival in elderly AML patients who are considered to be able to tolerate such treatment based on factors at diagnosis.

5-Azacytidine Versus Intensive Chemotherapy or BSC in Elderly (>60 years) Acute Myeloid Leukemia Patients. A Retrospective Analysis

Abstract 2612 BACKGROUND:5-Azacytidine (AZA) has proven to prolong overall survival (OS) in higher-risk MDS patients and elderly patients with WHO-defined AML and low bone marrow blast count (20–30%) compared to conventional care regimens. These exciting results have prompted us to seek the potential role of AZA on the treatment of elderly (> 60 years) patients with AML compared to best-supportive care (BSC) or intensive chemotherapy (ICT). PATIENTS & METHODS:We have performed a retrospective analysis in 182 elderly AML patients, median age: 70y (60–84). Out of them, 67 patients from 9 Spanish centers diagnosed between Jan/07 to Feb/11 and not eligible for ICT, received 5-AZA as first line therapy by compassionate use. AZA was administered subcutaneously (75–100 mg/m2/d) for 7 days of every 28d. Patients received a median of 6 AZA cycles (1–24). For comparisons, historical cohort (N= 115) diagnosed at same period from University Hospital Reina Sofia was used. Among them, 68 patients unfit for ICT had received only BSC consisting on oral chemotherapy agents, blood product transfusions and antibiotics with granulocyte colony-stimulating factor for neutropenic infection. In this historical cohort 47 patients had received ICT consisted of induction with cytarabine (100–200 mg/m2/d by continuous infusion) for 7 days plus idarubicin (9–12 mg/m2/d) for 3 days followed by Autologous (N=9) or Allogeneic (N=4) Transplant. Outcome measures were performed according to the International Working Group criteria (AML-IWG-2006). RESULTS:Clinical characteristics of patients are detailed in Table 1. Meaningfully, patients in ICT group were significantly younger than those in BSC or AZA arms and also had significantly better ECOG scores. By contrast, patients in AZA group had significantly lower WBC and bone marrow blast count than those receiving ICT. There were not statistical differences in the presence of MDS features or gender distribution (M/F) comparing three arms. Most importantly the percentage of patients with intermediate-adverse cytogenetics was comparable between three arms.Median follow-up for surviving patients from the start of therapy was 5, 13 and 7.4 months for BSC, ICT and AZA groups respectively. The 12 months Overall Survival (OS) was 9%, 52% and 43% for BSC, ICT and AZA groups respectively. The 2y-OS was 0%, 20% and 18% for BSC, ICT and AZA groups respectively. Median OS months for BSC were 2.03 whereas for ICT and AZA groups were significantly longer: 11.2 and 13.7 respectively (Figure 1). We found statistical differences when comparing OS in BSC group with either ICT or AZA, but there was not statistical differences comparing ICT with AZA groups (p=0,75, HR=0,13; 95% CI=0,2–1,2). In multivariable Cox regression analysis, considering variables such as cytogenetic risk group, % BM Blasts and type of treatment AZA vs ICT, only high ECOG scores (p=0,01, HR=2,76; 95% CI=1,2–6) were associated with inferior survival. CONCLUSIONS:These retrospective data suggest that AZA can be an effective alternative option for elderly AML patients unfit for ICT. In our experience, these patients can achieve comparable OS at 2 years than those suitable for ICT, although ECOG score remained the most independent significant variable impacting on outcome. There is a need for prospective clinical trials in order to determine the place of this approach within the growing therapeutic opportunities for elderly patients with AML.Table 1:Clinical characteristics of 182 elderly AML patients.BSC N=68Intensive CT N=475-AZA N=67PMedian age, y (Range)76 (62–89)65 (60–75)*71 (60–84)*0.04 <0,01*Sex (M/F)37/3130/1748/190.11Median leucocyte count x109/L (range)17.6 (0.4–211)28.6 (0.8–166)*4.4 (0.2–17.5)*0.01 <0,01*Median BM Blasts count (%) (range)47 (21–90)64 (24–93)34 (20–84)0.003 <0,01*ECOG ≥ 260 (88%)7 (15%)45 (67%)<0.01 <0,01*Cytogenetic Risk*, N (%)0.67Intermediate39 (57.3)32 (68)46 (68.6)0.86*Adverse12 (17.6)12 (25.5)15 (22.3)NT1736MDS features, N (%)37 (54.4)21 (44.6)34 (50.7)0.16Patients alive, N (%)10 (14.7)9 (19.1)26 (38.8)0.004 0,06*Median,follow-up of survivors, months5 (0–10)13 (2–46)7.4 (1–28,3)0.03 0,06*Median Overall Survival, months2,0311,2*13,7*<0.001 0,75*OS at 1 year9%52%*43%*<0.001 0,75*OS at 2 years0%20%*18%* [Display omitted] Disclosures:Off Label Use: Azacitidine in AML.

Postremission therapy for acute myeloid leukemia in the first remission

The medical records of 99 patients with acute myeloid leukemia (AML; except AML, M3) in the first remission from 1995 to 2004 were retrospectively reviewed. When they achieved complete remission, at first complete remission (CR1), patients received allogeneic (n = 23), autologous hematopoietic stem cell transplantation (HSCT) (n = 35), or intensive chemotherapy (n = 41) according to prognostic factors and donor availability. There was an advantage in terms of event-free survival (EFS, p = 0.0001) and overall survival (OS, p = 0.0002) with HSCT as compared to those of intensive chemotherapy. However, the EFS and OS were not different between allogeneic HSCT and autologous HSCT. In high-risk patients, the EFS and OS of allogenic or autologous HSCT group were higher compared with those in the intensive chemotherapy group (p < 0.01). However, there was no difference between allogeneic HSCT and autologous HSCT in terms of EFS and OS. In the intermediate- or low-risk group, there was no significant difference in the outcome according to the postremission modalities.

Acute Myeloid Leukemia in the Elderly, Intensive or Maintenance Therapy? Our Experience in Patients over 65 Years.

The treatment of acute myeloid leukemia in elderly with age > 65 years is still debated. Various reported studies have valued the feasibility of intensive chemotherapy in these setting of patients. The aim of the our study is to value the difference in DFS and OS among 2 groups of elderly patients with AML treated with intensive chemotherapy (IC) or maintenance (M). From June 2001 to May 2005 we have accepted in our Division 45 patients affected by AML aged up to 65 years. 25 were male and 20 were female, with a median age of 75 years (range 67–86 years). 22 patients (12 M and 10 F, median age: 71 years) received intensive chemotherapy (I.C. Flag and MICE) and 23 (13 M and 10 F, median age: 78 years) received or maintenance therapy (low dose cytarabine) or only support. In IC group 11 patients (50%) have obtained to complete remission (CR) with a DSF and OS media of 7,5 and 6,3 months respectively, and a TRM rate of 27%. In the M group the CR has been documented in 6 patients (35%) treated with low dose of cytarabine, with a DFS and OS media of 6,9 and 4,4 months respectively (graph 1–2). This results have shown, as expected, a better CR rate in the IC group, but without any advantage in terms of OS and DFS when compared with the M group. Difference is not statistically significant between the two groups (p: 0.5). Despite a good CR rate, Intensive chemotherapy do not improves survival in elderly patients. This is probably due to the combination of either a high TRM in patients treated with intensive chemotherapy or a high relapse rate. New therapeutics strategies are needed to improve DFS and OS in these patients. Interesting is the use of specific monoclonal antibodies (anti CD33) in this poor risk disease especially in maintenance after a CR obtainable with a low intensive or low dose chemotherapy. [Display omitted]

Autologous or Allogeneic Bone Marrow Transplantation Compared with Intensive Chemotherapy in Acute Myelogenous Leukemia

Allogeneic or autologous bone marrow transplantation and intensive consolidation chemotherapy are used to treat acute myelogenous leukemia in a first complete remission. After induction treatment with daunorubicin and cytarabine, patients who had a complete remission received a first course of intensive consolidation chemotherapy, combining intermediate-dose cytarabine and amsacrine. Patients with an HLA-identical sibling were assigned to undergo allogeneic bone marrow transplantation; the others were randomly assigned to undergo autologous bone marrow transplantation (with unpurged bone marrow) or a second course of intensive chemotherapy, combining high-dose cytarabine and daunorubicin. Comparisons were made on the basis of the intention to treat. A total of 623 patients had a complete remission; 168 were assigned to undergo allogeneic bone marrow transplantation, and 254 were randomly assigned to one of the other two groups. Of these patients, 343 completed the treatment assignment: 144 in the allogeneic-transplantation group, 95 in the autologous-transplantation group, and 104 in the intensive-chemotherapy group. The relapse rate was highest in the intensive-chemotherapy group and lowest in the allogeneic-transplantation group, whereas the mortality rate was highest after allogeneic transplantation and lowest after intensive chemotherapy. The projected rate of disease-free survival at four years was 55 percent for allogeneic transplantation, 48 percent for autologous transplantation, and 30 percent for intensive chemotherapy. However, the overall survival after complete remission was similar in the three groups, since more patients who relapsed after a second course of intensive chemotherapy had a response to subsequent autologous bone marrow transplantation. Other differences were also observed, especially with regard to hematopoietic recovery (it occurred later after autologous transplantation) and the duration of hospitalization (it was longer with bone marrow transplantation). Autologous as well as allogeneic bone marrow transplantation results in better disease-free survival than intensive consolidation chemotherapy with high-dose cytarabine and daunorubicin. Transplantation soon after a relapse or during a second complete remission might also be appropriate.

Current Management, Local Management, and Survival Statistics of High-Grade Osteosarcoma

To report the current management of high-grade osteosarcoma in Japan, the authors studied the results of 55 cases treated in the authors' institutions and data provided by Osaka University (59 cases), Chiba Oncology Group (97), and Sapporo National Hospital (70). Twenty-five of the 55 cases in the authors' series were treated by limb-salvage surgery, 27 by amputation, and the remainder by chemotherapy. In all 226 cases from the three institutes, 106 were treated by amputation and 120 by limb-salvage surgery. Two local recurrences (4%) were found in the authors' series, three in the Osaka series, and eight in the Chiba series. Five-year accumulative survival rates in this study showed some differences, depending upon the institution or upon the protocol employed: in the authors' series it was 60% overall and 68% for a stronger chemotherapy group; in the Osaka series, it was 50% in a mild chemotherapy group and 72% in an intensive chemotherapy group; and in the Sapporo series, it was 36% and 73%, respectively. This study showed that local control of IIB osteosarcoma was successfully achieved by preoperative adjuvant chemotherapy and wide resection, and that an intensive chemotherapeutic combination of high-dose methotrexate, cisplatinum, and doxorubicin is promising.

Low-dose cytarabine versus intensive chemotherapy in the treatment of acute nonlymphocytic leukemia in the elderly.

We conducted a randomized multicenter trial comparing low-dose cytarabine (LD ARA-C) (20 mg/m2 for 21 days) with an intensive chemotherapy (rubidazone [a daunorubicin-derived agent], 100 mg/m2 for 4 days, ARA-C 200 mg/m2 for 7 days) in 87 patients over 65 years of age with de novo acute nonlymphocytic leukemia (ANLL). Forty-one patients received LD ARA-C and 46 received intensive chemotherapy. The number of complete remissions (CRs) but also of early deaths was higher in the intensive chemotherapy group, while partial remissions (PRs) and failures were more frequent in the LD ARA-C group (P less than .001). Infectious complications during induction treatment were more numerous and more severe in the intensive chemotherapy group (P less than .01). Patients treated with LD ARA-C required fewer RBC transfusions (P less than .02), fewer platelet transfusions (P less than .01), and had a shorter hospital stay for induction treatment (P less than .01). Overall survival and CR duration were not significantly different in either group. In the LD ARA-C group, the survival of patients with PR and those of patients in CRs was identical. We conclude that in a selected group of elderly patients with de novo ANLL a higher number of CRs may be obtained with intensive chemotherapy, but that with LD ARA-C, the number of early deaths is lower, and long-lasting PRs are obtained, resulting in a similar overall survival.