Southwest Oncology Group Criteria Research Articles

The efficacy of 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in patients with metastatic neuroendocrine tumours: a systematic review and meta-analysis.

To evaluate the efficacy of 177Lu-DOTA0-Tyr3-octreotate (177Lu-DOTATATE) radionuclide therapy in patients with inoperable or metastatic neuroendocrine tumours (NETs), (PROSPERO ID CRD42019130755). All published clinical studies of NETs treated with 177Lu-DOTATATE were identified based on systematic searches in the PubMed, EMBASE, Cochrane Library, Web of Science and ClinicalTrials.gov databases up to January 2019. Among these studies, only the reports evaluated with the "Response Evaluation Criteria in Solid Tumours (RECIST)" or "Southwest Oncology Group (SWOG)" criteria or both were included. We analysed the disease response rate (DRR) and disease control rate (DCR) of each group to evaluate the efficacy of 177Lu-DOTATATE. Fifteen studies were selected from 715 references. The pooled effect in the RECIST group (13 studies) was 27.58% (95% confidence interval (CI) 21.03-35.27%) for the DRR and 79.14% (95% CI 75.83-82.1%) for the DCR. In the SWOG criteria group (7 studies), the pooled effect was 20.59% (95% CI 10.89-35.51%) for the DRR and 78.28% (95% CI 74.39-81.72%) for the DCR. Therefore, the RECIST and SWOG groups showed similar DRRs and DCRs after177Lu-DOTATATE treatment, indicating that 177Lu-DOTATATE treatment has excellent efficacy with a control rate of approximately 78-79%. Moreover, adverse effects of 177Lu-DOTATATE were minimal, including fatigue, nausea, vomiting and hormonal disorders. For patients with inoperable or metastatic NETs, 177Lu-DOTATATE is an effective treatment with minimal side effects.

The therapeutic efficacy of 177Lu-DOTATATE/DOTATOC in advanced neuroendocrine tumors

Background:Somatostatin analog therapies showed great potential for patients suffering advanced neuroendocrine tumors (NETs). This study was aimed to evaluate the therapeutic efficacy of 177Lu-DOTATATE/DOTATOC (177Lu-octreotate/octreotide) peptide receptor radionuclide therapy (PRRT) in advanced or inoperable NETs patients.Methods:Pubmed, Web of Science, Embase and Cochrane Library were searched from 1950 to April 2019. Eligible studies should include randomized or nonrandomized controlled trials (RCTs)-based investigations of 177Lu-octreotate/octreotide PRRT for NETs. All these studies were assessed with Response Evaluation Criteria in Solid Tumors (RECIST), RECIST 1.1, Southwest Oncology Group (SWOG) criteria or World Health Organization (WHO) criteria. Disease response rates (DRRs) and disease control rates (DCRs) were calculated according to each response criteria group. DRRs were defined as the percentages of patients with complete response (CR) + partial response (PR), while DCRs represented the percentages of patients with CR+ PR+ stable disease (SD). The pooled proportions were calculated with either a fixed-effects model or a random-effects model depending on the test for heterogeneity.Results:A total of 22 studies (1758 patients) were included in this meta-analysis: 8 studies with 478 patients met RECIST criteria, 10 studies with 1127 patients met RECIST 1.1 criteria, 5 studies with 459 patients met SWOG criteria, and 1 study with 40 patients met WHO criteria, and among these articles 1 study met both RECIST and RECIST 1.1 criteria and 1 met both RECIST 1.1 and SWOG criteria. The pooled DRRs were 33.0% (95% CI: 25.0%-42.0%, I2 = 65%), 35.0% (95% CI: 26.0%-45.0%, I2 = 91%) and 25.0% (95% CI: 14.0%-36.0%, I2 = 84%) according to RECIST, RECIST 1.1 and SWOG criteria, respectively. The pooled DCRs were 79.0% (95% CI: 75.0%-83.0%, I2 = 97%), 83.0% (95% CI: 78.0%-88.0%, I2 = 0) and 82.0% (95% CI: 75.0%-89.0%, I2 = 91%), respectively.Conclusion:In advanced NETs patients, DRRs and DCRs were significantly elevated after initial treatment with 177Lu-DOTATATE PRRT, which shows that this treatment would be beneficial and promising for advanced or inoperable NETs patients.

PP#127 - The efficacy of the available peptide receptor radionuclide therapy for neuroendocrine tumors: a meta-analysis

Aim This study was carried out to compare the efficacy of Y, Lu, and combination of both radiotracers (tandem) peptide receptor radionuclide therapy (PRRT) in patients with inoperable and metastatic neuroendocrine tumors. Materials and methods Systematic searches of PubMed and SciVerse Scopus databases were performed till December of 2016. The data were categorized into three groups: Y-PRRT, Lu-PRRT, and tandem-PRRT. Each group was subdivided on the basis of the response criteria used: Response Evaluation Criteria in Solid Tumors (RECIST) or Southwest Oncology Group (SWOG) criteria. Disease response and disease control rates of each group were analyzed. Results For the RECIST group, Y-PRRT disease response rates ranged from 22.81 to 56.1%, with a pooled random effect of 42.92%, and the disease control rate was 100%. Lu-PRRT disease response rates ranged from 27.63 to 57.35%, with a pooled random effect of 33.41%, and disease control rates ranged between 71.88 and 100%, with a pooled fixed effect of 79.32%. As for tandem-PRRT, disease response rates ranged between 42.11 and 66.67%, with a pooled fixed effect of 50.52%, and the disease control rate ranged between 93.33 and 100%, with a pooled fixed effect of 98.97%.For the SWOG group, Y-PRRT disease response rates ranged from 5.13 to 26.56%, with a pooled random effect of 13.4%, and disease control rates ranged between 76.56 and 85.9%, with a pooled fixed effect of 80.93%. Lu-PRRT disease response rates ranged from 6.06 to 60.29%, with a pooled random effect of 26.4%, and the disease control rates between 48.48 and 85.29%, with a pooled random effect of 74.53%. Conclusion Y-PRRT had the highest disease control rates under both RECIST and SWOG criteria. Tandem-PRRT had the highest disease response rate in the RECIST criteria, indicating that PRRT should be customized to each patient individually for maximum benefit.

Efficacy of 177Lu Peptide Receptor Radionuclide Therapy for the Treatment of Neuroendocrine Tumors: A Meta-analysis.

The purpose of this study was to assess the efficacy of Lu-labeled peptide receptor radionuclide therapy (PRRT) induction treatments for patients with unresectable metastatic neuroendocrine tumors. MEDLINE, EMBASE, and Ovid were systematically searched with keywords "lutetium," "Lu-177," "PRRT," "neuroendocrine," and "prognosis." Studies evaluating treatment with Lu-labeled PRRT were assessed for disease response and/or disease control rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 or 1.1, modified RECIST, Southwest Oncology Group (SWOG), or modified SWOG criteria. Pooled proportions of disease response and control rates were calculated for both fixed- and random-effects models. Eighteen studies with 1920 patients were included (11 with 1268 patients using RECIST and 6 with 804 patients using SWOG). By RECIST criteria, the pooled disease response rate by random-effects model was 29.1% (95% confidence interval [CI], 20.2%-38.9%), and disease control rate was 74.1% (95% CI, 67.8%-80.0%). By SWOG criteria, the pooled disease response rate by random-effects model was 30.6% (95% CI, 20.7%-41.5%), and disease control rate was 81.1% (95% CI, 76.4%-85.4%). Induction therapy, typically 4 treatments, with Lu PRRT is an effective method of treating unresectable metastatic neuroendocrine tumors with significant disease response and control rates.

Myeloid Leukemia with Myelodysplasia-Related Changes Was Not a Prognostic Factor Under Allogenic Hematopoietic Stem Cell Transplantation

Introduction and Objectives Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is briefly defined as an AML which have multilineage dysplasia (MLD), a history of myelodysplastic syndrome (MDS) and/or an MDS-related cytogenetic abnormalities. Recent study showed that AML-MRC exhibits a worse clinical outcome than AML not otherwise specified (AML-NOS). Though allogenic hematopoietic stem cell transplantation (allo-SCT) is believed to improve the outcome of AML-MRC, few reports had referred to its benefit. The purpose of this study was to clarify the outcome and the prognostic factors of patients (pts) with AML-MRC who underwent allo-SCT. Methods Between January 2008 to December 2017, a total of 138 consecutive AML-MRC (n = 50) and AML-NOS (n = 88) pts who underwent allo-SCT in Japanese Red Cross Nagoya Daiichi Hospital were retrospectively analyzed. The classifications of diagnoses were made according to the criteria of the 2008 WHO classification and data of clinical, pathologic and cytogenetic features were collected. Results Among 138 pts, the median age at SCT was 45.5 years (range, 17 to 66 years), and 59 (43%) pts were female. Performance status was 2-4 for 7 (5%) pts and HCT-CI was ≧3 for 14 (10%) pts. The cytogenetic features were classified as intermediate risk for 78 (57%) pts and high or unknown risk for 60 (43%) pts according to the Southwest Oncology Group (SWOG) criteria. Ninety-five (69%) pts were in complete remission (CR) at SCT. Twenty-four (17%) pts had related donor and 71 (51%), 31 (22%), and 36 (26%) pts received bone marrow, peripheral blood stem cell, and cord blood, respectively. Myeloablative conditioning was performed in 87 (63%) pts. The median follow-up period for survivors was 51 months (range, 3 to 108 months). Compared to AML-NOS pts, pts with AML-MRC had significantly low frequency of CR at SCT (48% vs 81%, p Subgroup analysis was performed and SWOG high risk cytogenetics was identified as independent prognostic factor in the pts with AML-NOS (HR 2.31, p = 0.01). Among pts with AML-MRC, MDS-related cytogenetics (HR 4.52, p Conclusion Here we show that cytogenetic features, but not a diagnosis of AML-MRC, is one of the most important prognostic factors when performing allo-SCT,

The efficacy of the available peptide receptor radionuclide therapy for neuroendocrine tumors: a meta-analysis.

This study was carried out to compare the efficacy of Y, Lu, and combination of both radiotracers (tandem) peptide receptor radionuclide therapy (PRRT) in patients with inoperable and metastatic neuroendocrine tumors. Systematic searches of PubMed and SciVerse Scopus databases were performed till December of 2016. The data were categorized into three groups: Y-PRRT, Lu-PRRT, and tandem-PRRT. Each group was subdivided on the basis of the response criteria used: Response Evaluation Criteria in Solid Tumors (RECIST) or Southwest Oncology Group (SWOG) criteria. Disease response and disease control rates of each group were analyzed. For the RECIST group, Y-PRRT disease response rates ranged from 22.81 to 56.1%, with a pooled random effect of 42.92%, and the disease control rate was 100%. Lu-PRRT disease response rates ranged from 27.63 to 57.35%, with a pooled random effect of 33.41%, and disease control rates ranged between 71.88 and 100%, with a pooled fixed effect of 79.32%. As for tandem-PRRT, disease response rates ranged between 42.11 and 66.67%, with a pooled fixed effect of 50.52%, and the disease control rate ranged between 93.33 and 100%, with a pooled fixed effect of 98.97%.For the SWOG group, Y-PRRT disease response rates ranged from 5.13 to 26.56%, with a pooled random effect of 13.4%, and disease control rates ranged between 76.56 and 85.9%, with a pooled fixed effect of 80.93%. Lu-PRRT disease response rates ranged from 6.06 to 60.29%, with a pooled random effect of 26.4%, and the disease control rates between 48.48 and 85.29%, with a pooled random effect of 74.53%. Y-PRRT had the highest disease control rates under both RECIST and SWOG criteria. Tandem-PRRT had the highest disease response rate in the RECIST criteria, indicating that PRRT should be customized to each patient individually for maximum benefit.

Karyotype plus NPM1 mutation status defines a group of elderly patients with AML (≥60 years) who benefit from intensive post-induction consolidation therapy.

Although it is generally appreciated that a subset of elderly patients with acute myeloid leukemia (AML) may benefit from intensive consolidation, little is known about variables predicting such benefit. We analyzed 192 consecutive patients with de novo AML aged ≥60 years who were treated with intensive chemotherapy. About 115 patients (60%) achieved complete hematologic remission (CR). Among several parameters, the karyotype was the only independent variable predicting CR (P < 0.05). About 92% (105/115) of the CR-patients received up to four consolidation cycles of intermediate dose ARA-C. Median continuous CR (CCR) and disease-free survival (DFS) were 1.3 and 1.1 years, respectively. CCR, DFS, and survival at 5 years were 23%, 18%, and 15%, respectively. Only karyotype and mutated NPM1 (NPM1mut) were independent predictors of survival. NPM1mut showed a particular prognostic impact in patients with normal (CN) or non-monosomal (Mkneg) karyotype by Haemato-Oncology Foundation for Adults in the Netherlands (HOVON)-criteria, or intermediate karyotype by Southwest Oncology Group (SWOG)-criteria. The median CCR was 0.94, 1.6, 0.9, and 0.5 years for core-binding-factor, CN/Mkneg-NPM1mut, CN/Mkneg-NPM1-wild-type AML, and AML with monosomal karyotype, respectively, and the 5-year survival was 25%, 39%, 2%, and 0%, respectively (P < 0.05). Similar results (0.9, 1.5, 0.9, and 0.5 years) were obtained using modified SWOG criteria and NPM1 mutation status (P < 0.05). In summary, elderly patients with CN/Mkneg-NPM1mut or CBF AML can achieve long term CCR when treated with intensive induction and consolidation therapy whereas most elderly patients with CN/Mkneg-NPM1wt or Mkpos AML may not benefit from intensive chemotherapy. For these patients either hematopoietic-stem-cell-transplantation or alternative treatments have to be considered. Am. J. Hematol. 91:1239-1245, 2016. © 2016 Wiley Periodicals, Inc.

Outcomes of 1st Remission Induction Chemotherapy in Acute Myeloid Leukemia Cytogenetic Risk Groups

Background:Diagnostic karyotyping analysis is routinely used in acute myeloid leukemia (AML) clinics. Categorization of patients into risk stratified groups (favorable, intermediate and adverse) according to cytogenetic findings can serve as a valuable independent prognostic factor.Method and Material:A retrospective descriptive study was conducted based on the patient records of newly diagnosed non-M3 AML young adult cases undergoing standard 3+7 i.e, Daunorubicin and Ara-C (DA) as remission induction chemotherapy. Diagnostic cytogenetic analysis reports were analyzed to classify the patients into risk stratified groups according to South West Oncology Group criteria and prognostic significance was measured with reference to achievement of haematological remission after 1st induction chemotherapy.Results:A normal karyotype was commonly expressed, found in 47.2% of patients, while 65% (n=39) appeared to have intermediate risk cytogenetics, and 13.3% (n=8) adverse or unclassified findings. Favourable cytogenetics was least frequent in the patient cohort, accounting for only 8.3 % (n=5). The impact of cytogenetic risk groups on achievement of haematological remission was evaluated by applying Pearson Chi-square, and was found to be non-significant (df=12, p=0.256) but when the outcomes of favourable risk groups with intermediate, adverse and unclassified findings compared, results were highly significant (df=6, p=0.000) for each comparison. In patients of the favourable cytogenetic risk group, HR?? was reported in 40% (n=2/5), as compared to 62.2% (n=23/37) in the intermediate cytogenetic risk group, 57.1% (n=4/7) in the adverse cytogenetic risk group and 28.6% (n=2/7) in hte unclassified cytogenetic risk group.Conclusion:Cytogenetic risk stratification for AML cases following criteria provided by international guidelines did not produce conclusive results in our Pakistani patients. However, we cannot preclude an importance as the literature clearly supports the use of pretreatment karyotyping analysis as a significant predictive marker for clinical outcomes. The apparent differences between Pakistani and Western studies indicate an urgent need to develop risk stratification guidelines according to the specific cytogenetic makeup of South Asian populations.

Preclinical activity of the novel B-cell-specific Moloney murine leukemia virus integration site 1 inhibitor PTC-209 in acute myeloid leukemia: Implications for leukemia therapy.

Curing patients with acute myeloid leukemia (AML) remains a therapeutic challenge. The polycomb complex protein B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) is required for the self-renewal and maintenance of leukemia stem cells. We investigated the prognostic significance of BMI-1 in AML and the effects of a novel small molecule selective inhibitor of BMI-1, PTC-209. BMI-1 protein expression was determined in 511 newly diagnosed AML patients together with 207 other proteins using reverse-phase protein array technology. Patients with unfavorable cytogenetics according to Southwest Oncology Group criteria had higher levels of BMI-1 compared to those with favorable (P = 0.0006) or intermediate cytogenetics (P = 0.0061), and patients with higher levels of BMI-1 had worse overall survival (55.3 weeks vs. 42.8 weeks, P = 0.046). Treatment with PTC-209 reduced protein level of BMI-1 and its downstream target mono-ubiquitinated histone H2A and triggered several molecular events consistent with the induction of apoptosis, this is, loss of mitochondrial membrane potential, caspase-3 cleavage, BAX activation, and phosphatidylserine externalization. PTC-209 induced apoptosis in patient-derived CD34(+)CD38(low/-) AML cells and, less prominently, in CD34(-) differentiated AML cells. BMI-1 reduction by PTC-209 directly correlated with apoptosis induction in CD34(+) primary AML cells (r = 0.71, P = 0.022). However, basal BMI-1 expression was not a determinant of AML sensitivity. BMI-1 inhibition, which targets a primitive AML cell population, might offer a novel therapeutic strategy for AML.

Outcome of peptide receptor radionuclide therapy with 177Lu-octreotate in advanced grade 1/2 pancreatic neuroendocrine tumours

The clinical benefit of peptide receptor radionuclide therapy (PRRT) in patients with pancreatic neuroendocrine tumours (pNET) has not yet been well described and defined in its full extent due to limited data in this tumour subgroup. This study was intended to obtain robust, comparative data on the outcome and toxicity of standardized PRRT with (177)Lu-octreotate in a well-characterized population of patients with advanced pNET of grade 1/2 (G1/2). We retrospectively analysed a cohort of 68 pNET patients with inoperable metastatic disease consecutively treated with (177)Lu-octreotate (four intended cycles at 3-monthly intervals; mean activity per cycle 8.0 GBq). Of these 68 patients, 46 (67.6 %) had documented morphological tumour progression during the 12 months before initiation of treatment, and PRRT was the first-line systemic therapy in 35 patients (51.5 %). Response was evaluated according to modified Southwest Oncology Group (SWOG) criteria and additionally with Response Criteria in Solid Tumors (RECIST) 1.1. Survival was analysed using Kaplan-Meier curves and Cox proportional hazards model for univariate and multivariate analyses. Toxicity was assessed by standard follow-up laboratory work-up including blood count, and liver and renal function, supplemented with serial (99m)Tc-DTPA clearance measurements. The median follow-up period was 58 months (range 4 - 112). Reversible haematotoxicity (grade 3 or more) occurred in four patients (5.9 %). No significant nephrotoxicity (grade 3 or more) was observed. Treatment responses (SWOG criteria) consisted of a partial response in 41 patients (60.3 %), a minor response in 8 (11.8 %), stable disease in 9 (13.2 %), and progressive disease in 10 (14.7 %). Median progression-free survival (PFS) and overall survival (OS) were 34 (95 % CI 26 - 42) and 53 months (95 % CI 46 - 60), respectively. A G1 proliferation status was associated with longer PFS (p = 0.04) and OS (p = 0.044) in the multivariate analysis. Variables linked to impaired OS, on the other hand, were a reduced performance status (Karnofsky score ≤ 70 %, p = 0.007), a high hepatic tumour burden (≥ 25 % liver volume, p = 0.017), and an elevated plasma level of neuron-specific enolase (NSE >15 ng/ml, p = 0.035). The outstanding response rates and survival outcomes suggest that PRRT is highly effective in advanced G1/2 pNET when compared to data of other treatment modalities. Independent predictors of survival are the tumour proliferation index, the patient's performance status, tumour burden and baseline plasma NSE level.

Predictors of Long-Term Outcome in Patients with Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors After Peptide Receptor Radionuclide Therapy with 177Lu-Octreotate

Outcome analyses for patients with gastroenteropancreatic neuroendocrine tumors (GEP NET) after peptide receptor radionuclide therapy (PRRT) are still limited, especially with regard to the impact of the Ki-67 index. Using a single-center analysis, we aimed to establish predictors of survival. We retrospectively analyzed a consecutive cohort of 74 patients who had metastatic GEP NET and underwent PRRT with (177)Lu-octreotate (mean activity of 7.9 GBq per cycle, aimed at 4 treatment cycles at standard intervals of 3 mo). Patients (33 with pancreatic NET and 41 with nonpancreatic GEP NET) had unresectable metastatic disease graded as G1 or G2 (G1/G2) and documented morphologic or clinical progression within less than 12 mo or uncontrolled disease under somatostatin analog treatment. Responses were evaluated according to modified Southwest Oncology Group criteria. Potential predictors of survival were analyzed with the Kaplan-Meier curve method (log-rank test) and multivariate analysis (P < 0.05). The response rates were 36.5% partial response, 17.6% minor response, 35.1% stable disease, and 10.8% progressive disease for the entire cohort; 54.5% partial response, 18.2% minor response, 18.2% stable disease, and 9.1% progressive disease for pancreatic NET; and 22.0% partial response, 17.1% minor response, 48.8% stable disease, and 12.2% progressive disease for nonpancreatic GEP NET. The median progression-free survival and overall survival were 26 mo (95% confidence interval, 18.3-33.7) and 55 mo (95% confidence interval, 48.8-61.2), respectively. Besides the Ki-67 index, a Karnofsky performance score of less than or equal to 70%, a hepatic tumor burden of greater than or equal to 25%, and a baseline plasma level of neuron-specific enolase of greater than 15 ng/mL independently predicted shorter overall survival (hazard ratio, 2.1-3.1). Patients with a Ki-67 index of greater than 10% still had median progression-free survival and overall survival of 19 and 34 mo, respectively. The results of this study demonstrated the favorable response and long-term outcome of patients with G1/G2 GEP NET after PRRT. Independent predictors of survival were the Ki-67 index, the patient's performance status (Karnofsky performance scale score), the tumor burden, and the baseline neuron-specific enolase level. Even patients with a Ki-67 index of greater than 10% seemed to benefit from PRRT, with a good response and a notable long-term outcome. We present the first evidence, to our knowledge, that even in patients with metastatic disease the distinction between G1 and G2-in particular, between G1 (Ki-67 index of 1%-2%) and low-range G2 (Ki-67 index of 3%-10%)-provides prognostic stratification.

Comparison of Response Evaluation in Patients with Gastroenteropancreatic and Thoracic Neuroendocrine Tumors After Treatment with [177Lu-DOTA0,Tyr3]Octreotate

Response Evaluation Criteria In Solid Tumors (RECIST) (unidimensional), Southwest Oncology Group (SWOG) solid tumor response criteria (bidimensional), and their modified variants are commonly used in the tumor response assessment after treatment of gastroenteropancreatic and thoracic neuroendocrine tumors (NETs). In the current study, RECIST, SWOG criteria, modified RECIST (mRECIST), and modified SWOG (mSWOG) criteria were compared in patients with NETs treated with [(177)Lu-DOTA(0),Tyr(3)]octreotate ((177)Lu-octreotate). Two-hundred sixty-eight Dutch patients with NETs who had been treated with (177)Lu-octreotate between January 2000 and April 2007 were studied. CT or MR imaging scans were analyzed using RECIST, SWOG criteria, mRECIST, and mSWOG criteria (including the tumor response class minor response [decrease of 13%-30% for mRECIST and 25%-50% for mSWOG]). The outcomes were correlated with progression-free survival (PFS) and overall survival (OS). Eleven patients had an unknown tumor response and were excluded. The rates of objective response (OR) (complete response + partial response [+minor response for mRECIST/mSWOG]), stable disease, and progressive disease (PD) were 28%, 49%, and 24%, respectively, according to RECIST; 25%, 49%, and 26%, respectively, according to SWOG; 44%, 33%, and 24%, respectively, according to mRECIST; and 45%, 29%, and 26%, respectively, according to mSWOG. In patients who had OR, stable disease, or PD, the median PFS was 26-30, 27-34, and 8 mo, respectively, with any of the 4 response criteria. In patients who had OR, stable disease, or PD, the median OS was 55-57, 56-74, and 11-12 mo, respectively, with any of the 4 response criteria. Subanalyses for patients who had progression before treatment start were comparable. Patients with PD as treatment outcome had significantly shorter PFS and OS than patients with an OR or stable disease with all 4 scoring systems. PFS and OS were comparable for patients with tumor regression and stable disease. The addition of the response class minor response did not improve the correlation with PFS and OS. The 4 scoring systems gave comparable results in terms of PFS and OS per categorized outcome.

Autologous peripheral blood stem cell transplantation with granulocyte colony-stimulating factor combined conditioning regimen as a postremission therapy for acute myelogenous leukemia in first complete remission

We retrospectively analyzed the outcomes of 81 patients with non-M3 acute myelogenous leukemia (AML) in first complete remission (CR1) who were treated with high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplantation (Auto-PBSCT) by the Fukuoka Blood and Marrow Transplantation Group between 1989 and 2005. Cytogenetically, 16 patients were defined as good risk, 56 as intermediate risk, and nine as poor risk, following the Southwest Oncology Group criteria. The pre-transplant conditioning regimen consisted of high-dose busulfan, etoposide, and cytarabine (BEA regimen), combined with priming by granulocyte colony-stimulating factor (G-CSF). Disease-free survival (DFS) and overall survival at 5years were 64.0% (95% CI 52.5-73.4) and 66.4% (95% CI 54.9-75.6) after Auto-PBSCT at a median follow-up time of 103months (range 3-240months), respectively. Two patients died of transplant-related pulmonary complications 6months after Auto-PBSCT without relapse. The 5-year DFS rates of patients in the genetically good-, intermediate-, and poor-risk groups were 80.8, 64.3, and 33.3%, respectively, but there was no significant difference statistically among the risk groups (log-rank p=0.0579). These observations suggest that HDCT supported by Auto-PBSCT with the BEA regimen combined with G-CSF priming is a therapeutic option for postremission therapy of AML in CR1.

Prospective Phase II Multicenter Study of Conditioning with Treosulfan, Fludarabine and Low-Dose (2 Gy) Total Body Irradiation Followed by Hematopoietic Cell Transplantation From Related or Unrelated Donors for Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome

AbstractAbstract ▪963▪This icon denotes a clinically relevant abstract Background:We showed previously that a transplant conditioning regimen of treosulfan combined with fludarabine was associated with low non-relapse mortality (NRM) and a high probability of survival in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) with low or intermediate risk cytogenetics (Nemecek et al, BBMT 2011). Relapse rates were high, however, in patients with high-risk cytogenetics, which resulted in a 2-year relapse-free survival of 39% in this group. Objective:The objective of the present study was to reduce the relapse incidence and improve overall survival (OS) in patients with high-risk AML or MDS by adding low-dose TBI (2 Gy) to the treosulfan plus fludarabine regimen. Patients and methods:Ninety-six patients with AML (n=60) or MDS (n=36) were enrolled. Patients were 60 years of age or younger (median age: 50 years) and had high-risk MDS, unfavorable or intermediate-risk AML in first complete remission (CR) or any AML beyond first CR. Cytogenetic risk in AML was stratified using the Southwest Oncology Group criteria, while the World Health Organization-based Prognostic Scoring System was used in patients with MDS. Patients received intravenous (IV) treosulfan, 14 g/m2/day on days -6 to -4, IV fludarabine 30 mg/m2/day on days -6 to -2, and 2 Gy TBI on day 0, followed by infusion of marrow (n=11) or peripheral blood stem cells (n=85) from related (n=27) or unrelated (n=69) donors. Donors were single HLA allele-level mismatched in 9 patients and HLA-matched at the allele level in 87 patients. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate (10 mg/m2 on days +1, +3, +6 and +11 post-HCT) and tacrolimus (days –1 to +180). Results:All evaluable patients engrafted. With a median follow-up of 12.8 (range, 0.2 – 34.7) months in surviving patients, the estimated 2-year progression-free survival and OS were 59% and 68%, respectively. The cumulative incidences of relapse or progression and NRM at 2 years were 30% and 11%, respectively (Figure 1). The incidences of grade II (grades III-IV) acute and extensive chronic GVHD at 2 years were 48% (11%) and 40%, respectively.Relapse occurred in 39% of patients with AML and 18% of patients with MDS (Figure 2A). OS was 61% among patients with AML and 79% in patients with MDS (Figure 2B). In univariate analyses, cytogenetic risk status did not impact relapse for the entire cohort nor for patients with AML or MDS analyzed separately (Figures 3A and 3B). As a result, 2-year OS rates were similar in patients with favorable/intermediate and unfavorable cytogenetic risk AML (64% and 57%, respectively) or in good/intermediate and poor risk MDS (88% and 71%, respectively). Patients with AML with minimal residual disease (MRD; n=10) or in refractory relapse (n=4) at the time of HCT, had higher relapse rates (87% vs. 25%) and lower OS (25% vs. 81%) at 2 years than patients in remission without MRD at the time of HCT. Conclusions:In summary, treosulfan, in combination with fludarabine and low-dose TBI was an effective conditioning regimen for allogeneic HCT in patients with AML (in CR at the time of HCT) or MDS. Relapse and OS rates in patients with high-risk cytogenetics did not differ significantly from those in patients with low or intermediate risk karyotypes. The relapse rate was particularly low in patients with MDS, including those with high risk cytogenetics, and further trials with treosulfan-based regimens are warranted. For patients with AML who have residual disease at HCT novel regimens need to be developed. The data suggest that in patients with AML high risk as defined by cytogenetics had a different impact on outcome than high risk as defined by other parameters, such as tumor burden. [Display omitted] [Display omitted] [Display omitted] Disclosures:Gyurkocza:medac GmbH, Hamburg, Germany: Research Funding. Off Label Use: Off-label usage of treosulfan, fludarabine, methotrexate and tacrolimus will be discussed. Sickle:medac GmbH, Hamburg, Germany: Research Funding. Baumgart:medac GmbH, Hamburg, Germany: Employment. Deeg:medac GmbH, Hamburg, Germany: Research Funding.

Effectiveness of first line treatment with bortezomib prior to autologous stem cell transplantation for multiple myeloma

Background: In this retrospective study we evaluated effectiveness and safety of first- line treatment with bortezomib and dexamethasone in multiple myeloma patients, comparing our results with already published clinical studies. Methods: Patients received bortezomib as part of everyday clinical practice and according to the latest guidelines of the Združenje hematologov Slovenije . Patients who were previously treated with first-line VAD (vincristine, doxorubicin modified with farmarubicine, dexamethasone), but due to uneffectiveness changed the treatment to bortezomib, were also included in the study. In 30 patients effectiveness was evaluated after average 3–4 cycles of bortezomib and dexamethasone according to the modified Southwest Oncology Group criteria. Treatment effectiveness was evaluated according to the previous VAD treatment, renal function and cytogenetic analysis. Side effects and reasons for early treatment discontinuation were described. Results: Patients received 2 to 8 cycles (median 4 cycles) of bortezomib and dexamethasone treatment. After average 3–4 cycles, 80 % of patients acheived good treatment response (56.7 % very good partial response, 23.3 % partial response). We observed that the treatment effectiveness was not influenced by previous VAD treatment, renal insufficiency and negative cytogenetic analisys, since we observed similar rates of very good partial response and partial response in patients without previous VAD treatment (82.3 % vs. 76.9 %), normal renal function (85.7 % vs. 75 % ) and normal cytogenetics (77.8 % vs. 80 %), although statistical evaluation was not possible due to small number of patients. The most common side effect was neuropathy (40 %) and in 5 patients (16.6 %), due to grade 3 or more, the treatment was discontinued. Other side effects were: anemia (26.6 %), infection (166 %), thrombocytopenia (10 %), neutropenia (6.6 %), gastrointestinal problems (23.3 %) and herpes zooster (6.6 %). Conclusions: Bortezomib (Velcade) in combination with dexamethasone is an effective and safe first-line multiple myeloma treatment and is not influenced by renal insuficience, unfavourable cytogenetic analysis or previous uneffective VAD treatment.

Liver, Gastrointestinal, and Cardiac Toxicity in Intermediate Hepatocellular Carcinoma Treated With PRECISION TACE With Drug-Eluting Beads: Results From the PRECISION V Randomized Trial

The purpose of our study was to evaluate hepatic, gastrointestinal, and cardiac toxicity after PRECISION transarterial chemoembolization (TACE) with drug-eluting beads (DEB) versus conventional TACE with doxorubicin in the treatment of intermediate-stage hepatocellular carcinoma (HCC). Two hundred twelve patients (185 men and 27 women; mean age, 67 years) were randomized to TACE with DEB or conventional TACE. The majority of patients (67% in both groups) presented in a more advanced stage. Safety was measured by rate of adverse events (Southwest Oncology Group criteria) and changes in laboratory parameters. Cardiotoxicity was assessed with left ventricular ejection fraction (LVEF) mainly on MRI or echocardiography. The mean maximum postchemoembolization alanine transaminase increase in the DEB group was 50% less than in the conventional TACE group (p < 0.001) and 41% less in respect to aspartate transaminase (p < 0.001). End-of-study values returned to approximately baseline levels but with greater variability in conventional TACE patients. Treatment-emergent adverse events in the hepatobiliary system organ class occurred in 16.1% of DEB group patients compared with 25% of conventional TACE patients. There were fewer liver toxicity events in the DEB group. There was a small but statistically significant difference in mean change from baseline in LVEF between the two groups of 4 percentage points for the conventional TACE group (95% CI, 0.71-7.3; p = 0.018). PRECISION TACE with DEB loaded with doxorubicin offers a safe therapy option for intermediate-stage HCC, even in patients with more advanced liver disease.

Liver, gastrointestinal, and cardiac toxicity in intermediate hepatocellular carcinoma treated with PRECISION TACE with drug-eluting beads: Results from the PRECISION V randomized trial.

e14660 Background: To evaluate the toxicity focussing on hepatic, gastrointestinal and cardiac parameters following PRECISION TACE with DC Bead versus conventional transarterial chemoembolization (cTACE) in the treatment of intermediate-stage hepatocellular carcinoma (HCC). Methods: This prospective, randomized, multicenter study was conducted under best practice trial management and authorized by local institutional review boards. Informed consent was obtained. 212 patients (185 men/27 women; mean: 67 years) were randomized to be treated with DC Beads or cTACE. The majority of both groups presented in a more advanced stage. Safety was measured by rate of adverse events (South West Oncology Group criteria) and changes in laboratory parameters. Cardiotoxicity was assessed by means of left ventricular ejection fraction (LVEF) in MRI or echocardiography. Results of the two groups were compared using the chi-square test and Student's t-test. Mean maximum alanine transaminase increase in the DC Bead group was 50% in the cTACE group (p<0.001) and 59% for aspartate transaminase (p<0.001). For bilirubin, mean increase was 5.30±15.13 vs. 13.53±73.89μmol/L. Concerning gastrointestinal disorders 120 adverse events (AEs) occurred in 57/93 (61.3%) patients in the DC Bead group vs. 114 in 49/108 (45.4%) in cTACE. Concerning hepatobiliary disorders serious AEs occurred in 8/93 (8.6%) vs. 11/108 (10.2%) patients. LVEF showed an increase in the DC Bead group by +2.7±10.1 percentage points and a small decrease by -1.5±7.6 in the cTACE group, p=0.018. PRECISION TACE is safe, even in more advanced HCC patients. Serious liver and cardiac toxicity were significantly lower in the DC Bead group. No significant financial relationships to disclose.

Salvage Therapy with 177Lu-Octreotate in Patients with Bronchial and Gastroenteropancreatic Neuroendocrine Tumors

Regular therapy with the radiolabeled somatostatin analog (177)Lu-octreotate (22.2-29.6 GBq) in patients with gastroenteropancreatic or bronchial neuroendocrine tumors results in tumor remission in 46% of patients, including minor response. We present the effects of additional therapy with (177)Lu-octreotate in patients in whom progressive disease developed after an initial benefit from regular therapy. Thirty-three patients with progressive disease after an initial radiologic or clinical response were treated with additional cycles of (177)Lu-octreotate. The intended cumulative dose of additional therapy was 14.8 GBq in 2 cycles. Responses were evaluated using Southwest Oncology Group criteria, including minor response (tumor size reduction of >or=25% and <50%). Median time to progression (TTP) after regular therapy was 27 mo. In 4 patients, the intended cumulative dose was not achieved (2 had progressive disease, 2 had long-lasting thrombocytopenia). Hematologic toxicity grade 3 was observed in 4 patients, and grade 4, in 1. The median follow-up time was 16 mo (range, 1-40 mo). No kidney failure or myelodysplastic syndrome was observed. Renewed tumor regression was observed in 8 patients (2 partial remission, 6 minor response), and 8 patients had stable disease. Median TTP was 17 mo. Treatment outcome was less favorable in patients with a short TTP after regular cycles. Treatment effects in patients with pancreatic neuroendocrine tumors were similar to those in patients with other gastroenteropancreatic neuroendocrine tumors. Most patients tolerated additional cycles with (177)Lu-octreotate well. None developed serious delayed adverse events. Additional cycles with (177)Lu-octreotate can have antitumor effects, but effects were less than for the regular cycles. This may be because of a worse clinical condition, more extensive tumor burden, or changed tumor characteristics. We conclude that this salvage therapy can be effective and is safe.

AML Patients with Monosomal Karyotype Are Characterized by Absence of NPM1 and FLT3 Mutations and Worse Clinical Outcome.

Abstract 2638Poster Board II-614 Background:The importance of cytogenetics in prognosis of AML is now widely recognized and accepted in clinical practice. A recent study found that autosomal chromosomal monosomy predicted for an adverse outcome. The goal of this study is to characterize patients with monosomal karyotype by mutation status and clinical features. Methods:One-hundred forty consecutive AML patients diagnosed at Stanford University Hospital between 2005 and 2008 with adequate material for mutation analysis were studied. Cases were classified using the 2008 WHO criteria. Diagnostic cytogenetic findings were reviewed and patients were stratified into risk groups using Southwest Oncology Group criteria. An abnormality was considered clonal when at least two metaphases had the same aberration, except for clonal monosomy, which required at least three metaphases. The karyotype analysis was based on 20 or more metaphases. All samples were tested for NPM, FLT3 (ITD and D835) and CEBPA mutations. Clinical parameters including hemogram data at time of diagnosis were reviewed. Clinical follow-up including overall survival (OS), progression free survival (PFS) and complete remission (CR) rates were retrospectively determined. Kaplan-Meier methods and univariate Cox proportional hazards regression analysis were used to compare the clinical data. Results:The cases included 77 males and 63 females with a median age of 58 (range 17-83). Cytogenetic risk-group stratification resulted in 14 patients with favorable, 88 with intermediate and 28 with unfavorable risk status. Loss of one or more autosomal chromosomes was present in 18 /130 patients (13.8%) with available cytogenetic studies. A single autosomal monosomy was found in 5 patients while 13 patients had two or more autosomal monosomies. The most common chromosomes lost in these 18 patients included 7 (55% of 18 cases), 5 (50%), 17 (33%), 21 (22%), 20 (22%), 22 (17%) and 18 (11%). Using the 2008 WHO criteria, there were 66 AML with myelodysplasia-related changes (AML-MRC), 55 AML not otherwise specified (AML-NOS), 14 AML with either t(8;21), inv(16) or t(15;17) and 5 therapy related AMLs. Overall, 35 patients (25% of all patients) had a NPM1 mutation (19 of which were FLT3 mutated), 33 had FLT3-ITD mutation (24%), 11 had FLT3-D835 (8%) and 11 had a CEBPA mutation (8%) (4 of which were FLT3 mutated). Patients with monosomal karyotype were significantly older (83 vs. 59 years, p=0.0125) and presented with lower WBC (34 vs. 66 K/uL, p=0.0006), lower platelets (41 vs. 64 K/uL, p=0.0111), and lower blasts (38% vs. 65%, p=0.0030) as compared to the rest of AML patients. In addition, patients with monosomal karyotype were more frequently diagnosed with AML-MRC (16/18 vs. 48/107, p=0.0034) and exhibited a decreased frequency of NPM1 mutation (0/18 vs. 28/107, p=0.0138) and FLT3-ITD mutation (0/18 vs. 29/107, p=0.0117). Clinical outcome data showed that patients with monosomal karyotype had a significantly worse OS, PFS and CR compared to the rest of AML patients (OS p=0.001, PFS p=0.002 and CR p=0.0262). Dividing patients by number of monosomies showed that patients with 2 or more monosomies had a significantly worse OS (p=0.0001) and PFS (p=0.0045) than patients without any monosomies. However, no difference in OS or PFS was seen when comparing patients with 1 monosomy to those with 2 or more monosomies. Within the AML-MRC group, monosomal karyotype correlated with lower WBC (17 vs. 37 K/uL, p=0.0005), lower platelets (21 vs. 35 K/uL, p=0.0095), lower blasts (19% vs. 36%, p=0.0015) and shorter OS (p=0.0322) and PFS (p=0.0084). Conclusion:AML patients with monosomal karyotype exhibit a significantly worse OS, PFS and lower CR as compared to other AML patients. Most of patients fall within the newly defined AML-MRC group and are characterized by significant absence of NPM1 and FLT3-ITD mutations. Disclosures:No relevant conflicts of interest to declare.

Black Patients with Acute Myeloid Leukemia (AML) Are Younger and More Commonly Female, but Have a Higher Incidence of Complex Karyotypes When Compared to Whites.

Abstract 2649Poster Board II-625Racial differences in clinical characteristics and treatment outcomes have been identified in a number of malignancies, but these relationships have not been extensively studied in the adult AML population. A single cooperative group study of a population that included 10% blacks (Sekeres, Blood 2004;103:4036) reported a higher incidence of several translocations, both favorable and unfavorable, as well as more frequent favorable and unfavorable and less frequent normal karyotypes in blacks, compared to whites. This study's goal was to examine the prevalence of karyotype abnormalities and FLT3 mutations in unselected patients of different racial backgrounds treated in our Cancer Center, which is in a large urban medical center with a diverse patient population. Secondary leukemia patients and older patients, who are underrepresented in clinical trials, were included in our study population. We retrospectively reviewed patients with a diagnosis of AML evaluated and treated at the University of Maryland Greenebaum Cancer Center during the years 2000-2009. Cases were reviewed for age, sex, race, de novo or secondary AML onset, karyotype and FLT3 mutation status. Cytogenetic data were categorized into the favorable karyotypes t(15;17), t(8;21), inv(16) or t(16;16), normal and other intermediate karyotypes, and complex (3 or more unrelated numerical or structural cytogenetic changes) and other unfavorable karyotypes by Southwest Oncology Group criteria (Slovak, Blood 2000;96:4075). A total of 498 AML patients were identified. Cytogenetic data were available for 463 patients (93%), and FLT3 data for 153 (31%). Of the patients with available karyotype data, 333 (72%) were white, 91 (20%) black, 19 (4%) Hispanic, and 19 (4%) Asian. t(15;17), defining acute promyelocytic leukemia (APL, FAB M3), was more common in non-whites than whites (16% vs. 7%; p=0.006). As 92% of our population was white or black, further subgroup analysis was limited to differences between these two groups. Blacks presented at a significantly younger age than whites (54.5 years vs. 59.8 years; p<0.001) and were more frequently female (55% vs. 47%; p<0.001). The prevalence of secondary leukemia was similar in blacks and whites (24% vs. 28%). A strikingly higher incidence of complex karyotypes was seen in blacks when compared to whites (28% vs. 13%; p=0.001). When considering only patients with complex karyotypes, black and white patients had a similar age of AML presentation (median 57 vs. 61 years; p = 0.16), but the proportion of women was significantly higher among blacks, compared to whites (64% vs. 39%, p<0.001). The incidence of secondary AML (38% vs. 37%) and of both therapy-related AML (21% vs. 24%) and antecedent hematological disorders (16% vs. 14%) was similar in blacks and whites with complex karyotypes. A similar proportion of black and white patients with complex karyotypes underwent stem cell transplantation (16% vs. 20%). Survival among both black and white patients with complex karyotypes was similarly poor, with long-term survival in only 1 of 25 black patients and 2 of 44 white patients. No other significant differences in karyotype distributions were found between black and white patients, and the frequency of FLT3 mutations did not differ between races when examined across all karyotypes (n= 140, black and white patients) or only in patients with normal karyotypes (n=64, black and white patients). Although black patients with AML in our population presented at a younger age, were more frequently female and had a similar incidence of secondary leukemia, they had a significantly higher incidence of complex karyotypes when compared to white AML patients. Risk factors responsible for this difference remain to be identified. Disclosures:No relevant conflicts of interest to declare.