Increase In Treatment-related Mortality Research Articles

The health risk of social disadvantage is transplantable into a new host

Low socioeconomic status (SES) is a risk factor for mortality and immune dysfunction across a wide range of diseases, including cancer. However, cancer is distinct in the use of allogeneic hematopoietic cell transplantation (HCT) as a treatment for hematologic malignancies to transfer healthy hematopoietic cells from one person to another. This raises the question of whether social disadvantage of an HCT cell donor, as assessed by low SES, might impact the subsequent health outcomes of the HCT recipient. To evaluate the cellular transplantability of SES-associated health risk, we analyzed the health outcomes of 2,005 HCT recipients who were transplanted for hematologic malignancy at 125 United States transplant centers and tested whether their outcomes differed as a function of their cell donor's SES (controlling for other known HCT-related risk factors). Recipients transplanted with cells from donors in the lowest quartile of SES experienced a 9.7% reduction in overall survival (P = 0.001) and 6.6% increase in treatment-related mortality within 3 y (P = 0.008) compared to those transplanted from donors in the highest SES quartile. These results are consistent with previous research linking socioeconomic disadvantage to altered immune cell function and hematopoiesis, and they reveal an unanticipated persistence of those effects after cells are transferred into a new host environment. These SES-related disparities in health outcomes underscore the need to map the biological mechanisms involved in the social determinants of health and develop interventions to block those effects and enhance the health of both HCT donors and recipients.

Maintenance therapy for chronic lymphocytic leukaemia.

Maintenance therapy for chronic lymphocytic leukaemia.

Donor Socioeconomic Status As a Predictor of Altered Immune Function and Treatment Response Following Hematopoietic Cell Transplantation for Hematologic Malignancy

Introduction: Hematopoietic cell transplantation (HCT) carries significant risks for mortality, which are not proportionally shared across individuals. Among HCT recipients, we have previously shown that low socioeconomic status (SES) is predictive of increased mortality following HCT, and the underlying mechanism for this outcome is not fully explained by race, insurance status or access to care. Furthermore, following HCT, the donor immune system replaces that of the recipient, leading to long-term engraftment with donor-derived immune cells. Previous work has not addressed the influence of donor socioeconomic factors on HCT recipient outcomes. Therefore, we hypothesized that SES would impact donor hematopoietic cells and this effect would be transferrable and associated with adverse recipient outcomes.Methods: Recipients of matched unrelated donor allogeneic peripheral blood stem cell HCT between 2000-2013 for hematologic malignancy, resided in the United States (US) with a documented ZIP code, and had a HCT donor with documented US ZIP code were identified from the Center for International Blood and Marrow Transplantation Research (CIBMTR). Using donor ZIP code, SES measures of household income, poverty, education, housing and employment were derived from the U.S. Census American Community Survey. A standardized donor SES composite score was computed as an equally weighted average of the 5 standardized SES variables (mean composite score = 0, standard deviation (SD) = 1). Multivariable models, adjusted for donor and recipient characteristics, were used to evaluate associations between donor SES composite score with HCT recipient disease free survival (DFS), overall survival (OS), treatment related mortality (TRM), relapse, and acute and chronic graft versus host disease (GVHD). Results were considered significant if P < 0.01.Results: Among 2,005 HCT recipients, median age at diagnosis was 51 years (range 1-77), 44% were female, and 55% had acute myeloid leukemia. Median post-HCT follow up was 120 months (range 4-219). Donors were 44% female and median age at hematopoietic cell donation was 34.7 years (range 18-62). The standardized donor composite scores ranged from -2.6 to 3.9, with a higher composite score indicative of greater socioeconomic disadvantage. Multivariable analyses identified significant associations between the standardized donor SES composite score and DFS (HR 1.07 per SD SES, 95% CI 1.02-1.13; p=0.0088), OS (HR 1.09 per SD SES, 95% CI 1.04-1.15; p=0.0007), and TRM (HR 1.10 per SD SES, 95% CI 1.03-1.17; p=0.0049). Significant associations were not identified between donor SES and relapse or GVHD. Quantitatively, recipients transplanted with cells from a donor of greater socioeconomic disadvantage (i.e. SES composite score 2 SD above the mean) experienced a 10% reduction in DFS and OS, and a 5% increase in TRM at 3 years compared with those transplanted with cells from a high-SES donor (SES composite score 2 SD below the mean) (Figure).Conclusions: For the first time, we have demonstrated that socioeconomic disadvantage among HCT donors results in adverse transplant outcomes in the HCT recipient. This novel finding suggests that SES has biologic impacts down to the stem cell level that persist even when transplanted into a new host during HCT. The implications of these findings are broad and suggest the need for public health interventions targeting socioeconomic support as a means for preventing social disparities in cancer treatment outcomes. [Display omitted] DisclosuresVerneris: Novartis: Other: advisory board; jazz: Other: advisory board; Fate Therapeutics: Consultancy.

MM-196: Efficiency and Safety in Autologous Stem Cell Transplant Versus Tandem in Patients with Multiple Myeloma with New Diagnosis

Context: Currently, the therapy of high doses of chemotherapy followed by autologous stem cell transplant (ASCT) is considered standard treatment for patients with newly diagnosed multiple myeloma (MM). However, recently it has been demonstrated that tandem transplant is useful in the subgroup of patients with high-risk myeloma. Objective: Evaluate the efficiency and safety of high-dose chemotherapy therapy followed by ASCT vs tandem in patients with high-risk multiple myeloma and plasma cell leukemia. Design: Retrospective cohort study Setting: Single-center study in a private referral hospital. Patients or other participants: Patients with a recent diagnosis of multiple myeloma according to the IMWG 2014 criteria and high-risk features or plasma cell leukemia that underwent a single or tandem ASCT at our center between 2009 and 2018 were included in the study. High-risk multiple myeloma was defined to patients who cytogenetic analysis of high risk and FISH with (17p); t(4;14); t(14;16) or alteration of chromosome 1 and/or extraosseous extramedullary disease. Main outcome measures: We analyzed the assessed overall survival (OS), event-free survival (EFS), event-free survival and treatment-related mortality (TRM). Results: We included a total of 54 patients, with a median follow-up of 48 months. Time from diagnosis of multiple myeloma to first transplant was 6.6 months and the time between one transplant and the other was 98 days in the tandem group. Patients treated with tandem did not have better OS; HR for mortality for patients treated with tandem transplant vs single transplant=0.8 or EFS (HR=0.76). Response rate was statistically significantly better with tandem (risk ratio=0.69), but with a statistically significant increase in TRM (risk ratio=1.71) Conclusions: The therapy of ASCT continues to be considered efficient and safe for patients with MM. The use of tandem did not result in improved OS or EFS and is associated with improved response rates but increased mortality; however, the tandem is a strategy in a group of patients with high-risk diseases.

HLA discrepancy between graft and host rather than that graft and first donor impact the second transplant outcome.

Second allogeneic hematopoietic stem cell transplantation is a curative treatment option for patients with hematologic malignancies. However, it is unclear whether HLA discrepancy between graft and first donor has an impact on the outcome of second transplantation. We retrospectively analyzed 646 patients receiving second transplantation after an initial HLA mismatched transplantation. With regard to graft-versus-host, the one-allele mismatch (1 mismatch) group (SHR, 1.88; 95%CI: 0.79-4.45; P=0.163) and more than one-allele mismatch group (≥ 2 mismatch) (SHR, 1.84; 95%CI, 0.75–4.51; P=0.182) had higher risks of grade III–IV acute graft-versus-host disease (GvHD) compared to the HLA-matched (0 mismatch) group. In contrast, no difference in risk of acute GvHD was found among the 0, 1, and ≥ 2 mismatch group with respect to graft-versus-first donor. With regard to graft-versus-host, the ≥ 2 mismatch group showed a significantly higher risk of treatment-related mortality (SHR, 1.90; 95%CI, 1.04–3.50; P=0.038) compared to the 0 mismatch group, while the risk of relapse was slightly lower in the ≥ 2 mismatch group (SHR, 068; 95%CI, 0.44–1.06; P=0.086). In contrast, with regard to graft-versus-first donor, there were no significant differences in treatment-related mortality or relapse among the three groups. These findings suggested that HLA discrepancy between graft and host induces transplant-related immunological responses in second transplantation leading to an increase in treatment-related mortality, in contrast, the biological effects of HLA discrepancy between graft and first donor on outcome may be negligible.

High Dose Cytarabine Is Superior to Intermediate Dose Cytarabine As Post-Remission Therapy for Younger Patients with Favorable Risk Acute Myeloid Leukemia

▪In the initial CALGB study and the retrospective analysis that followed 4 years later, high dose cytarabine, used as postremission chemotherapy in patients with acute myeloid leukemia (AML), resulted in significantly better overall survival and sustained remission when compared to lower doses of cytarabine, especially in young patients with core binding factor mutations (CBF). However, the toxicity seen with high dose cytarabine (HiDAC) prompted several studies to evaluate the role of intermediate dose cytarabine (MidAc). These studies concluded that MidAc produced similar overall survival and leukemia free survival to HiDAC while achieving a better side effect profile. Following these later findings, the consolidation protocol for AML patients 60 years or younger treated in the Singapore General Hospital was changed to 3 - 4 cycles of cytarabine 1.5g/m2 q12 D1, 3, and 5 (MidAc) from 3g/m2 q12 D1, 3, and 5 (HiDAC) in 2011. Cytarabine dose for older patients remain unchanged at 1g/m2 q12 D1, 3, and 5. A five year landmark analysis was performed to assess the difference in outcomes between these two regimens.Patients with non-M3 AML treated between 2004 and 2015 who received a cytarabine consolidation after achieving complete morphologic remission post standard 3+7 induction procotol (idarubicin 12mg/m2 D1-3 and cytarabine 100mg/m2 as a continuous infusion from D1-7) were included in the analysis. Patients who received an autologous or allogeneic hematopoietic stem cell transplant at first complete remission were excluded.92 patients were identified for analysis with median age of 47 (range 16-76). The majority of patients belonged to the ELN favorable risk group (62 out of 92). 77 patients were aged 60 years or younger amongst which 48 patients received HiDAC and 29 patients received MidAc after a change in protocol. The median follow up for patients receiving HiDAC and MidAc was 104 and 39 months respectively.The 5-year overall survival (OS) between patients who had HiDAC and MidAc was 66.7% and 45.7% (p=0.16); and the 5-year leukemia free survival (LFS) was 51.9% and 41.6% (p=0.23). For comparison, the 5-year OS for patients above the age of 60 treated before and after 2011 was 16.7% and 46.7% (p = 0.3) and LFS was 16.7% and 55.6% (p= 0.35) respectively.Amongst 55 patients aged 60 or younger with favorable ELN risk, the survival outcomes were significantly better in the cohort receiving HiDAC compared with MidAc. 5 year OS were 86.1% vs. 44.5%, median OS not reached vs. 45 mths (p= 0.004). 5 year LFS were 63.9 vs. 36.8%, median LFS not reached vs. 20mths (p= 0.03). The cumulative incidence of relapse at 5 years was 33.4% in HiDAC and 61.1% in MidAc (p=0.04). No survival differences between the HiDAC and MidAc cohort were seen in the non-favorable risk group; 5 year OS was 26.7% vs 36.7% (p = 0.22), 5 year LFS was 26.7% vs 33.3%(p = 0.78) respectively.13 (23.7%) favorable risk patients aged 60 or younger died during the follow up period. 5 patients died of complications of treatment, 4 (8%) in the HiDAC cohort and 1(3%) in the MidAc group (p= 0.4). Most deaths (4 out of 5) were attributable to neutropenic sepsis. Median age of patients who died during treatment was 54 years (range: 36 to 58) compared to 45 years (range: 15 to 60), (p = 0.23) amongst those who did not die from treatment related complications.In conclusion, in our cohort of patients consolidated with cytarabine monotherapy, HiDAC offers a better OS and LFS outcomes compared with MidAc in younger patients with favorable risk profile, albeit with a non-significant trend to an increase in treatment related mortality. Further studies looking into the interaction of cytarabine dose with specific genetic and cytogenetic AML sub-groups are warranted.OS of patients aged 60 or younger with ELN favorable risk AML (p= 0.01)Cumulative Incidence of Relapse of patients aged 60 or younger with ELN favorable risk AML (p= 0.04) [Display omitted] [Display omitted] DisclosuresHwang:Roche: Honoraria, Other: Travel support; Celgene: Honoraria, Other: Travel support; Pfizer: Honoraria, Other: Travel support; Sanofi: Honoraria, Other: Travel support; Janssen: Honoraria, Other: Travel support; MSD: Honoraria, Other: Travel support; Novartis: Honoraria, Other: Travel support; BMS: Honoraria, Other: Travel support.

Single HLA Mismatch Unrelated Donor Allogeneic Stem Cell Transplantation in Caucasian Recipients: Outcomes in HLA-A, -B, -C, -DRB1 and -DQB1 Mismatch Hematopoietic Stem Cell Transplantation: A Study on Behalf of the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC) and the Francophone Society for Histocompatibility and Immunogenetics (SFHI)

▪INTRODUCTION: Matching all alleles of the HLA-A, -B, -C, and -DRB1 loci (8/8 match) is associated with the highest overall survival (OS) rates after unrelated donor (URD) hematopoietic stem cell transplantation (HSCT). In Europe, patients (pts) are also matched at the HLA-DQB1 loci (10/10 match), although there is no evidence of better OS. Data on Caucasian pts receiving a single HLA mismatch URD HSCT are still controversial. We therefore conducted a multicenter retrospective study to assess the impact of a single HLA mismatch (9/10 match) on outcomes after URD HSCT in a large cohort of French pts. METHODSWe collected data from 1092 pts who underwent HSCT between January 2000 and December 2012 at 32 French transplantation centers. Informed consent was obtained in accordance with the Declaration of Helsinki. High-resolution typing was performed for HLA-A, -B, -C, -DRB1, -DQB1 loci for all donor/recipient pairs. Clinical data were obtained through ProMISe (Project Manager Internet Server), an internet-based system shared by all French transplantation centers. Endpoints of interest were classical HSCT outcomes: engraftment, Graft versus host disease (GvHD), treatment related mortality (TRM) and relapse. GvHD free relapse free survival was also studied (defined as alive with no previous grade III-IV aGvHD, no moderate or severe chronic GvHD (cGvHD) and no relapse). Myeloablative conditioning was defined as a combination of agents expected to produce profound pancytopenia and myeloablation within 1-3 weeks after administration; pancytopenia is long lasting, usually irreversible and in most instances fatal, unless hematopoiesis is restored by hematopoietic stem cell infusion (Bacigalupo, et al.. Biology of Blood and Marrow Transplantation, 2009). Models were adjusted for disease risk, recipient age, CMV and sex matching, stem cell source, GVHD prophylaxis and conditioning regimen. For adjusted analysis DQB1 was used as the reference category. Disease risk was classified as standard or high risk using the American Society for Blood and Marrow Transplantation Request for Information 2006 risk scoring schema. RESULTSPopulation characteristics are shown in Table 1. Gender balance was the only difference between groups (p<0.013). Median follow-up was 84 months. Engraftment rates were not different between groups (overall, 91.8% (95% Confidence interval (CI) (90.1 to 93.4)). Overall Cumulative Incidence of aGVHD grade II-IV and grade III-IV were 39.9% (95% CI, (38.0 to 41.8)) and 22.2% (95% CI, (20.2 to 24.2)), respectively. Myeloablative Conditioning (MAC) using Total Body Irradiation (TBI)>4Gy [Hazard Ratio (HR) HR:1.95 (95% CI, 1.45 to 2.63)] and high disease risk [HR :1.34 (95% CI, 1.09 to 1.66)] were significantly associated with an increased cumulative incidence of grade II-IV aGVHD, whereas only MAC with TBI>4Gy was a risk factor for grade III-IV aGVHD [HR:1.91 (95% CI, 1.28 to 2.87)].Overall Cumulative Incidence of cGVHD was 38.1% (95% CI, 35.9 to 40.1) at 84 months. Overall relapse rate was 33.8% (95% CI, 30.5 to 37.1) with no differences according to HLA mismatch subtype. CI of TRM was 36.0% (95% IC, 32.9 to 39.1). Single HLA-A mismatch [HR:1.55 (95% CI , 1.11 to 2.17)], high disease risk [HR:1.40 (1.12 to 1.74)], a female donor for a male recipient [HR:1.41 (1.10 to 1.79)], and the use of a MAC regimen [HR:1.50 (1.08 to 2.08)] were significantly associated with a higher TRM after adjusted analysis. Overall GRFS was 14.5% (12.1 to 17.3). Single HLA-A mismatch [HR:1.25 (95% IC, 1.01 to 1.54)] and high disease risk [HR:1.45 (95% IC, 1.26 to 1.67)] were significantly associated with a lower GRFS (Figure1). CONCLUSIONIn this large cohort of Caucasian pts who received a single HLA mismatch URD HSCT, high disease risk was the major prognostic factor related to higher rates of both acute GvHD and treatment related mortality, and eventually a lower GRFS. HSCT outcomes were similar according to HLA single mismatches except for HLA-A mismatch, which was associated with a significant increase in TRM, and a worse GFRS. This study also highlights the high rates of both TRM and relapse after single mismatch URD HSCT (9/10) which justifies the use of reduced toxicity conditioning regimens, as well as the addition of targeted therapies pre- and post- HSCT in this setting. [Display omitted] [Display omitted] DisclosuresMichallet:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria. Peffault De Latour:Amgen: Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Sarcopenia impairs survival in patients with potentially curable hepatocellular carcinoma.

A reduction in skeletal muscle mass (sarcopenia) independently predicts poor survival in patients with hepatocellular carcinoma (HCC) undergoing treatment with curative intent. Whether this is due to an increased risk of recurrence and disease specific death, or due to an increased risk of postoperative morbidity and mortality is currently unclear. In this study, we investigate the association between sarcopenia and death in a cohort of HCC patients undergoing treatment with curative intent. Patients undergoing surgical resection or radiofrequency ablation for lesions ≤ 3 cm between 2002 and 2013 were identified. Clinicopathological characteristics, CT-assessed sarcopenia and outcomes were analyzed. Among 90 patients, 52 (57.8%) were found to be sarcopenic. Sarcopenic patients had a limited overall survival (median: 33 months vs. non-sarcopenic median: 105 months; P = 0.002), but not disease-free survival. Sarcopenia was an independent predictor for overall survival in multivariate Cox-regression analysis (HR 3.756; P = 0.001). Major complications (32.7% vs. 13.2%, P = 0.033) and treatment-related mortality (17.3% vs. 2.6%, P = 0.029) were more frequent in sarcopenic patients. Sarcopenia impairs survival in patients with potentially curable hepatocellular carcinoma, mainly due to an increase in treatment-related mortality.

Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL

AbstractThe randomized Haemato Oncology Foundation for Adults in The Netherlands 68 phase 3 trial compared front-line chemotherapy with chemotherapy plus the CD52 monoclonal antibody alemtuzumab for high-risk chronic lymphocytic leukemia, defined as at least 1 of the following: unmutated immunoglobulin heavy chain genes, deletion 17p or 11q, or trisomy 12. Fit patients were randomized to receive either 6 28-day cycles of oral FC chemotherapy (days 1 through 3: fludarabine 40 mg/m2 per day and cyclophosphamide 250 mg/m2 per day: n = 139) or FC plus subcutaneous alemtuzumab 30 mg day 1 (FCA, n = 133). FCA prolonged the primary end point, progression-free survival (3-year progression-free survival 53 vs 37%, P = .01), but not the secondary end point, overall survival (OS). However, a post hoc analysis showed that FCA increased OS in patients younger than 65 years (3-year OS 85% vs 76%, P = .035). FCA also increased the overall response rate (88 vs 78%, P = .036), and the bone marrow minimal residual disease–negative complete remission rate (64% vs 43%, P = .016). Opportunistic infections were more frequent following FCA, but without an increase in treatment related mortality (FCA: 3.8%, FC: 4.3%). FCA improves progression-free survival in high-risk chronic lymphocytic leukemia. As anticipated, FCA is more immunosuppressive than FC, but with due vigilance, does not lead to a higher treatment-related mortality. This study was registered at www.trialregister.nl as trial no. NTR529.

Screening With Spirometry Is A Useful Predictor Of Later Development Of Non-Infectious Pulmonary Syndromes In Patients Undergoing Allogeneic Stem Cell Transplantation

Background Non-infectious pulmonary syndromes (NIPS) frequently complicate allogeneic stem cell transplantation (alloSCT). The most common and serious is the bronchiolitis obliterans syndrome (BOS), characterized by irreversible fixed airflow obstruction, impaired quality of life and a high mortality. Treatment for established symptomatic disease is relatively ineffective. Although changes in spirometry parameters at day 80 have been shown to correlate with poorer lung function at one year, no screening test has been proven to clearly predict for the development of NIPS. We sought to determine whether early changes in spirometry parameters predict later development of NIPS. Secondary objectives were to determine pre-transplant predictors of NIPS and the impact of NIPS on relapse, treatment-related mortality (TRM) and survival. Methods Spirometry and DLCO were performed pre-alloSCT, at day 100 (D100) and one year post-alloSCT. We retrospectively analyzed spirometry, CT and bronchoalveolar lavage results in consecutive patients having alloSCT from 2004-2010 to identify cases of NIPS. Cases of BOS and cryptogenic organizing pneumonia (COP) were defined as per published guidelines (NIH consensus guidelines, 2005). Spirometry trends and baseline variables were compared between patients with and without NIPS to identify early predictors and risk factors for NIPS. Results Pulmonary function 257 patients underwent allo-SCT during the study period. 235 survived to D100 and were thus assessable for chronic GVHD (cGVHD) and NIPS. Of these, 23 (9.8%) developed NIPS, 18 with BOS and 5 with COP. Median time of onset was day 367 (IQR 144-544 days). All but one case developed prior to two years post-alloSCT. Change in FEV1.0 (ΔFEV1.0), was the best predictor of later NIPS development, while change in pulmonary diffusion capacity for carbon monoxide was not predictive. Median ΔFEV1.0 from pre-transplant to D100 in patients later developing NIPS was -12% (IQR -25% to -1%) vs -1% (IQR -7% to +6%) in those who did not, p=0.002. From pre-transplant to 1 year, it was -19% (IQR -37% to -6%) vs -3% (-10% to +4%), respectively, p&lt;0.001. Median FEV1.0 at diagnosis was 58% predicted (IQR 46-71%). Once fixed airflow obstruction was established, progressive deterioration in lung function with time was the rule; median change in FEV1.0 during follow-up, post-diagnosis of NIPS, was -2% per annum (IQR -7 to 0%). Median follow-up duration post-diagnosis of NIPS was 1 year, range 0-6 years. For those with BOS and &gt;6 months of follow-up, median change in FEV1.0 per year during follow-up was -8% (IQR -14% to -2%). In contrast, 4 of the 5 patients with COP had substantial improvement in FEV1.0 (11-36%) with normalization of FEV1.0 in 3 of these 4. Pre-transplant risk factors Busulfan-based, but not total body irradiation (TBI)-based conditioning increased the risk of NIPS [OR=8.87, 95%CI 3.33-23.63, p&lt;0.001]. No cases of NIPS were seen in 53 patients who received in vivo T-cell depletion with Thymoglobulin as part of their conditioning (p&lt;0.0001). Survival At a median follow-up of 44 months, overall survival was 59.1%. There was a trend towards increased all-cause mortality in those patients developing NIPS [HR = 2.02, 95%CI 0.92-4.44, p=0.08] and an increase in TRM [HR = 5.96, 95%CI 2.14-16.62, p=0.001], with eight patients (35%) with NIPS experiencing TRM. No statistically significant difference in disease relapse was seen between those with and without NIPS [HR = 0.24, 95%CI 0.03–1.80], although only one patient with NIPS experienced disease relapse. This may reflect the small numbers of patients with NIPS. Conclusions Spirometry is a potentially useful screening test for identification of pre-symptomatic NIPS. We recommend 3-monthly spirometry surveillance for up to two years post-transplant, given the moderately severe obstruction at diagnosis (median FEV1.0 58% predicted) and the incidence of 50% of cases between one and two years post-allo-SCT. Our findings require prospective validation to identify patients in whom earlier intervention may potentially modify the natural history of this disease. Disclosures: No relevant conflicts of interest to declare.

UKALL 2003, A Randomised Trial Investigating Treatment Intensification for Children and Young Adults with Minimal Residual Disease Defined High Risk Acute Lymphoblastic Leukaema

AbstractAbstract 136▪▪This icon denotes a clinically relevant abstractTreatment modification according to Minimal Residual Disease (MRD) status at the end of induction and week 11 was investigated in a randomised control trial, UKALL 2003. Consecutively diagnosed children and young adults (up to age 25 years) with ALL were recruited from the UK and Republic of Ireland between October 2003 and June 2011. In the trial overall, we have observed a significant improvement in event-free survival (EFS) compared with its predecessor, ALL 97/99 (5-year EFS 87 vs 80%, log rank p<0.0005) most probably related to use of dexamethasone and pegylated asparaginase in all patients. Here we report the results of the MRD high risk randomisation which closed to recruitment on 30 June 2011.Patients in the trial were initially stratified by NCI risk, blast karyotype, and morphological marrow response at day 8/15 of induction for allocation to one of 3 treatment regimens, escalating in intensity (A, B, C). NCI standard risk (SR) patients received a 3 drug induction (Regimen A) whilst high risk (HR) patients received 4 drugs including daunorubicin (Regimen B). Patients with a slow early response at day 8 (NCI HR) or day 15 (NCI SR) of induction and patients with poor risk cytogenetics were transferred to Regimen C. Patients without poor risk cytogenetics and who had a rapid early response were eligible for the MRD randomisations. MRD was measured using Real Time Quantitative PCR with a sensitivity of 10−4.Five hundred and thirty three patients who had an MRD >/= 10−4at day 29 of induction were entered into a randomisation comparing standard treatment (Regimens A or B = standard arm, n = 266) with the more intensive Regimen C (intensification arm, n = 267). Of these, 332 (62%) were NCI SR and 201 (38%) NCI HR. With follow-up to October 2011 (median 3 years 11 months), the 5 year EFS is significantly better for patients in the intensification arm (91%) compared with the standard arms (82%) due to a halving of relapse risk (OR 0.57, 95% CI 0.34 – 0.95, 2p = 0.03). The improved EFS translates into a trend for better overall survival (OR 0.57, 95% CI 0.31 – 1.05, p= 0.07). There was no heterogeneity in benefit of Regimen C for sub-groups defined by NCI risk, immunophenotype or cytogenetics. The risk of death in remission was not significantly different in the two arms (Intensification = 7, Standard = 9, OR 0.76, 2p = 0.6) but there was an excess of SAEs and AEs related to asparaginase (hypersensitivity, p=0.0003 and pancreatitis, p = 0.01) and intravenous methotrexate (mucositis, p=0.03 and vomiting, p = 0.03) in the intensification arm.This randomised study provides evidence that treatment intensification is of benefit to patients defined as high risk by MRD measured at day 29 of induction. The excess toxicity related to asparaginase and intravenous methotrexate did not result in an increase in treatment related mortality. Taken together with the results of the low risk randomisation, reported at ASH in 2010, UKALL 2003 has demonstrated that within a NCI directed CCG backbone, MRD based stratification provides the optimal approach to risk directed therapy. Disclosures:No relevant conflicts of interest to declare.

TREATMENT Toxicity in Adolescents and Young ADULT (AYA) PATIENTS COMPARED with Younger PATIENTS TREATED for HIGH RISK B-Precursor ACUTE LYMPHOBLASTIC LEUKEMIA (HR-ALL): A REPORT From the CHILDREN'S Oncology GROUP STUDY AALL0232

Abstract 1510Historically, AYA patients (>16yrs of age) with HR-ALL have lower event free survival and overall survival compared to younger patients (1–15 yrs of age) with HR-ALL. This inferior outcome is related to both a higher relapse rate and increased toxicity of therapy. Several underlying factors have been identified that may contribute to these differences including leukemia biology, host pharmacodynamics, relative intensity of treatment protocols, adherence to therapy, and supportive care measures, although their relative importance is largely unknown.AALL0232 was a Phase 3 randomized trial for patients 1–30 years old with newly diagnosed B-precursor HR-ALL that utilized a 2 × 2 factorial design with an augmented intensity Berlin- Frankfurt-Münster (BFM) backbone. Patients were randomized to receive dexamethasone versus prednisone during Induction and high dose methotrexate versus escalating Capizzi methotrexate during Interim Maintenance I. The study accrued 3051 eligible, evaluable, non-Down Syndrome patients between January 2004 and January 2011. AYA patients comprised 20% of study enrollments (n=601) with 555 patients in the 16–21 year range and 46 patients in the 22–30 year range. Toxicities were graded using Common Terminology Criteria for Adverse Events (CTCAE version 4.0) and all grades 3 and 4 are reported. Bone toxicities including avascular necrosis are not included in this analysis.During Induction, AYA patients when compared to younger patients had lower rates of febrile neutropenia (7.0% versus 13.4%, p<0.0001), higher rates of hyperglycemia (22.0% versus 15.4%, p=0.0002), hyperbilirubinemia (6.7% versus 3.7%, p=0.0022), but comparable rates for other measured toxicities including pancreatitis and thrombosis. There was no significant difference in Induction mortality between AYA patients and younger patients (2.2% versus 1.7%, p=0.39).Post-induction, AYA patients experienced higher rates of oral mucositis secondary to methotrexate during Interim Maintenance I (18.5% versus 11.3%, p=0.0002), and higher rates of peripheral motor neuropathy during protocol therapy (11.5% versus 7.4%, p=0.0015). Despite lower rates of febrile neutropenia throughout protocol therapy (35.6% versus 48.6%, p<0.0001), AYA patients had a significantly greater likelihood of death during remission. The 5-year cumulative incidence of remission death for AYA patients was 4.4 + 1.1% compared to 1.8 + 0.4% for younger patients (p=0.0015). Of the 16 remission deaths in AYA patients, 11 occurred within one year post-induction and the remaining within 3 years post-induction. Of the 29 remission deaths in younger patients, 22 occurred within one year post-induction, 6 occurred between 1–3 years, and one between 4–5 years. Infectious complications were responsible for 11 of 16 (69%) of the remission deaths in AYA patients compared to 15 of 29 (52%) of the remission deaths in younger patients.In conclusion, AYA patients experienced higher rates of hyperbilirubinemia and hyperglycemia during Induction, oral mucositis during Interim Maintenance I, and peripheral motor neuropathy throughout protocol therapy. Importantly, AYA patients experienced a higher rate of death during remission, predominantly due to infectious etiologies. Further analyses are needed to determine reasons for the increase in treatment related mortality, including, an evaluation of the responsible organisms, identification of periods of increased vulnerability because of concomitant mucositis, neutropenia, and/or delivery of specific chemotherapeutic agents. Disclosures:No relevant conflicts of interest to declare.

Comparison of Troponin T and N-Terminal-Pro-Brain Natriuretic Peptides In Two Models of Treatment Related Mortality In AL Amyloidosis Patients Following Autologous Stem Cell Transplantation

AbstractAbstract 3572High dose melphalan and autologous stem cell transplantation (ASCT) is an effective treatment for light chain amyloidosis (AL) but high treatment related mortality (TRM) limits its use. Both cardiac troponin T (cTnT) and N-terminal-pro-brain natriuretic peptide (NT-pro-BNP) are sensitive predictors of high risk patients. Aim of this study is to compare two models of TRM, one using cTnT and the other BNP. Patients who underwent ASCT between 7/1996 and 7/2009 at the Mayo Clinic were analyzed retrospectively. Variables were chosen for ease of measurement and reproducibility thus echocardiographic parameters were excluded. Each additional risk factor must contribute to a significant increase in TRM. Also, since NT-pro-BNP and cTnT are already highly associated with mortality, the other risk factors must be independent predictors. Univariate analysis revealed serum albumin, B-2-microglobulin, cTnT, NT-pro-BNP, and uric acid were associated with TRM while age, sex, alkaline phosphatase, serum creatinine, CRP, proteinuria were not (Table 1). Multivariate analysis showed albumin and uric acid were independent risk factors to cTnT and NT-pro-BNP (Table 2). Of the 412 patients, 347 (8.9% TRM) could be evaluated by the cTnT, albumin and uric acid (TAU) model and 282 (9.2%) TRM could be evaluated by the NT-pro-BNP, albumin, uric acid (BAU) model. Both models showed increasing TRM with additional risk factors beyond 1 risk factor (Table 3 and 4). Albumin and uric acid were found to be significant contributors in both models. Patients with elevated cTnT alone had a 0% TRM vs 23.4% if they had 1 additional risk factor, p = 0.03. Similarly, TRM was 3.7% in patients with elevated NT-pro-BNP alone but 18.0% if they had 1 other risk factor, p = 0.05. NT-pro-BNP and cTnT could not be used in the same model because cTnT becomes non-significant. Both models were superior to visceral organ involvement which had TRM of 5.3% with 1, 9.2% with 2 and 16.7% with 3 organ involvement. Both models were also predictive of overall survival (Figure 1 and Figure 1b). Our results show that these models show that albumin and uric acid with either cTnT or NT-pro-BNP can accurately predict TRM in AL patients undergoing ASCT. Multivariate analysis shows that the NT-pro-BNP containing model may be superior since cTnT loses it significance when added to the model. Our results suggest these models could be very helpful in identifying high risk patients not suitable for ASCT. [Display omitted] [Display omitted] Table 1Patient characteristicsControlTRMp-valueN318 29Age58 (25–73)55 (35–75) 0.54Sex (male)58.2%72.4%0.13Albumin (g/dl)2.7 (0.8–4.4)2.2 (0.8–3.7)0.02Alkaline phosphatase (U/L)89 (28–1014)86 (31–1394)0.22b2m (mg/ml)2.6 (1.0–35.1)3.2 (1.3–15.2)0.007NT-pro-BNP (pg/ml)564 (12–35000)1661 (21–35001)0.03CRP (mg/L)0.3 (0.01–16.6)0.3 (0.05–3.2)0.34cTnT (ng/ml)0.01 (0–1.0)0.03 (0.01–0.22)<0.001Scr (mg/dl)1.1 (0.4–12)1.2 (0.8–2.3)0.09Proteinuria (g/d)3.4 (0.01–35.4)5.1 (0.1–20.5)0.10Uric acid (mg/dl)6.2 (1–14.8)7.5 (3.7–13.2)0.02Organ Involvement194.7%5.3%0.04290.7%9.3%383.3%16.7%Table 2Multivariate analysis using proportional hazard modelcutoffs>Risk Ratio>p-valueModel TAUcTnT0.04 ng/ml2.780.01Albumin3.3 g/dl3.110.03Uric acid8.5 mg/dl2.690.02Model BAUNT-pro-BNP1270 pg/ml3.770.003Albumin3.3 g/dl3.530.04Uric acid8.5 mg/dl3.110.03Table 3Model of cTnT, albumin and uric acidTAU RiskFactorsnTRMp-valueRisk Ratio0692.9%12055.9%0.3326116.4%0.0092.9831241.7%0.058.52Table 4Model of NT-pro-BNP, albumin and uric acidBAU Risk Factors>n>TRM>p-value>Risk Ratio0280%11615.6%0.2028214.6%0.022.731145.5%0.0110.8 Disclosures:Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Lacy:Celgene: Research Funding.

Prevalence and Clinical Implications of N-RAS Mutations in Childhood AML – A Report From the Children's Oncology Group.

Abstract 3115Poster Board III-52Mutations in the RAS proto-oncogenes are frequent in acute myeloid leukemia (AML) and serve as prototypic Class I lesions, initiating key downstream hyper-proliferative signal transduction pathways. N-RAS mutations (N-RASmut) are common in AML, occurring in 10-20% of adult and pediatric AML patients; however their prognostic significance in both adults and children remains disputed. Due to a frequent association with a normal karyotype, delineating the impact of these mutations on outcome may enable appropriate risk-adapted therapeutic approaches. Here, we report on the incidence and prognostic significance of N-RASmut in a cohort of 825 pediatric AML patients treated on 2 recent co-operative group studies, CCG-2961 and COG AAML03P1. In total, of the 825 children with de novo AML who underwent N-RAS mutational analysis, 86 (10%) were positive. Gender, age, race, presence of hepatosplenomegaly and FAB subtype were comparable between patients with and without N-RASmut. There was no statistically significant difference between those with and without N-RASmut with respect to specific chromosome class. FLT3/Internal tandem duplications (FLT3/ITD) were less common in those with N-RASmut (2% vs. 9%, p=0.03). In contrast, nucleophosmin (NPM) mutations were more common in those with N-RASmut (13% vs. 5%, p=0.02). Overall, N-RASmut showed a significant correlation with low risk AML (CBF, CEBPαa, or NPM, p=0.04) and an inverse relationship with high risk disease (-5/5q- or -7, FLT3/ITD/high allelic ratio, p=0.007). Patients with N-RASmut had similar complete remission (CR) rates following two courses of induction chemotherapy compared with non-mutated patients (79% vs. 79%, p=0.92). Those in CR had a similar relapse rate regardless of the presence of N-RASmut (RR 39% vs. 36%, p=0.97). Five year event free survival (EFS) and overall survival (OS) from study entry were also comparable, however N-RASmut patients demonstrated a marked increase in overall treatment related mortality (TRM) (21% vs. 14%, p=0.03), which was maintained when high and low risk patients were excluded (22% vs. 11%, p=0.05). Evaluation of TRM in CCG-2961 compared with COG AAML03P1 demonstrated that increased TRM in N-RASmut was only seen in patients treated on CCG-2961 and TRM was primarily due to invasive fungal and gram negative infections. Interestingly, for patients treated on CCG-2961, who received interval compressed intensive induction therapy, this increase in TRM correlated with a decrease in both OS and disease free survival from CR. Remission specimens from patients with N-RASmut were negative for the mutation, demonstrating that an increased infectious risk could not be attributed to a host polymorphism. We found N-RASmut did not contribute to increased disease recurrence in pediatric AML. Our findings indicate that N-RAS mutations do not identify a high risk population, however, as such mutations lead to downstream activation of signal transduction pathways, they may identify a target for directed therapy. DisclosuresNo relevant conflicts of interest to declare.

Prospective Phase II Study of Pre-Administration of Rabbit Antithymocyte Globulin (rATG, Thymoglobulin ®) to Maximize Early T-Cell Chimerism Following Allogeneic Reduced Intensity Conditioning Transplant (RICT) through Differential in-Vivo Depletion of Recipient Versus Donor T-Cells.

Abstract 3371Poster Board III-259 Background:Failure to achieve high levels of donor T-cell chimerism in the early period after RICT may be associated with eventual graft rejection, disease relapse and poor disease-free survival [Maris et al Blood 102:2021-2030 (2003); Saito et al Biol Blood Marrow Transplant 14:1148-1155 (2008)]. We hypothesized that pre-administration of reduced-dose rATG two weeks prior to stem cell transplant (SCT) would produce selective in-vivo depletion of host but not donor T-cells due to in-vivo decay of active rATG levels. Patients and methods:Twenty-two pts with HLA-identical sibling donors were enrolled on this study. The median age 57 yrs (24-68); F (n=10) M (n=12); NHL (n=9), MDS (n= 7), MPS (n=2), AML (n=2), HD (n=1), MM (n=1). Seven pts had a prior auto transplant. Disease status at transplant was CR (n=8), PR (n=4), HI (n=3), not in remission (n=5), untreated (n=2). CIBMTR risk stratification was high (n=12), intermediate (n=6) and low (n=4). RIC consisted of rATG 1 mg /kg d-16 & 3.5 mg/kg d-15, fludarabine 30 mg/m2/d (d-7 to -3), busulfan 130 mg/m2 IV (d -4, -3), and cylophosphamide 1.5 g/m2 d-2. Mobilized PBSC were infused on d 0. GVHD prophylaxis consisted of tacrolimus and methotrexate. All pts were admitted on d -16,-15 for rATG administration and were then discharged to receive the remaining therapy in the outpatient clinic. Results:Median active rATG levels at day -14, -7, and 0 were 4.4 mcg/mL (1.37-12.2), 1.35 mcg/mL (0.2-2.6), and 0.5 mcg/mL (0-3.2). Fifteen evaluable pts (83%) had a sub therapeutic active ATG level (<1 mcg/mL) on day 0. Of evaluable pts, the median (range) peripheral blood CD 3+ cell chimerism on day 15, 30, 60, 90 & 360 was 93% (75-100%), 95% (75-100%), 100% (87-100%), 100 (88-100%) and 100% (93-100%) respectively. Median CD 33+ cell chimerism was consistently > 95% (range 90-100%) at all time points. Readmission prior to d 100 occurred in 17 pts and was most commonly due to febrile neutropenia (n=7), GI toxicity (n=6) and acute GVHD (n=4). The median length of hospitalization was 5 days (range 1-34 days). Post transplant infections included CMV reactivation (n=5), Adenovirus (n=1), BK virus (n=3), Parainfluenza (n=1), HSV oral (n=1), Candida Parapsilosis (n=1), C.Difficile (n=3), Pseudomonas (n=4) Giardia (n=1), MRSE (n=17), MRSA (n=1) Gram positive organisms (other; n=9) and other bacteria (n=5). Estimated cumulative incidence of treatment related mortality (TRM) at d 100 and 1 year was 0% and 17.9%.The maximum cumulative incidence of aGVHD grade II-III and grade III-IV was 44% and 5% respectively. Chronic GVHD (all stages) developed in 70% of evaluable patients but was extensive severe for only 8%. One patient developed steroid refractory GVHD. Estimated probability of 2 year overall survival & progression-free survival are 59.9% and 39.8%. Cause of death included progression of malignancy (n=2), chronic GVHD (n=1), bacterial infection (n=1), pulmonary failure (n=1). Conclusions:Pre-administration of rATG (on d-16 and -15) with this RIC regimen results in sub-therapeutic serum active rATG levels on d 0 in the majority of patients thus avoiding significant in-vivo donor T-cell depletion. It produces high levels of early and sustained donor T-cell chimerism without an apparent increase in TRM or GVHD. Disclosures:Off Label Use: Anti-thymocyte globulin off label use for stem cell transplant. Bashey:Genzyme: Research Funding.

Re: Tandem vs Single Autologous Hematopoietic Cell Transplantation for the Treatment of Multiple Myeloma: A Systematic Review and Meta-analysis

Background Evidence bearing on the efficacy of tandem autologous hematopoietic transplant (AHCT) vs a single AHCT in patients with multiple myeloma (MM) is conflicting. We performed a systematic review and metaanalysis to synthesize the existing evidence related to the effectiveness of tandem vs single AHCT in patients with MM. Methods We searched Medline, conference proceedings, and bibliographies of retrieved articles and contacted experts in the field to identify randomized controlled trials (RCTs) reported in any language that compared tandem with single AHCT in patients with MM through March 31, 2008. Endpoints were overall survival (OS), event-free survival (EFS), response rate, and treatment-related mortality (TRM). Data were pooled under a random-effects model. Results Six RCTs enrolling 1803 patients met the inclusion criteria. Patients treated with tandem AHCT did not have better OS (hazard ratio [HR] for mortality for patients treated with tandem transplant vs single transplant = 0.94; 95% confidence interval [CI] = 0.77 to 1.14) or EFS (HR = 0.86; 95% CI = 0.70 to 1.05). Response rate was statistically significantly better with tandem AHCT (risk ratio = 0.79, 95% CI = 0.67 to 0.93), but with a statistically significant increase in TRM (risk ratio = 1.71, 95% CI = 1.05 to 2.79). There was statistically significant heterogeneity among RCTs for OS and EFS. Conclusion In previously untreated MM patients, use of tandem AHCT did not result in improved OS or EFS. We conclude that tandem AHCT is associated with improved response rates but at risk of clinically significant increase in TRM.

Re: Tandem vs Single Autologous Hematopoietic Cell Transplantation for the Treatment of Multiple Myeloma: A Systematic Review and Meta-analysis

Background Evidence bearing on the efficacy of tandem autologous hematopoietic transplant (AHCT) vs a single AHCT in patients with multiple myeloma (MM) is conflicting. We performed a systematic review and metaanalysis to synthesize the existing evidence related to the effectiveness of tandem vs single AHCT in patients with MM. Methods We searched Medline, conference proceedings, and bibliographies of retrieved articles and contacted experts in the field to identify randomized controlled trials (RCTs) reported in any language that compared tandem with single AHCT in patients with MM through March 31, 2008. Endpoints were overall survival (OS), event-free survival (EFS), response rate, and treatment-related mortality (TRM). Data were pooled under a random-effects model. Results Six RCTs enrolling 1803 patients met the inclusion criteria. Patients treated with tandem AHCT did not have better OS (hazard ratio [HR] for mortality for patients treated with tandem transplant vs single transplant = 0.94; 95% confidence interval [CI] = 0.77 to 1.14) or EFS (HR = 0.86; 95% CI = 0.70 to 1.05). Response rate was statistically significantly better with tandem AHCT (risk ratio = 0.79, 95% CI = 0.67 to 0.93), but with a statistically significant increase in TRM (risk ratio = 1.71, 95% CI = 1.05 to 2.79). There was statistically significant heterogeneity among RCTs for OS and EFS. Conclusion In previously untreated MM patients, use of tandem AHCT did not result in improved OS or EFS. We conclude that tandem AHCT is associated with improved response rates but at risk of clinically significant increase in TRM.

Tandem Versus Single Autologous Hematopoietic Cell Transplantation for the Treatment of Multiple Myeloma: A Systematic Review and Meta-analysis

Evidence bearing on the efficacy of tandem autologous hematopoietic transplant (AHCT) vs a single AHCT in patients with multiple myeloma (MM) is conflicting. We performed a systematic review and meta-analysis to synthesize the existing evidence related to the effectiveness of tandem vs single AHCT in patients with MM. We searched Medline, conference proceedings, and bibliographies of retrieved articles and contacted experts in the field to identify randomized controlled trials (RCTs) reported in any language that compared tandem with single AHCT in patients with MM through March 31, 2008. Endpoints were overall survival (OS), event-free survival (EFS), response rate, and treatment-related mortality (TRM). Data were pooled under a random-effects model. Six RCTs enrolling 1803 patients met the inclusion criteria. Patients treated with tandem AHCT did not have better OS (hazard ratio [HR] for mortality for patients treated with tandem transplant vs single transplant = 0.94; 95% confidence interval [CI] = 0.77 to 1.14) or EFS (HR = 0.86; 95% CI = 0.70 to 1.05). Response rate was statistically significantly better with tandem AHCT (risk ratio = 0.79, 95% CI = 0.67 to 0.93), but with a statistically significant increase in TRM (risk ratio = 1.71, 95% CI = 1.05 to 2.79). There was statistically significant heterogeneity among RCTs for OS and EFS. In previously untreated MM patients, use of tandem AHCT did not result in improved OS or EFS. We conclude that tandem AHCT is associated with improved response rates but at risk of clinically significant increase in TRM.

Efficacy of Hypo-Methylating Agents in the Treatment of Myelodysplastic Syndromes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background: With the FDA approval of two hypomethylating agents (HA) for the treatment of myelodysplastic syndromes (MDS), both azacitidine (AZA-C) and decitabine have shown widespread usage. These agents improved response rates (RR) in phase III registration trials, however, overall survival (OS) was not significantly improved. Furthermore, head to head comparison of AZA-C versus decitabine is lacking. We performed a systematic review of randomized controlled trials (RCTs) to assess the efficacy of AZA-C and decitabine versus supportive care (SC), and AZA-C versus decitabine for the treatment of MDS.Methods: A comprehensive literature search of MEDLINE, EMBASE and Cochrane library database was undertaken to identify all phase III randomized controlled trials (RCT) published through July 2008. Meetings abstracts from ASCO, ASH and European Society for Hematology were searched for the years 2006–2007. Data extraction and meta-analysis on benefits and harms of HA for MDS was performed as per the methods recommended by the Cochrane Collaboration. Indirect comparison of AZA-C versus decitabine was conducted according to the methods developed by Bucher et al and Glenny et al and were extended to calculate hazard ratios (HR). We created the following chain of inference: we first pooled RCTs that compared AZA-C with SC, and decitabine versus SC. We then compared the pooled estimates to obtain the unbiased estimate in treatment differences between decitabine and AZA-C.Results: We found 4 RCTs assessing the efficacy of HA for the treatment of MDS. Two RCTs compared AZA-C versus SC, and 2 compared decitabine versus SC. The results from 1 trial describing the effects of decitabine versus SC were reported as a press release stating that OS was not significant between two arms, however, data were not available for this analysis. The results for all comparisons are summarized in the table below. Meta-analysis of RCTs comparing HA versus SC showed significantly better OS, EFS, and RR in favor of HA without a significant increase in treatment-related mortality (TRM). Comparison of AZA-C versus SC also showed significantly better OS, EFS and RR favoring AZA-C without significant risk of TRM. In one RCT comparing decitabine versus SC, RR was significantly superior in the decitabine arm. However, there was no difference in OS, EFS and TRM between decitabine and SC. Evaluation of decitabine versus AZA-C showed significantly better OS and RR favoring AZA-C, whereas EFS and TRM were similar.Conclusion: This first systematic review on the efficacy of HA versus SC shows that OS, EFS and RR are superior with HA without significant TRM. Additionally, use of AZA-C is associated with significantly improved OS and RR compared to decitabine. In order to definitively confirm these findings, a prospective RCT comparing AZA-C and decitabine is warranted. Results from this systematic review on the efficacy of AZA-C and decitabine should be considered the threshold against which efficacy of future agents in MDS should be tested.OutcomeComparisonsHypo-methylating agents versus supportive care (3 RCTs; N=719)ConclusionAzacitidine versus supportive care (2 RCTs; N= 549)ConclusionDecitabine versus supportive care (1 RCT; N=170)ConclusionAzacitadine versus Decitabine (Indirect comparison)ConclusionOverall Survival Hazard ratio (HR)(95% Confidence Intervals) P-valueHR=0.79 (0.67, 0.95) p=0.01Hypo- methylating agents betterHR=0.62 (0.48, 0.78) p=0.00Azacitidine betterHR=1.064 (0.82, 1.38) p=0.636No differenceHR=0.579 (0.41, 0.82) p=0.002Azacitidine betterEvent-free survival Hazard ratio (HR) (95% Confidence Intervals) P-valueHR=0.59 (0.46, 0.75) p=0.00Hypo- methylating agents betterHR=0.58 (0.44, 0.76) p=0.00Azacitidine betterHR=0.64 (0.35, 1.19) p=0.16No differenceHR=0.89 (0.46, 1.80) p=0.753No differenceResponse rate Risk ratio (RR) (95% Confidence Intervals) P-valueRR=1.28 (1.19, 1.37) p=0.00Hypo- methylating agents betterRR=1.37 (1.25, 1.52) p=0.00Azacitidine betterRR=1.2 (1.08, 1.31) p=0.00Decitabine betterRR=1.15 (1.0, 1.314) p=0.05Azacitidine betterTreatment-related mortality Risk ratio (RR) (95% Confidence Intervals) P-valueRR=0.69 (0.36, 1.32) p=0.264No differenceRR=2.79 (0.12, 67.64) p=0.528No differenceRR=0.65 (0.34, 1.26) p=0.203No differenceRR=4.29 (0.16, 111.1) p=0.381No difference

Tandem Versus Single Autologous Hematopoietic Cell Transplantation for Treatment of Multiple Myeloma: A Meta-Analysis of Randomized Controlled Trials (RCT).

Background: Single autologous hematopoietic cell transplantation (AHCT) is considered standard therapy for patients with multiple myeloma (MM). Several observational studies and some RCTs have shown superior outcomes with tandem transplants; others have shown conflicting results. The objective of this study is to present the totality of evidence by conducting a systematic review to assess the efficacy of double ASCT in previously untreated MM patients.Methods: A systematic and comprehensive search of the literature was performed using MEDLINE, and Cochrane library databases from 1966–2007 for all phase III randomized controlled trials (RCT) comparing single versus tandem AHCT in previously untreated MM patients with previously. Additionally, we searched ASCO, ASH and European Society for hematology meeting abstracts between 2003–2007 years. Data was extracted and pooled on benefits and harms as per the methods recommended by the Cochrane Collaboration.Results: Altogether 5 RCTs enrolling 1569 patients met the inclusion criteria. Data were available from all trials for overall survival, and for the remaining outcomes data were extractable from 3 RCTs. As shown in figure 1a. overall survival was not significantly different between tandem and single transplant (hazard ratio [HR]=0.91, 95% CI 0.81 to 1.02, p=0.09). However, there was a significant improvement in event free survival (HR=0.74, 95%CI 0.64, 0.85; p=0.00002, see figure 1b.) and response rates (HR=0.72, 95%CI 0.52 to 0.99; p=0.04, see figure 2a.) favoring tandem AHCT, but at the expense of significant increase in treatment related mortality (HR=1.79, 95%CI 1.03 to 3.11; p=0.04, see figure 2b.). There was no statistically significant heterogeneity between trials (see figure 1 and 2). [Display omitted] [Display omitted] Conclusion: The available existing evidence shows that, in patients with previously untreated MM, tandem AHCT does not result in improved survival. Tandem AHCT is associated with improved event-free survival and response rates but at the cost of significant increase in fatal side effects (see figure). However, the latter conclusion can also be attributed to “outcome reporting bias” since data for non-survival outcomes were only available in 3 out of 5 RCTs.