Terms Of Complete Remission Rate Research Articles

Post-Transplant Nivolumab Plus Unselected Autologous Lymphocytes in Truly Refractory Hodgkin Lymphoma Patients Is Highly Effective and Responses Are Mediated By NK Cells

Background In the relapsed/refractory Hodgkin Lymphoma (HL) setting (RHL), the achievement of complete remission (CR) is fundamental in order to proceed with allogeneic stem cell transplantation (HSCT) consolidation. Immune checkpoint inhibitors (CI) have demonstrated clinical activity in patients relapsing after ASCT, although only 20% CR rate is observed. In order to improve the efficacy of CI in RHL, we previously reported a salvage treatment based on early CI therapy following post-autologous stem cell transplantation (ASCT) with the reinfusion of unselected autologous lymphocytes infusions (ALI). The rationale of this approach is based on the achievement of a disease debulking through ASCT conditioning. Early administration of CI (nivolumab) is performed on a minimal disease burden, while reinfusions of ALI reduce post ASCT immune depression eliciting CI efficacy. Aims The aim of this study was to evaluate the efficacy of the procedure in terms of CR rates and overall survival (OS) after an extended follow up. Biological endpoint was to investigate the lymphocyte subpopulations involved in the mechanism of response and investigate the role of NK-cells mediating anti tumor responses in HL. Methods Patient were eligible to this study after failure to respond to first line treatment (i.e. positive PET2 or PET6 scan) and underwent autologous lymphocyte apheresis upon enrollment. All patients received conventional 2nd line chemo followed by 3rd line chemo-immunotherapy with Brentuximab-Vedotin (BV) in non-responding patients. Patient failing to achieve CR after BV were enrolled in the treatment arm and proceeded to ASCT + CI and ALI, whereas patients responding to 2nd- or 3rd treatment received ASCT followed by ALI alone, as a control cohort (figure 1A). NK cell degranulation assay was evaluated by staining for CD107a (LAMP-1) expression on healthy-donors derived NK cells exposed to HL cell lines (L428 and L250), in the presence or absence of monoclonal antibodies targeting inhibitory or activating receptors. Surface and intracellular staining was performed prior to flow cytometry and analysis was performed on the CD3-/CD56+ gated population. Results Twenty-one patients with RHL (median age 32 years; range 18-65) underwent lymphocyte apheresis after failure of 1st line chemo and then proceeded to salvage therapy. Thirteen patients failed to respond to 2nd and 3rd line therapy and thus received early post-transplant CI supported with four ALI. Eight patients responded to 2nd line chemo (n=6) or 3rd line BV (n=2) and received ASCT followed by ALI alone. No adverse events were recorded, specifically, no immune-related toxicity was observed. All patients receiving ALI + CI (treated patients) achieved negative PET scan CR. Eight of them received HSCT consolidation. One patient refusing HSCT after achieving CR in this study relapsed and responded to CI re treatment followed by HSCT. All patients in the treatment arm are alive and disease-free after a median follow-up of 32 months (95% CI 26.4-51.0). Median disease-free survival (DFS) was not reached in treatment arm (Fig 1B). Four of the patients in the control arm relapsed (50%). Three of them responded to 3rd line therapy and proceeded to HSCT. One patient achieved CR with conventional CI treatment but refused HSCT and the other relapsing patient died because of progressive lymphoma after failure to achieve CR with conventional single agent CI. Median DFS in the control arm was 22 months (Fig 1B). NK cells showed higher expansion and a faster maturation in the treatment arm, compared to the control arm (p<0.05). As expected, HL cells lines do not express HLA class I and II, but express activating NK cells receptors (aNKG2D, aNKp30, aNKp46, aDNAM-1). In vitro, the activation of each of those receptors was able to trigger NK cells degranulation. Similarly, PD-L1 and PD-L2 blockade on HL cell lines significantly increased NK cell degranulation (p<0.05). Taken together, those observations support the role of NK cells in this setting. Conclusions Our data show very high anti-tumor activity of ALI + CI for RHL, allowing most patients to proceed to HSCT. RHL patients in the treatment arm had an excellent outcome if compared to the control arm, which included patient who did respond to conventional treatment. Biological data suggests that this approach may accelerate NK cell development/maturation and suggest that NK cells may mediate response to CI in HL.

Intensification of Therapy and Pharmacogenetic Personalization Mitigate Racial Disparities in Pediatric Acute Myeloid Leukemia Outcomes

Introduction Recent reports have highlighted disparities in outcomes for black children, adolescents, and young adults with acute myeloid leukemia (AML) compared to their non-Hispanic white counterparts. An analysis of pediatric AML patients treated from 1996-2013 revealed that black race was associated with inferior event-free survival (EFS) and overall survival (OS) (Conneely 2021). In a study of adolescent and young adult patients with AML, black race was a predictor of poor outcome, particularly among patients 18-29 years old (Larkin 2022). Addressing these outcome disparities and developing treatment strategies to overcome them is crucial. In this study, we evaluated the interactions between outcomes by race and cytarabine pharmacogenomics in pediatric AML patients treated on two multi-institutional clinical trials. Methods Pediatric patients with newly diagnosed AML treated on AML02 (NCT00136084) or AML08 (NCT00703820) were included. Patients received high-dose cytarabine, daunorubicin, and etoposide (HDAC), low-dose cytarabine, daunorubicin, and etoposide (LDAC), or clofarabine and cytarabine (Clo/AraC) as initial therapy. The pharmacogenomics ACS10 scores, derived from combination of 10 single nucleotide polymorphisms, were calculated as reported (Elsayed 2022). Results Overall, 86 patients were black and 359 were white; 68 had other or unknown racial backgrounds and were not included in this analysis. Complete remission rates after two courses of induction therapy did not differ between black and white patients (92.6% vs 95.0%, p=0.63), nor did the rates of MRD negativity after one course of therapy (55.8% vs 55.4%, p=0.85). The EFS rates of black and white patients were nearly identical, with 5-year estimates of 58.3% (95% CI = 48.8%-69.8%) and 58.2% (95% CI = 53.2%-63.6%; p=0.89, Fig 1). Likewise, OS did not differ between black and white patients (63.8%; 95% CI = 54.3%-74.8% vs 69.4%; 95% CI = 64.7%-74.5%; p=0.24). The cumulative incidence (CI) of relapse did not differ by race (26.0% vs 26.1%, p=0.99), nor did the CI of treatment-related mortality (7.0% vs 6.8%, p=0.78). The prevalence of core binding factor (CBF) leukemia was higher in black patients as compared with white patients (30% vs 19%, p=0.04), but we did not find differences in EFS between black and white patients with or without CBF AML. We recently showed that low ACS10 scores were associated with worse outcomes in patients treated with low-dose cytarabine-based induction. In the present study, there was a significant difference in the distribution of ACS10 scores according to race, with low scores occurring in 73% of black patients compared with 30% of white patients (p<0.001). When patients on all treatment regimens were considered, there were no differences in EFS between black and white patients with low (p=0.88) or with high ACS10 scores (p=0.72). However, black patients with low ACS10 scores had significantly better outcomes after treatment with Clo/Ara-C induction compared with LDAC induction (p=0.01 for EFS and p=0.04 for OS, Fig 2). In multivariable model adjusting for age, risk group, and leukocyte count, Clo/Ara-C induction was identified as the best treatment option for black patients with low ACS10 scores (EFS: HR = 0.2, p=0.03). Discussion Our findings contrast with recent reports, as we did not observe significant outcome differences between black and white patients in terms of complete remission rates, EFS, OS, CI of relapse, or CI of treatment-related mortality. The higher prevalence of low ACS10 scores in black patients compared with white patients likely contributes to outcome disparities observed among patients treated with LDAC in the present study and those in the literature, which have included patients who almost exclusively received low-dose cytarabine-based induction therapy. In the present study, black patients with low ACS10 scores had significantly worse outcomes compared to those with high scores when treated with LDAC. However, these differences in outcome were eliminated by the use of HDAC or Clo/Ara-C induction. By contrast, black patients with high ACS10 scores did not appear to benefit from HDAC or Clo/Ara-C induction. Our results suggest that pharmacogenomics differences between black and white patients should be considered when tailoring induction regimens to improve outcomes of black patients and bridge the racial disparity gap in AML treatment.

PB1812: CORE BINDING FACTOR ACUTE MYELOID LEUKEMIA IN PEDIATRIC POPULATION: THE RESULTS OF A MONOCENTRIC EXPERIENCE

Background: The core binding factor acute myeloid leukemia (CBF-AML) is characterized by t(8;21) and inv(16)(p13q22)/t(16;16)(p13;q22) cytogenetic abnormalities. It is associated with a good prognosis. Aims: In this study, we aimed to assess the treatment outcome of the pediatric CBF- AML in comparison with non CBF-AML treated in our center. Methods: We retrospectively reviewed data of patients under the age of 20 diagnosed with de novo AML in our center during january 2005 and december 2020. The treatment protocol includes: a course of induction (Cytarabine 200mg/m2/day associated with Daunorubicine (DNR) 60 mg/m2/day or Novantrone 12mg/m2/day). If a complete remission (CR) is achieved the chemotherapy is followed by: a cure of ADE (Cytarabin, DNR, Etoposide) associated with 2 cures of high dose of Cytarabine (12g/m2) before 2011 and a cure of ADE associated with 3 cures of high dose of cytarabine (18g/m2) after January 2011. Allogeneic stem cell transplantation (ASCT) from matched sibling donors was limited to patients who are in CR1, having an HLA-identical family donor before January 2011 and for patients who are in CR2 after January 2011. Endpoints were complete remission (CR), overall survival(OS), event free survival (EFS) and relapse rate. Survival statistical analysis performed with Kaplan Meyer method. Results: A total of 52 patients were included, of whom 16 (30%) presented CBF genes. The median age was 10years. The median white blood cells count at diagnostic was 28G/L. Distribution according to the FAB classification was as followed: 1(6%)M1, 8(50%) M2, 6(38%) M4 and 1(6%) M6.the most frequent subgroup was M2 (vs M1 in non CMF-AML, p=0.001). Cytogenetic analysis showed the Inv 16 (p13;q22) in 3 cases (18%) and t(8;21) (q22;q22) were observed in 11 cases (68%). Two patients had both CBFB–MYH11and AML-ETO rearrangement. Six cases (38%) had additional cytogenetic abnormalities. The correlation between cases with and without additional cytogenetic abnormalities did not conclude to any significent difference in terms of CR rate, OS and EFS. We observed a comparatively higher CR rate (87% vs 51% p=0.018) and also a better OS rate (83% vs 35%, p=0.02) at 5 years between CBF-AML and non CBF-AML. In contrast, there was no statisticly significent difference in terms of the EFS (67%vs 62%, p=0.4) and the relapse rate (31% vs 43%, p=0.3) between the 2 groups. Relapse occurred in 5 cases (31%) at a median of 13 months. A second remission was obtained in 2/5 patients. ASCT was performed in only 4 cases (3 after RC1 and 1 after relapse). Summary/Conclusion: The frequency of core binding AML in our study is higher than what has been reported in the literature (30 vs 15%) with predominance of The cytogenetic t(8,21) (68%). The additional cytogenetic abnormalities has no prognostic value. Long term survival in our series compared favorably with results reported by cooperative groups. It can be concluded that ASCT in CR1 for pediatric CBF-AML is no longer indicated.

Efficacy and safety of mycophenolate mofetil versus cyclophosphamide in the treatment of Henoch-Schönlein purpura nephritis with nephrotic-range proteinuria in children: a prospective randomized controlled trial

Objective To study the efficacy and safety of mycophenolate mofetil (MMF) versus cyclophosphamide (CTX) in the treatment of children with Henoch-Schonlein purpura nephritis (HSPN) and nephrotic-range proteinuria. Methods A prospective clinical trial was conducted in 68 pediatric patients who were admitted to the Department of Nephrology, Children's Hospital Affiliated to Capital Institute of Pediatrics and who were diagnosed with HSPN and nephrotic-range proteinuria from August 2016 to November 2019. The patients were randomly divided into two groups:MMF treatment (n=33) and CTX treatment (n=35). The two groups were compared in terms of complete remission rate, response rate (complete remission + partial remission), urinary protein clearance time, and adverse events. Results At months 3, 6, and 12 of treatment, there was no significant difference in the complete remission rate and the response rate between the MMF treament and CTX treatment groups (P > 0.05). There was also no significant difference between the two groups in the urinary protein clearance time and the incidence rate of adverse events (P > 0.05). Conclusions MMF and CTX have similar efficacy and safety in the treatment of HSPN children with nephrotic-range proteinuria.

CAG Regimen for Refractory or Relapsed Adult T-Cell Acute Lymphoblastic Leukemia: A Retrospective, Multicenter, Cohort Study

Background: Adult patients with relapsed or refractory T cell acute lymphoblastic leukemia (R/R-T-ALL) have limited therapeutic options and extremely poor prognoses, representing an urgent unmet medical need. Finding an optimal salvage regimen to bridge to transplantation is a priority. The CAG regimen [cytarabine, aclarubicin and granulocyte colony-stimulating factor(G-CSF)], has been initially used from one group in China, showing unexpectedly promising results in 11 R/R-T-ALL patients. Here, we report the multi-center results from the Chinese Leukemia Cooperation Group. Methods: In this retrospective analysis, we included all patients aged ≥ 15 years old with R/R-T-ALL who received the CAG regimen as salvage therapy from September 2012 to June 2019 from the Chinese Leukemia Cooperation Group. Totally,41 adult R/R-T-ALL patients received the CAG regimen as salvage therapy. The CAG regimen consisted in cytarabine,10 mg/m2, q12h, d1-14; aclarubicin, 20 mg/d, d1-4; and G-CSF 200 mg/m2 from days 1 until neutrophil recovery. Outcomes were assessed in terms of complete remission rate, event-free survival, and overall survival. Findings: After one cycle of the CAG regimen among 41 patients, the complete and partial remission was achieved in 33 (80.5%) and 2(4.9%) patients, respectively. Failure to response was observed in 6 patients (14.6%). Early T-cell precursor (ETP) (n=26) and non-ETP (n=15) patients had a similar CR rate (80.8% vs 80.0%, p=0.95). Twenty-seven (66%) patients received allo-HSCT and 24 patients were still alive. With a median follow-up time of 12 months (range, 1-63 months), the estimated 2-year overall survival was 68.8% (95% CI, 47.3%-83.0%), and the event-free survival was 56.5% (95% CI, 37.1%-71.9%). The CAG regimen was well-tolerated, and no early death occurred. Interpretation: Our multicenter results show that the CAG regimen was highly effective and well-tolerated, representing a novel, optimal choice for adult patients with R/R-T-ALL and providing a better bridge to transplantation. Funding: Foundation for the National Natural Science Foundation of China. Declaration of Interest: We declare no competing interests. Ethical Approval: The study was conducted in accordance with the declaration of Helsinki, and approval was granted by the relevant ethics committees.

Tripterygium glycosides in treatment of henoch-schonlein purpura nephritis: a systematic review of randomized controlled trials

To evaluate the clinical efficacy and safety of tripterygium glycosides (TG) in the treatment of henoch-schonlein purpura nephritis(HSPN). Seven English and Chinese databases (up to Nov. 9, 2017), were searched to collect the RCTs on TG for HSPN. Two researchers independently screened the literature according to inclusion criteria and exclusion criteria, extracted data, and evaluated the quality of the literature. After completion, cross-checking was performed and Meta-analysis was performed using RevMan 5.3 software. At the same time, different outcomes of the interventions were analyzed subgroupically. A total of 46 RCTs were included, with 1 659 in the experimental group and 1 596 in the control group. All the clinical studies showed a low quality. In terms of complete remission rate, the group with TG performed better than the group with conventional therapy or GC（RR=1.82，95%CI[1.39，2.39];RR=2.03，95%CI[1.37，2.99]），the group with TG+GC performed better than the group with GC（RR=1.46，95%CI[1.32，1.60]），and the group with CTX+GC performed better than the group with TG+GC（RR=0.35，95%CI[0.16，0.75]）. In terms of total effective rate, the group with TG performed better than the group with conventional therapy or GC（RR=1.44，95%CI[1.19,1.74];RR=1.30，95%CI[1.16，1.46]），the group with TG+GC performed better than the group with GC（RR=1.27，95%CI[1.21，1.34]），and the group with CTX+GC performed better than the group with TG+GC（RR=0.60，95%CI[0.43，0.85]）. No significant difference was found between the group with TG+GC and LEF+GC（RR=0.68，95%CI[0.30，1.53]）. In terms of urinary protein, urine occult blood negative time，the group with TG performed better than the group with conventional therapy（MD=-9.00，95% CI[-11.99，-6.01];MD=-12.00，95%CI[-16.13，-7.87]），the group with TG+GC performed better than the group with GC（MD=-8.86，95%CI[-10.08，-7.64];MD=-16.24，95%CI[-23.80，-8.67]）. In terms of recurrence rate, the group with TG+GC was lower than the group with GC（RR=0.13，95%CI[0.06，0.25]）, but there were no significant difference between the group with TG and conventional therapy（RR=0.43，95%CI[0.15，1.19]）. In adverse reactions, the common adverse effects of TG were gastrointestinal discomfort, liver damage and leucopenia. TG for the treatment of HSPN can improve clinical efficacy, reduce recurrence, and the adverse reactions are relatively safe. Due to the generally low methodological quality of the included studies, which affected the accuracy and reliability of the result. Therefore, more high-quality, large samples and multi-center randomized controlled trials are necessary for further evidence.

The clinical significance of FLT3 ITD mutation on the prognosis of adult acute promyelocytic leukemia

ABSTRACTBackground and aims: To explore the relationship between FLT3 (encoding Fms related tyrosine kinase 3) internal tandem duplication (ITD) mutations with the prognosis of acute promyelocytic leukemia. The PubMed database, the Cochrane Library, conference proceedings, the EMBASE databases, and references of published trials and review articles were searched. Two reviewers independently assessed the quality of the trials and extracted the data. Odd ratios (ORs) for complete remission (CR) rate after induction therapy, 5-year overall survival (OS), and 5-year disease free survival (DFS) were pooled using the STATA package.Main results: Seventeen trials involving 2252 patients were ultimately analyzed. The pooled OR showed that the FLT3 ITD mutation group had a poor prognosis in terms of CR rate (OR = 0.53, 95% confidence interval (CI), 0.30–0.95, P = 0.03), 5-year OS (OR = 0.47, 95% CI, 0.29–0.75, P = 0.002), and as 5-year DFS (OR = 0.48, 95% CI, 0.29–0.78; p = 0.003).Conclusions: The results suggested that FLT3 ITD mutations could become an indicator of poor prognosis of APL, and these patients should receive more intensive therapy according to current guidelines.

Intesive fludarabine-high dose cytarabine-idarubicin combination as induction therapy with risk-adapted consolidation may improve treatment efficacy in younger Acute Myeloid Leukemia (AML) patients: Rationales, evidences and future perspectives.

Acute Myeloid Leukemia (AML) is the commonest form of leukemia in the adults, with an incidence of 3-4 cases per 100,000 people/year. After the first description of the effective cytarabine + antracycline (3+7) induction regimen, in the last 3 decades, no effective targeted drug has been included in the standard treatment of AML. Many efforts of modifying 3+7 adding a third drug or increasing the dose of anthracycline, cytarabine or both did not lead to substantial improvements, mainly due to increased toxicity. Many in vitro and in vivo evidences suggested that fludarabine may increase efficacy of cytarabine through a synergistic effect. Considering the continuous improvements in supportive care and management of infectious complications the feasibility of more intensive induction strategies have increased and a renewed interest in fludarabine-containing induction strategies arose. The recent MRC AML 15 trial has shown that a fludarabine-containing induction, FLAG-Ida, resulted superior to conventional 3+7 in terms of complete remission rates, relapse incidence and survival, although only a minority of patients could complete the whole planned consolidation program due to an excessive hematological toxicity. Our group recently published a 10-year experience with a fludarabine-containing induction that slightly differed from the MRC one and resulted in good efficacy and higher feasibility. In this commentary we review the major evidences supporting the employ of a fludarabine-containing induction in AML, and discuss the future perspectives.

Gemtuzumab-Ozogamicin Containing Regimens As Induction Therapy Give the Highest Complete Remission Rate and the Longest Overall Survival Compared with Other Induction Regimens in Patients with Newly Diagnosed Acute Myeloid Leukemia

Introduction. Conventional induction treatment in young non APL-Acute Myeloid Leukemia (AML) patients is still represented by the association of an antracycline and Cytarabine, which offers a complete remission (CR) rate not inferior to 60%. The addition of Gemtuzumab Ozogamicin (GO) as a third or fourth drug, already demonstrated to improve clinical outcome, in terms of CR rates.Aims of the study. We retrospectively evaluated and compared the efficacy of different induction schedules, in terms of CR rates and Overall Survival (OS), administered to two groups of AML patients. Group 1 (n=139) was treated with a GO containing course (MyFLAI or MyAIE schedules); Group 2 (n=270) received a non-GO based regimen including or not Fludarabine (FLAI, FLAN, FLAG, 3+7 or DAE).Patients and Methods. From 1997 to 2014,409 newly diagnosed AML patients were treated in 3 Italian Institutions. Their median age was 53 (range 19-74) and 52 (range 17-75) years, respectively.According to karyotype (performed in 392/409 patients), FLT3 (available for 244/409 patients), and NPM1 mutational status (available for 157/409 patients), based on the NCCN-2013 risk stratification criteria, 35.2% of the patients were considered at High Risk (HR) (31.6% and 36.4% in the two groups, respectively) and 7.6% at low risk (LR) (7.8% and 7.0%, respectively).Results. The complete remission (CR) rate after induction was 81.4% and 70.4% for Group 1 and 2, respectively (p=0.01). Deaths during induction (DDI), occurring in the first 50 days from 1st line therapy, were 4/139 (2.9%) in Group 1 and 22/270 (8.1%) in Group 2 (p=0.003).Patients treated with GO showed a better OS than patients of Group 2 (Figure 1); the 5-years OS in the two groups was 54.01% and 34.9%, respectively, and different according to age (54.0% and 34.9% respectively (p=0.0003) in patients <60 years, 30.2% and 13.5% respectively (p=0.001) in patients ³60 years). The 5-years Event Free Survival (EFS) in the two groups was 45.6% and 30.8% respectively (p=0.0003) (Figure 2).Then, with a logistic univariate regression analysis.,we explored the impact of GO therapy in terms of CR rate. The use of GO was identified as a strong predictor of the achievement of a 1st CR (p=0.008). Moreover, a logistic multivariate regression analysis (risk and age) confirmed the role of the compound as a predictor of higher CR rate (p=0.013).We also performed a Cox Regression analysis, to investigate the impact of GO therapy, age and risk on OS: the use of GO was confirmed to be an independent predictor of better OS (p<0.0001) with a Hazard Ratio of 1.966 (p<0.0001).In a sub-analysis performed on HR patients, we observed a significantly better outcome in Group 1 than in Group 2 in terms of OS (p=0.0074, 5-year OS 47.7%; in group 2 OS 21.0% respectively, Figure 3) and EFS (p=0.001). However, there was no difference in terms of CR rate (p=ns). In particular, HR patients with adverse karyotype, may benefit from GO induction therapy in terms of OS (5-years OS 42.9% and 12.8% in Group 1 and 2, respectively, p=0.02); nevertheless FLT3 mutations negative impact canÕt be overcome by the drug administration (5-years OS 66.6% and 61.3% in Group 1 and 2, respectively).In SR AML, GO offered a better OS (p=0.036, 5-years OS 51.4% and 41.9% respectively).Comparing with Fisher's exact test the rate of increment in 5-years OS between Group1 and Group2 in HR and SR AML, we demonstrate that treatment with GO gave the higher benefit in HR AML (p=0.0005).Conclusions. These data showed that a four-drugs intensified induction therapy is a feasible approach in AML patients: adding GO at any induction regimen is an independent and strong predictor of better OS and higher CR rates. In our population, GO was not associated with a higher incidence of DDI.This approach, could be strongly recommended in SR and HR AML patients, due to karyotype abnormalities, in which showed an advantage in term of OS if compared with other standard regimens. On the contrary, we donÕt suggest the same schedule in FLT3 mutated patients, in which no benefits have been observed.Acknowledgments Work supported by ELN, AIL, AIRC, Progetto Regione-Universitˆ 2010-12 (L.Bolondi), FP7 NGS-PTL project. [Display omitted] [Display omitted] [Display omitted] DisclosuresSoverini:Novartis, Briston-Myers Squibb, ARIAD: Consultancy. Fanin:Novartis Farma: Speakers Bureau. Cavo:BMS: Honoraria; Millenium Pharmaceuticals: Honoraria; Jansenn: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Onyx: Honoraria; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Martinelli:Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; ROCHE: Consultancy; MSD: Consultancy; AMGEN: Consultancy; Ariad: Consultancy.

A Prospective Randomized Comparison of Idarubicin and High-Dose Daunorubicin in the Induction Chemotherapy for Acute Myeloid Leukemia

▪Introduction: We conducted a randomized trial comparing two different doses of daunorubicin as induction chemotherapy in young adults with acute myeloid leukemia (AML) and showed intensification of induction therapy using a high daily dose of daunorubicin (90 mg/m2/d x 3d) improved both complete remission (CR) rate and survival duration compared to standard daunorubicin dose (45 mg/m2/d x 3d) (Lee JH et al. Blood 2011;118:3832). As it is necessary to compare the effects of high-dose daunorubicin with that of other agents, especially idarubicin, we performed another randomized trial comparing two induction regimens in young adults with AML: idarubicin vs. high-dose daunorubicin (ClinicalTrials.gov #NCT01145846). Here, we present final results of the study.Methods: Between May 2010 and March 2014, a total of 316 patients (65 years or younger) with newly diagnosed AML except acute promyelocytic leukemia were registered in this study. Seventeen patients were removed from the study (change of diagnosis in 11, patient's refusal to be randomized in 3 and other in 3) and the remaining 299 patients were analyzed. After random assignments, 149 patients received idarubicin (AI, 12 mg/m2/d x 3d) and 150 patients received high-dose daunorubicin (AD, 90 mg/m2/d x 3d) in addition to cytarabine (200 mg/m2/d x 7d) for induction of CR. Patients with persistent leukemia received the second attempt of induction chemotherapy, consisting of idarubicin (AI, 12 mg/m2/d x 2d) or daunorubicin (AD, 45 mg/m2/d x 2d) plus cytarabine (5d). Patients who attained CR received 4 cycles of high-dose cytarabine (3 g/m2 x 6 doses) in patients with good- or intermediate-risk cytogenetics and 4 cycles of cytarabine (1 g/m2 x 6d) plus etoposide (150 mg/m2 x 3d) in those with high-risk cytogenetics. Hematopoietic cell transplantation (HCT) was performed according to attending physician's discretion after one or two cycles of consolidation chemotherapy in most transplant cases.Results: CR was induced in 232 (77.6%) of 299 patients. Reasons for induction failure were resistant disease in 50, hypoplastic death in 5, and indeterminate cause in 12. As postremission therapy, 3 patients received no further treatment, 71 received consolidation chemotherapy without HCT, 137 underwent allogeneic HCT, and 21 underwent autologous HCT. The CR rates were not significantly different between two arms: 80.5% (120 of 149, AI) vs. 74.7% (112 of 150, AD) (P=0.224). With a median follow-up of 1046 days, overall survival probabilities at 4 years were 51.1% in AI vs. 54.7% in AD (P=0.756). The probabilities at 4 years for relapse-free survival were 63.5% in AI vs. 74.2% in AD (P=0.181) and those for event-free survival were 44.8% in AI vs. 50.7% in AD (P=0.738). Toxicity profiles were similar between two arms. Interestingly, overall and event-free survivals of 44 patients with FLT-ITD mutants (27 in AI and 17 in AD) were significantly different according to the induction regimens (AI vs AD; overall survival, 30.8% vs. 61.9%, P=0.030; event-free survival, 31.4% vs. 61.9%, P=0.025).Conclusions: The results of this phase 3 trial, which compared idarubicin (12 mg/m2/d x 3d) with high-dose daunorubicin (90 mg/m2/d x 3d), did not show significant differences between two arms in the outcomes of patients in terms of CR rates and overall, relapse-free or event-free survivals. In subset analysis, high-dose daunorubicin seems to be more effective than idarubicin in patients with FLT-ITD mutants. DisclosuresKim:Celgene: Research Funding; Alexion Pharmaceuticals: Research Funding; Il-Yang: Research Funding; Novartis: Research Funding.

Up-Front Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia Arising from the Myelodysplastic Syndrome

In patients with secondary acute myeloid leukemia (s-AML) arising from the myelodysplastic syndrome (MDS), treatment outcome is unsatisfactory. We compared up-front allogeneic hematopoietic cell transplantation (HCT) to induction chemotherapy (IC) as an initial treatment in patients with s-AML arising from MDS. This retrospective study included 85 patients who were diagnosed with s-AML arising from MDS; 11 patients proceeded to up-front HCT without IC (HCT group) and 74 received IC (IC group) as an initial treatment for s-AML, 28 of whom subsequently underwent HCT. In the IC group, 41.9% achieved complete remission (CR) compared to 81.8% in the HCT group (p = 0.013). The HCT group showed a significantly longer event-free survival (EFS) than the IC group (median 29.2 vs. 5.2 months, p = 0.042). Overall survival of the HCT group was higher than that of the IC group, but the difference was not statistically significant (median 34.6 vs. 7.6 months, p = 0.149). After adjustment for other clinical factors, outcome in the HCT group was significantly better than in the IC group in terms of CR rate (hazard ratio, HR, 11.195; p = 0.007) and EFS (HR, 0.384; p = 0.029). Up-front HCT is a viable option in s-AML arising from MDS if an appropriate donor is available. © 2014 S. Karger AG, Basel

Different safety profiles of first-line bendamustine-rituximab (BR), R-CHOP, and R-CVP in an open-label, randomized study of indolent non-Hodgkin lymphoma (NHL) and mantle cell lymphoma (MCL): The BRIGHT study.

8565 Background: The BRIGHT study demonstrated that first-line BR was non-inferior to R-CHOP/R-CVP in terms of complete remission rate in indolent NHL and MCL. This is the first detailed analysis of the safety and tolerability of the study regimens. Methods: Patients were preselected for R-CHOP or R-CVP, and then randomized to 6-8 cycles of BR (28-d cycle) or the preselected standard regimen (21-d cycles). BR dosing was bendamustine 90 mg/m2/d as a 30-min infusion on days 1 and 2 plus rituximab 375 mg/m2given before bendamustine on day 1. Colony stimulating factors (CSFs) and antiemetics were given per local standards. Results: In patients preselected for R-CHOP, 103 received BR and 98 R-CHOP. In patients preselected for R-CVP, 118 received BR and 116 R-CVP. For all regimens, ≥ 88% of patients received the planned 6 cycles. Main differences in adverse events (AEs), all grades, are shown in the Table. Incidence of grade 3/4 AEs was 69% for R-CHOP vs 56% BR, and 50% for R-CVP vs 56% BR. Grade 3/4 drug hypersensitivity, neuropathy, and rash were infrequent. Antiemetic use was similar between groups except use of aprepitant as an adjunct to 5-HT3 antagonists was higher with R-CHOP (23% [19% in cycle 1]) than BR (9% [2%]) or R-CVP (3% [2%]). CSF use was higher with R-CHOP (61%) than BR (29%) or R-CVP (27%). Analyses of event prevalence over the treatment period and by region will also be presented. Conclusions: BR, R-CHOP, and R-CVP have significantly distinct AE profiles. More nausea, vomiting, and hypersensitivity occurred with BR while more constipation, neuropathy, and alopecia occurred with RECHOP/R-CVP. Support: Teva BPP R&amp;D, Inc. Clinical trial information: NCT00877006. [Table: see text]

Inclusion of hemoglobin level in prognostic score provides better prognostic stratification in patients with acute promyelocytic leukemia (APL)

The clinical outcomes of acute promyelocytic leukemia (APL) have improved greatly, but treatment failure still occurs. Identification of patients with poor prognosis is fundamental, and we propose a new clinical prognostic system (CBC-score) consisting of WBC, platelet count, and hemoglobin level. Between 1995 and 2009, 156 patients with APL from seven institutes in Korea were retrospectively reviewed. In the new CBC-score system, each of the following (WBC ≥ 10 × 109/L, platelet <40 × 109/L, hemoglobin <8.0 g/dL) was considered as a risk factor; the sum of each was designated as the CBC-score. With a median follow-up of 8.4 years, the complete remission (CR) rate was 81.4 % (127/156), while 24 (15.4 %) were considered as treatment failures due to early death (ED). The 5-year overall survival (OS), leukemia-free survival, and cumulative incidence of relapse were 73.8, 82.8, and 13.5 %, respectively. Compared to the individual CBC parameters, combined prognostic systems such as PETHEMA or CBC-score provided better prognostic stratification. Compared to PETHEMA stratification, the proposed prognostic CBC-score system showed better stratification of APL patients in terms of CR rates (p = 0.004), OS (p = 0.004), and ED (p = 0.008). This retrospective study suggests that the proposed CBC-score may provide better prognostic stratification of APL patients.

IS5-5 - Immediate Allogeneic Hematopoietic Cell Transplantation (HCT) in Acute Myeloid Leukemia (AML) Arising from Myleodysplastic Syndrome (MDS)

ABSTRACT Background In treating secondary AML arising from MDS, the complete remission (CR) rate after standard induction chemotherapy is low and relapse is common without allogeneic HCT. We therefore analyzed the benefit of immediate allogeneic HCT versus induction chemotherapy in AML arising from MDS. Methods Between 1991 and 2010, 95 patients were diagnosed with AML arising from MDS. After the diagnosis of AML, 10 patients received supportive care only. This retrospective study involved analysis of data from remaining 85 patients; 11 proceeded to immediate allogeneic HCT without induction chemotherapy (HCT group) and 74 were treated with induction chemotherapy (IC group). Results Patient characteristics at AML diagnosis were similar between the HCT and IC groups except total leukocyte counts, which were higher in the IC group than the HCT group (P = 0.009). Patients in the IC group were initially treated with induction chemotherapy consisted mostly of cytarabine plus daunorubicin or idarubicin, while those in the HCT group received allogeneic HCT from HLA matched sibling donors (n = 7) or unrelated volunteers (n = 4). CR was achieved in thirty-one patients (41.9%) in the IC group and 9 (81.8%) in the HCT group (P = 0.013). Of 74 patients in IC group, 28 underwent allogeneic HCT in the first CR (n = 13), primary refractory disease (n = 10), or the first or second relapse (n = 5). The median overall survival (OS) and event-free survival (EFS) were 8.3 and 6.4 months, respectively. Relapse probability at 5 years was 49.2%. The HCT group showed a significantly longer EFS than the IC group (median 29.2 versus 5.2 months, P = 0.042). OS of the HCT group was higher than that of the IC group, but the difference was not statistically significant (median 34.6 versus 7.6 months, P = 0.149). Relapse probability was not significantly different between the two groups (P = 0.278). After adjustment for other variables, the HCT group showed significantly better outcomes than did the IC group in terms of CR rate (HR, 11.195; 95% CI, 1.940–64.619; P = 0.007) and EFS (HR, 0.384; 95% CI, 0.163–0.905; P = 0.029). Conclusions Immediate allogeneic HCT is a viable option in AML arising from MDS if an appropriate donor is available.

Lack of negative impact of Philadelphia chromosome in older patients with acute lymphoblastic leukaemia in the thyrosine kinase inhibitor era: comparison of two prospective parallel protocols

Lack of negative impact of <scp>P</scp>hiladelphia chromosome in older patients with acute lymphoblastic leukaemia in the thyrosine kinase inhibitor era: comparison of two prospective parallel protocols

Activity of the Investigational Antibody–Drug Conjugate Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Hodgkin Lymphoma or Systemic Anaplastic Large-Cell Lymphoma: Comparisons with Meta-Analyses of Historical Control Chemotherapy Data

Abstract 4975 Background:Brentuximab vedotin (SGN-35) is an investigational CD30-directed antibody–drug conjugate consisting of the monoclonal chimeric antibody cAC10 specific for human CD30, the potent antimicrotubule agent monomethyl auristatin E (MMAE), and a protease-cleavable linker that covalently attaches cAC10 to MMAE. Two single-arm pivotal phase 2 trials in relapsed or refractory Hodgkin lymphoma (HL; SG035-0003, Younes et al, ICML 2011) and systemic anaplastic large-cell lymphoma (sALCL; SG035-0004, Shustov et al, ICML 2011) have shown brentuximab vedotin (1.8 mg/kg IV every 3 weeks for up to 16 cycles) to have durable antitumor activity in terms of overall response rate and complete remission (CR) rate with a manageable safety profile. In the absence of a suitable comparator regimen for the conduct of these trials, and per the ICH E10 (CHMP/ICH/364/96) guideline, we conducted meta-analyses of historical chemotherapy data to compare the activity of brentuximab vedotin in the pivotal single-arm trials to the activity of other therapies used for the treatment of relapsed or refractory HL and sALCL. Methods:CR rate was the endpoint since in both HL and aggressive non-Hodgkin’s lymphoma (NHL), achievement of CR has been shown to correlate with long-term clinical benefit (Josting & Schmitz, 2004; Lee et al, Ann Oncol 2011). For the HL meta-analysis, a PubMed search identified all prospective trials and retrospective case series in which ≥10 adult HL patients with relapsed or refractory disease were treated with gemcitabine alone or in combination; these regimens were selected for the control population because they constitute one of the most commonly used systemic therapies beyond second-line treatment in HL. Trials were classified as post-autologous stem cell transplant (ASCT; ≥33% of enrolled patients), or ASCT-naïve. For the sALCL meta-analysis, a PubMed search identified all trials since 2001 of aggressive relapsed or refractory NHL that included at least one sALCL patient. Due to the rarity of relapsed or refractory sALCL and the absence of standard therapy in this setting, no specific regimen was selected as a control. Quantitative statistical meta-analyses were carried out per pre-specified plans to minimize bias and ensure integrity of the statistical analysis, and performed using random effect models; estimates (95% CI) of overall CR rate were provided. Results:For the HL meta-analysis, 16 trials with 605 patients were identified, including nine post-ASCT trials (n=296, median of three prior regimens) in which a median of 44% (range 33–64%) of patients had prior ASCT, and seven ASCT-naïve trials (n=309, median of one prior regimen). CR rates are shown in the figure. The estimated overall CR rate in the post-ASCT subgroup was 15% (95% CI: 6.5, 23.5), which was significantly lower than the CR rate of 34% (95% CI: 25.2, 44.4; p=0.003) seen with brentuximab vedotin in SG035-0003, in which all patients had prior ASCT and the median number of prior regimens was 3.5. In the ASCT-naïve subgroup, the estimated overall CR rate was 35% (95% CI: 16.9, 52.2), which was not significantly different versus SG035-0003. However, patients in the historical ASCT-naïve subgroup had less advanced disease and were less heavily pretreated. Considering all trials, the estimated overall CR rate was 24% (95% CI: 14.2, 33.9), with a trend towards lower activity versus SG035-0003 (p=0.148). For the sALCL meta-analysis, 19 trials with 817 NHL patients (median of two prior regimens) were identified, which included 1.6–20.8% sALCL patients (n=48 in total). The estimated overall CR rate of 18% (95% CI: 11.3, 24.5) was significantly lower than with brentuximab vedotin in SG035-0004 (53% [95% CI: 39.9, 66.7], p<0.0001). Conclusions:The anti-tumor activity of brentuximab vedotin in relapsed or refractory post-ASCT HL patients, in terms of CR rate, appears to exceed that of gemcitabine-based therapies in this setting, and appears comparable to that seen with combination chemotherapy in ASCT-naïve patients with less advanced disease. The anti-tumor activity of brentuximab vedotin also appears to exceed that of other treatment options for aggressive relapsed or refractory NHL, including sALCL. Acknowledging the limitations of these comparisons, these meta-analyses suggest that brentuximab vedotin may provide meaningful long-term clinical benefit in relapsed or refractory HL and sALCL. [Display omitted] Disclosures:Gualberto:Millennium Pharmaceuticals, Inc.: Employment. Off Label Use: Brentuximab vedotin for the treatment of relapsed or refractory Hodgkin lymphoma and systemic anaplastic large-cell lymphoma. Chi:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment.

Immediate Allogeneic Hematopoietic Cell Transplantation (HCT) in Acute Myeloid Leukemia (AML) Arising From Myelodysplastic Syndrome (MDS)

Abstract 2031 Introduction:Treatment of secondary AML arising from MDS is unsatisfactory. Induction rate of complete remission (CR) is low with standard inuction chemotherapy regimen and relapse is common without allogeneic HCT. Immediate allogeneic HCT without induction chemotherapy can be an option if an appropriate donor is available in patients whose disease progress into AML from MDS. We intended to analyze the benefit of immediate allogeneic HCT versus induction chemotherapy in patients with AML arising from MDS. Methods:Between 1991 and 2010, 95 patients were diagnosed with AML that had evolved from antecedent MDS. After the diagnosis of AML, 10 patients received supportive care only. This retrospective study involved analysis of data from remaining 85 patients; 11 proceeded to immediate allogeneic HCT without induction chemotherapy (HCT group) and 74 were treated with induction chemotherapy (IC group). The clinical outcomes between the HCT group and the IC group were compared. Results:Median age was 48 years (range, 18–78). Patient characteristics at the time of AML diagnosis were similar between the HCT and IC groups except total leukocyte counts, which were higher in the IC group than the HCT group (P=0.009). Patients in the IC group were initially treated with induction chemotherapy consisted mostly of cytarabine plus daunorubicin or idarubicin, while those in the HCT group received allogeneic HCT from HLA matched sibling donors (n=7) or unrelated volunteers (n=4). Thirty-one patients (41.9%) in the IC group achieved CR with induction chemotherapy, whereas 9 (81.8%) in the HCT group achieved CR after HCT (P=0.013). Of 74 patients in IC group, 28 underwent allogeneic HCT in their disease status of the first CR (n=13), primary refractory disease (n=10), or the first or second relapse (n=5). The median follow-up duration for surviving patients was 8.2 months (range, 0.2–171.3). During this time, 62 patients died, 16 relapsed after CR, and 68 died or relapse. The median overall survival (OS) and event-free survival (EFS) were 8.3 and 6.4 months, respectively. Relapse probability at 5 years was 49.2%. The HCT group showed a significantly longer EFS than did the IC group (median 29.2 vs. 5.2 months, P=0.042). OS of the HCT group was higher than that of the IC group, but the difference was not statistically significant (median 34.6 vs. 7.6 months, P=0.149). Relapse probability was not significantly different between the two groups (35.7% vs. 53.1% at 5 years, P=0.278). After adjustment for other variables, the HCT group showed significantly better outcomes than did the IC group in terms of CR rate (HR, 11.195; 95% CI, 1.940–64.619; P=0.007) and EFS (HR, 0.384; 95% CI, 0.163–0.905; P=0.029). Conclusions:Immediate allogeneic HCT is a viable option in AML arising from MDS if an appropriate donor is available. Disclosures:No relevant conflicts of interest to declare.

Prognostic Value of Monosomal Karyotype in Patients with Primary Acute Myeloid Leukemia On Behalf of Spanish CETLAM Group.

Abstract 1003Poster Board I-25 Introduction:Recently, the cooperative group HOVON-SAKK has refined the prognostic impact of cytogenetic abnormalities in acute myeloid leukemia (AML) by introducing the concept of monosomal karyotype (MK). This consists of ≥ 2 autosomal monosomies or one autosomal monosomy in addition to a structural alteration. In their experience, MK would explain the poor prognosis of AML with a complex karyotype. Objective:To investigate the prognostic impact of MK in patients with primary (de novo) AML enrolled in the Spanish CETLAM group protocols (AML 94/99/03). Also, to determine whether considering MK added predictive value to the cytogenetic classification of the Medical Research Council (MRC). Methods:Retrospective analysis of data from 1149 AML patients. Chromosomal formula was centrally reviewed with karyotypes being classified by the presence of MK and allocated into the MRC risk categories. Complete remission (CR) rate, disease-free survival (DFS) and overall survival (OS) were calculated. Results:The karyotype was assessable in 904 (79%) of the 1149 cases. In 145 of the 904 cases (16%), abnormalities involving CBF gene were detected and in 437 (48%) the karyotype was normal (NK). In 253 (28%) additional patients the karyotype was not monosomal; of them, 61 (24%) belonged to the unfavorable MRC with 17 cases harboring a complex karyotype ≥ 5 abnormalities, 7 cases with rearrangements 3q, 13 cases with -7, 9 cases with 5q abnormalities and 16 cases with t(6;9)). The remaining 69 (7.7%) patients had a MK; of them, 59 (85.5%) were from the unfavorable MRC category and included 43 cases with complex karyotype ≥ 5 abnormalities, 6 cases with rearrangements 3q, 5 cases with -7, 5 cases with alterations of 5q). The following table summarizes the results in terms of CR rate, DFS and OS:CBFNKMK- (IP)*MK- (UP)**MK+***pCR92%82%76%68%52%< 0,001DFS (4 years) median (month)58%± 5114.845%± 322.638%± 516.320%± 812.315%± 74.73<0,001OS (8 years) median (month)62%± 4-35%± 321.234%± 416.016%± 612.83%± 36.6<0,001*MK- (IP): Non-monosomal karyotype in the intermediate prognosis MRC cytogenetic group.**MK -(UP): Non-monosomal karyotype in the unfavorable prognosis MRC cytogenetic group.***MK+ : Cases with MK Conclusions:The addition of MK to the MRC cytogenetic classification refines the prognostic prediction. In our series, the dismal outcome of patients with MK is confirmed; these patients had worse prognosis than those with adverse cytogenetics without MK. Alternative treatment strategies are mandatory for MK+ patients.Supported in part by grants: GR1-01075, ECO07/90065, PI080672 and RD06/0020/0101. Disclosures:No relevant conflicts of interest to declare.

Outcomes of patients who undergo aggressive induction therapy for secondary acute myeloid leukemia

Response and survival in 96 patients with secondary acute myeloid leukemia (sAML) who received aggressive induction chemotherapy was reviewed. The median follow-up of survivors was 2.3 years. A total of 70 (73%) patients achieved a morphologic complete remission (CR) confirmed by absence of leukemic blasts by flow cytometry. For all 96 patients, the median event-free survival (EFS) was 8 months, and overall survival (OS) was 13.6 months (range, 1-119 months). Eight patients died shortly after induction therapy because of disease or side effects, and 13 are currently in continuous first remission. The median disease-free survival (DFS) for all 70 patients who achieved a morphologic CR was 9 months (range, 1-51 months), with a 64% chance of surviving 1 year. Patients with AML after previous chemotherapy or radiation therapy had a higher morphologic remission rate compared with those arising from myelodysplastic syndrome or myeloproliferative disease (82% vs 62%; P = .027). However, among the patients from the 2 groups who attained a morphologic remission, there was no difference in terms of CR rate (P = .94), DFS, EFS, or OS (P = .55, .83, and .71, respectively). This is a similar DFS to the group of 7 patients who went directly to ablative allogeneic transplant rather than having induction therapy first. In this population of patients who received aggressive chemotherapy, Charlson comorbidity index or a higher number of factors recognized as high risk in leukemia patients did not affect the chance of OS, DFS, and EFS, although having more recognized leukemia risk factors was related to a lower chance of surviving 1 year. However, it is important to note that those with higher comorbidity indexes were underrepresented in this aggressively treated cohort. The data from the current study demonstrate that many patients with sAML can tolerate aggressive induction therapy and attain remission, but duration of response and the chance of long-term survival remain poor.

High-Dose Topotecan, Melphalan and Cyclophosphamide (TMC) with Autologous Stem Cell Support for Multiple Myeloma

Introduction High dose chemotherapy and autologous stem cell transplantation (auto SCT) was associated with prolonged event-free (EFS) and overall survival (OS) in selected patients with multiple myeloma (MM) in at least two randomized controlled trials. High-dose melphalan at 200 mg/m2 is considered the standard regimen, but the complete remission (CR) rate at best is 30–40% and the EFS approximately 2 years. Novel preparative regimens are being evaluated to improve the efficacy without increasing the toxicity. We evaluated the safety and efficacy of a new regimen, Topotecan, Melphalan and Cyclophosphamide (TMC) in patients undergoing auto SCT for MM.Methods The primary objectives were to determine the safety and to evaluate if TMC could increase the CR rate in MM patients undergoing auto SCT. Patients received cyclophosphamide at the dose of 1 g/m2 intravenously over 2 h on days -6, -5, -4; melphalan at the dose of 70 mg/m2 intravenously over 30 min on days -3 and -2 and topotecan at a dose of 3.5 mg/m2 over 30 min for 5 total doses on days -6 to -2.Results 44 patients (26 males, 18 females) with primary refractory disease or in first remission received the TMC regimen followed by auto SCT between August 2002 and March 2004. The median age of patients at auto SCT was 55 years (range 40–67) and the median interval between the diagnosis and auto SCT was 6.3 month (range 2.2– 42 months). Twelve patients (27%) had chromosomal abnormalities on conventional cytogenetic studies. Median follow-up in surviving patients was 47.8 months. Median time to neutrophil engraftment (ANC > 500/dl) and platelet engraftment (>20,000/dl) were 10 (range 7–11 days) and 9 days (range 6–9 days), respectively. Thirty seven patients (84%) were transplanted for consolidation of first remission and 7 for primary refractory disease (16%). Most common adverse events were: grade 1& 2 nausea (59%), grade 1 & 2 diarrhea (41%) and dysphagia (34%). Non-hematologic grade 3 & 4 toxicities were seen in 9 patients (20%) and included infectious complications (2 patients), congestive heart failure exacerbation (2 patients), electrolyte abnormalities including hypocalcemia and hypokalemia (1 patient each), GI complications like dysphagia and vomiting (1 patient each) and cardiac arrhythmia (1 patient). Febrile neutropenia occurred in 8 patients (18%). Thirty-three patients (75%) had a complete or partial response, 9 patients (21 %) had a minimal response or stable disease, while 2 patients had progressed within 3 months of auto SCT. At the time of this analysis, 31 patients are alive, 13 of whom in remission. Four-year EFS was 23.5%, and 4-year OS was 63%. Patients with chromosomal abnormalities had a shorter time to progression (13.9 vs. 19.7 months, p=0.18) that was not statistically significant. These results were similar to those reported by our group in 89 patients who received high-dose mephalan (200 mg/m2) only: complete + partial response rate of 66%; 4-year Kaplan-Meier estimates of EFS and OS 20% and 57%, respectively. (Anagnostoupoulos et al. Cancer 2004).Conclusion TMC is a safe preparative regimen for auto SCT for MM. There is no major advantage over high-dose melphalan alone in terms of CR rate or EFS in patients in first remission or primary refractory disease.