Prior auto-SCT Research Articles

Efficacy and safety of micafungin for prophylaxis of invasive fungal infections in patients undergoing haplo-identical hematopoietic SCT

Invasive fungal infections (IFIs) such as candidiasis and mold infections have caused significant morbidity and mortality among immunocompromised patients in recent years. Micafungin, a new echinocandin, inhibits fungal cell wall β-glucan synthesis, with potent activity against most species of Candida and Aspergillus. The aim of this observational study was to investigate the efficacy and safety of micafungin in prophylaxis of IFIs in 26 high-risk adult patients with various hematological diseases receiving haplo-identical Allo-SCT. Only two patients had a history of possible aspergillosis before transplant treated by voriconazole. The patients received a median of four lines (2-7) of treatment before Allo-SCT. Thirteen patients (50%) received at least one prior Auto-SCT; and eight patients (31%) received a previous Allo-SCT. Patients received a median of 29 infusions (range, 15-85) of micafungin (50 mg/day i.v. as a 1-h infusion). The treatment was initiated at the beginning of the transplant conditioning regimen until the hospital discharge. None of our patients discontinued the treatment for drug-related adverse events. Micafungin was not associated with any hepatotoxicity. Only one patient (4%) discontinued the treatment because of early disease progression. In all patients no Candida and/or Aspergillus species was documented after 3 and 6 months from transplant. None of our patients presented a positive galactomannan antigenemia >0.5. Nine patients (35%) presented a CMV reactivation. Four patients presented an acute GVHD grade II and two patients presented a chronic GVHD. The median follow-up was 11 months (3-23). At the last follow-up, there were 20 patients (77%) who were alive; four patients (12%) died because of disease progression and two patients because of graft failure. Micafungin has a good safety and tolerability profile, with an efficacy in preventing IFI in this high-risk population. Our data provide support for an efficacy study in a prophylaxis setting, but prospective and comparative clinical trials using micafungin are urgently needed to define the role of this drug in prophylaxis after haplo-identical Allo-SCT.

Reduced intensity-conditioned allogeneic stem cell transplantation for multiple myeloma relapsing or progressing after autologous transplantation: a study by the European Group for Blood and Marrow Transplantation

Outcomes and prognostic factors of reduced intensity-conditioned allo-SCT (RIC allo-SCT) for multiple myeloma (MM) relapsing or progressing after prior autologous (auto)-SCT are not well defined. We performed an analysis of 413 MM patients who received a related or unrelated RIC allo-SCT for the treatment of relapse/progression after prior auto-SCT. Median age at RIC allo-SCT was 54.1 years, and 44.6% of patients had undergone two or more prior auto-SCTs. Median OS and PFS from the time of RIC allo-SCT for the entire population were 24.7 and 9.6 months, respectively. Cumulative non-relapse mortality (NRM) at 1 year was 21.5%. In multivariate analysis, CMV seronegativity of both patient and donor was associated with significantly better PFS, OS and NRM. Patient-donor gender mismatch was associated with better PFS, fewer than two prior auto-SCT was associated with better OS, and shorter time from the first auto-SCT to the RIC allo-SCT was associated with lower NRM. The results of this study identify patient and donor CMV seronegativity as the key prognostic factor for outcome after RIC allo-SCT for MM relapsing or progressing after prior auto-SCT.

Comparison of PBSC Vs Cord Blood (CB) As Stem Cells Source for Reduced-Intensity Conditioning Regimen (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) in Adult Patients with Haematological Diseases: A Single Centre Analysis.

AbstractAbstract 3108 Introduction:RIC regimens are increasingly used for allo-SCT in older patients or patients with co-morbidities. The FB2 regimen (Fludarabine 120–150 mg/m2 + I.V. Busulfan 6.4 mg/Kg + ATG 5 mg/Kg) using PBSC as stem cell source is currently the most widely used RIC regimen in many European centres. On the other hand, in patients without a suitable HLA-matched donor, the use of umbilical cord blood stem cells for allo-SCT (uCBT) is increasingly considered, especially using the RIC regimen developed by the Minneapolis group. Series comparing PBSC vs CB as stem cells source for RIC allo-SCT are still scarce and using various RIC regimens before allo-SCT. Patients and Methods:This retrospective single centre analysis compared two homogeneously treated cohorts of patients who had received between January 2007 and November 2010 in our department either a FB2/PBSC allo-SCT (n=52, males: 61%; median age: 59 years (range: 22–70)) or a FC-TBI/uCBT (Fludarabine 200 mg/m2 + Cyclophosphamide 50 mg/Kg + TBI 2 Grays regimen; n=39, males 49%; median age 56 years (range: 22–70). Except for age (p=0.03), there were no significant differences between the 2 groups regarding patients and diseases characteristics: gender (p=0.22), interval between diagnosis and transplant (PBSC: 9 months vs CB: 10 months, p=0.85), disease type (PBSC: myeloid disease 63% vs CB: 67%, p=0.75), status at transplant (complete remission PBSC: 77% vs CB: 67%, p=0.28), prior auto-SCT (PBSC: 35% vs CB: 33%, p=0.90). Donors in the PBSC group were as follows: sibling donors, n=30; HLA-MUD n=20, mismatched unrelated n=2. All patients from the CB group received 2 CB units (HLA matching 4/6 n=25; 5/6 n=53). As for GVHD prophylaxis, patients received cyclosporine (CsA) alone in case of an HLA-identical sibling donor, and CsA+ mycophenolate mofetyl in all other cases. None of the patients from the PBSC group received G-CSF after transplant, while it was administered to all CB recipients. Results:Median follow-up was respectively 19 and 20 months for the PBSC and the CB groups (p=NS). Engraftment and median time for neutrophils recovery were similar between the 2 groups: PBSC: 96% vs CB: 90%, p=0.22; and 17 days (range: 0–39) vs 16 days (range: 8–60), p=0.88, respectively. The median time for platelets recovery (>20000/mm3) was significantly higher in the CB group: 38 days (range: 13–150) vs PBSC: 0 days (range: 0–186) (p<0.0001). The cumulative incidences of grade II-IV and grade III-IV acute GVHD were comparable between both groups: PBSC: 31% and 15% vs CB: 26% and 8% (p=0.72 and p=0.28) as also the 2-years incidence of chronic GVHD: PBSC: 35% vs uCBT: 25%, p=0.54. 2-years NRM was significantly higher after uCBT: 26% vs 6%, p=0.02. Finally, there were no differences between the two groups in terms of 2-years OS, DFS and Relapse Incidence: PBSC: 62.3% vs CB: 60.8% (p=0.51); 58.7% vs 50.4% (p=0.43) and 36% vs 23% (p=0.31). In multivariate analysis, the source of stem cells (CB) remains associated with NRM (HR: 0.16, 95%CI: 0.05–0.5, p=0.001) but was not predictable for survivals. Conclusion:Our study suggests that RIC uCBT is a valid alternative in patients lacking an HLA-matched related or unrelated donor and candidate for RIC allo-SCT. Prospective and randomized studies are warranted in order to establish the definitive role of uCBT, especially in patients with acute leukemia, where CB cells may offer a rapidly available source of stem cells in diseases with high tumor kinetics. Disclosures:No relevant conflicts of interest to declare.

Outcome and Prognostic Factors in Patients with Mantle Cell Lymphoma Relapsing After Autologous Stem Cell Transplantation: A Retrospective Study of the EBMT

AbstractAbstract 474 BACKGROUND:Autologous stem cell transplantation (autoSCT) is considered as standard treatment for non-frail patients with mantle cell lymphoma (MCL). However, little is known about outcome of MCL recurrence after autoSCT. We therefore conducted a retrospective analysis of patients with MCL who failed autoSCT using the EBMT database.PRIMARY OBJECTIVE was to analyse outcome and prognostic factors after relapse following autoSCT for MCL in the rituximab era.PRIMARY ENDPOINT was overall survival (OS) from relapse.ELIGIBLE were patients aged 18 years or more who relapsed following an autoSCT for MCL performed between 2000 and 2010 and who were registered with the EBMT. Centres were contacted to provide additional information on relapse treatment.STATISTICAL ANALYSIS was based on log-rank comparisons and multivariable testing using Cox regression models. RESULTS:1054 patients meeting the eligibility criteria could be identified in the EBMT registry. Of these, a full data set could be retrieved for 382 patients. Sixteen patients had to be excluded due to loss of follow up (n=7), wrong diagnosis (n=6), or falsely reported relapse (n=3). Median age at autoSCT of 366 evaluable patients was 59 years (range: 37 to 76), 290 patients (79%) were men. 64% had undergone autoSCT as part of 1st-line therapy; 68% and 49% had documented exposure to rituximab (RTX) and high-dose ara-C (HA) before autoSCT; and 12% had had refractory disease at autoSCT. Median time from autoSCT to relapse was 20 months (range: 0.4 to 117). 21 relapses (6%) occurred beyond 5 years after autoSCT.With a median observation time of 37 months (95% CI 32–43), median OS after relapse of the whole study group was 20 months. By univariate analysis, a long (>12mo) interval between autoSCT and relapse (p<0.001; HR 0.26; Figure 1A), 1st-line autoSCT (p=0.006; HR 0.7) refractory disease at autoSCT (p<0.001, HR 2.0) and more recent year of relapse (p<0.001, HR per year 0.9) significantly influenced OS from relapse, whereas age, gender, RTX and HA exposure did not. By multivariate analysis refractory disease at autoSCT (p<0.001, HR=2.14), remission duration after autoSCT (p<0.001 HR per 3 months 0.88) and calendar year of relapse (p<0.03, HR per year 0.93) were confirmed to be predictors for OS. In addition, HA exposure prior autoSCT adversely affected OS from relapse (p=0.06, HR 1.38).Salvage chemotherapy after relapse resulted in only 31% complete responses and 29% partial responses, whereas 40% of patients have been refractory to first salvage chemotherapy. 83 patients (23%) received an allogeneic SCT (alloSCT), whereas only 7 patients (2%) received a second autoSCT after relapse. Median time after relapse to second SCT was 7 months (range: 1 to 40). Survival after relapse for patients who received a second autoSCT was poor with no long-term survivor. AlloSCT performed for late relapse (>12mo) after autoSCT was associated with superior OS compared to patients who received an allograft upon a shorter remission duration after autoSCT (5-year OS from alloSCT 50% vs 0%; p=0.001; Figure 1B). Achievement of CR before alloSCT (p=0.05 HR=0.5), but not donor source, T-cell depletion or conditioning intensity affected OS after alloSCT. CONCLUSIONS:Patients with MCL who relapse within one year after autoSCT have an extremely dismal outcome even with alloSCT. In contrast, about half of the patients who have MCL recurrence beyond one year after autoSCT and can undergo salvage alloSCT enjoy long-term survival. It remains to be shown if a similarly good outcome can be achieved without alloSCT in this favourable selection of patients. A 2nd autoSCT does not appear to be a promising option in patients with MCL failing a 1st autoSCT. [Display omitted] Disclosures:Walewski:Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Cephalon: Research Funding.

Comparison of Autologous Vs. Allogeneic Stem Cell Transplantation for Non-Hodgkin Lymphoma

Abstract 2036 Background:Stem cell transplantation (SCT) is a common indication for patients with Non-Hodgkin lymphoma (NHL). Auto-SCT is recommended for patients with relapsed NHL or as consolidative therapy in first remission. Allo-SCT is reserved for pts with either relapsed or primary refractory disease. The outcomes of these pts in large prospective studies are lacking and current recommendations and timing of selection of auto vs. allo-SCT are influenced by variety of factors including physician bias. Transplant outcomes of auto or allo-SCT have not been elucidated as a single cohort. Methods:We report a retrospective analysis of 270 pts with NHL who underwent auto-SCT or allo-SCT between January 2000- December 2010 after obtaining institutional IRB approval. Data were analyzed using SPSS.19. Results:Of the 270 pts, 238 patients underwent SCT for B-cell lymphoma (178 auto, 60 allo-SCT), and 32 for T-cell lymphoma (21 auto and 11 allo-SCT). Fifteen pts (6%) received prior auto-SCT. The median age of transplant was 52 years for the entire group. For those who underwent allo-SCT, median age was 47 (range 22–65 yrs) and 54 yrs (range 22–77) for auto-SCT. One hundred seventy (62%) were male. Majority of pts (76%) had advanced stage disease (stages III and IV). Fifty four (20%) received radiation therapy either before or after transplantation. The median number of prior regimens for allo-SCT were 3 (range 1–5) and 2 for auto-SCT (range 1 to 4). Within the allo-SCT group (n=71), 45 received matched-related donor transplants, and 26 unrelated donor transplants; majority of pts (n=47) received reduced intensity conditioning regimen. The auto-SCT group predominantly received CBV as their conditioning regimen. Median time from diagnosis to allo-SCT or auto-SCT was 1.4 yrs (range 0.32–13.1 yrs) and 1.69 (range 0.38–13.7 yrs), respectively. The median follow up time for the entire cohort was 6.2 yrs. The overall survival (OS) rates for the B- cell and T-cell NHL were 58% and 50% respectively (allo-SCT 51% vs. 54% for B and T-cell NHL, and auto-SCT 60% vs. 47% for B and T-cell lymphoma, respectively) (p=0.26). Within the allo-SCT group the relapse and non-relapse mortalities were 45% and 16%, respectively. In the auto-SCT group, the relapse and non-relapse mortality were 46% and 7% respectively. In B-cell lymphoma the relapse rate was 48% and 45% for auto and allo-SCT respectively (p=0.80). In T-cell lymphoma the relapse rate was 40% and 45% for auto and allo-SCT (p=0.67). Multivariate analysis of pts receiving auto vs. allo-SCT in NHL will be presented. Conclusions:We conclude that in this highly selected patient population with otherwise minimal comorbidities but chemo-sensitive aggressive lymphomas, about 50% of patients achieve long term survival after either an auto or allo-SCT approach. Despite recent evidence, there are intricate difficulties in patient selection for allo vs. auto-SCT and outcome of either approach is not satisfactory. Post transplant relapse is the most common cause of post-SCT failure. Tandem auto followed by allo-SCT and maintenance strategies need to be explored. We propose a larger prospective analysis on transplant outcomes in both B and T-cell lymphoma and improve strategies to prevent relapses after SCT. Disclosures:No relevant conflicts of interest to declare.

Yttrium-90-Ibritumomab Tiuxetan (Zevalin) in Combination with a Fludarabine-Based Reduced Conditioning Regimen (RIC) Followed by Allogenic Stem Cell Transplantation for Advanced/Aggressive Non-Hodgkin's Lymphoma (NHL): A Prospective, Multicentre, Open Phase II Study

Abstract 3027Patients (pts) with advanced/aggressive NHL who relapse after autologous stem cell transplantation (auto-sct) or who fail to respond to front-line chemotherapy have a very bad prognosis with a poor survival. We performed a prospective and multicentre study (Clinical Trials.gov, NCT 00607854) to evaluate the tolerability and the benefit of Zevalin added to a fludarabine-based RIC followed by allogenic stem cell transplantation (allo-sct) in pts with a poor prognosis lymphoma.Between January 2008 and October 2010, 30 pts under 65 years old with NHL in relapse after at least 2 previous regimen with or without auto-sct underwent an allo-sct with this preparative regimen. The underlying disease was DLBCL (10 pts), MCL (9 pts) and low grade lymphoma (FL=9 and MZL=2). Patients had to be in CR or PR after the last salvage regimen (Cheson criteria) and to have a HLA-compatible (10/10) match-related (MRD) or unrelated (MUD) donor or 9/10 mismatched UD. GVH prophylaxis was based on CsA alone or in combination with Methotrexate in case of mismatch. The primary objective of the study was TRM at day 100.All the pts are evaluable Twenty two were male (73%) and the median age was 57 (32–64). Twenty nine pts (97%) had prior auto-sct. Twenty pts were transplanted from a sibling donor, 8 from MUD and 2 pts had a C or DQ mismatch. At time of allo-sct, 18 pts were in CR and 12 pts in PR. Median time between diagnosis and allo-sct and between auto-sct and allo-sct was 36 mo and 18 mo respectively. Four pts died from a-GVH (n=2) at d 40 and 70, multi-organ failure (n=1) at d 117 and disease progression (n=1) at d 114 respectively. The TRM up to day 100 was 7% (n = 2). The median follow-up is 16 mo (9–40). All pts had a rapid and sustained engraftment. Twenty five pts are alive in CR. One pt died in CR (suicide) one year after transplant. The actuarial 3-year event-free and overall survival are 83% (± 6%). Estimated EFS at 2 years for the 3 different subgroups of diagnosis are 100% for FL and MZL, 89% (± 10%) for MCL and 70% (± 14%) for DLBCL.We conclude that Yttrium-90-ibritumomab tiuxetan (Zevalin) in combination with a fludarabine-based regimen is safe with a very low TRM rate. The results we report here are in pts with a very bad prognosis are very encouraging with a very high response rate and survival. Disclosures:Off Label Use: Zevalin not licensed in France in this indication. Zevalin has been kindly provided by BayerHealthcare company for the study.

Gemcitabine, Fludarabine, and Melphalan (G-FM) as Reduced-Intensity Conditioning (RIC) Regimen for Allogeneic Stem Cell Transplantation (Allo-SCT) in Relapsed and Refractory Hodgkin Lymphoma (HL)

Abstract 3003▪FN2▪This icon denotes a clinically relevant abstract Objective:Progressive disease (PD) remains the main cause of treatment failure following RIC allo-SCT in HL (Peggs KS et al, BJH 2008: 143; 468). We elected to explore the feasibility of adding gemcitabine (G), a highly active agent in relapsed/refractory HL (Santoro A et al, JCO 2000 :18; 2615), to our standard fludarabine (F) - melphalan (M) RIC in patients with relapsed and refractory HL undergoing allo-SCT, with the ultimate goal to augment cytoreduction and reduce the incidence of PD. Main G-associated non-hematologic toxicities include pulmonary, skin toxicities and mucositis. Patients and Methods: Between 8/07 and 3/11, fifteen consecutive HL patients (Unique Patient Number/UPNs 1–15) underwent an allo-SCT with the G-FM regimen. They had failed multiple conventional treatments (median prior chemotherapy regimens: 4; range 2–9), radiation therapy (6/15) and a prior auto-SCT (7/15). The median age was 33 years (range 20–46). Disease status at SCT was chemosensitive relapse (n=4), untreated relapse (n=1), induction failure chemosensitive (n=2), complete remission undetermined (CRU1 and CRU2) (n=8). The median time to PD after auto-SCT was 10 months (range 3–19). The donor was an HLA-identical sibling (n=10) or matched unrelated donor (MUD; n=5, with UPN 6 having a 9/10 match). The conditioning regimen was G 800 mg/m sq IV x1 at day -7 (two patients, UPN 6 and UPN 7 received G 1000 mg/m sq IV x2, day -5 and day -2 as part of a dose escalation attempt stopped for excess toxicity), F (32 mg/m sq IV x4, day -5 to day -2), M (70 mg/m sq IV x2, day -3 and day -2; total dose 140 mg/m sq). Thymoglobulin (4 mg/kg IV) was added in MUD allografts. Graft-vs-host disease (GVHD) prophylaxis included tacrolimus and mini-dose methotrexate (5 mg/m sq). Results: Myeloid recovery was prompt, with an absolute neutrophil count (ANC)>500/mcL at day +12 (range 11–20). Median platelet recovery at 20K/mcL was at day +14 (range 9–26). Chimerism studies indicate 100% donor-derived engraftment in 13/13 evaluable patients (100%). Day 100/overall transplant-related mortality (TRM) were 2/15 (13%) and 2/15 (13%), respectively. Acute GVHD (grade II-IV) occurred in 8/14 evaluable patients, chronic GVHD in 7/13 evaluable patients (extensive in 7). Pulmonary toxicity was seen in four patients (26%). Grade 4 pulmonary toxicity was seen in UPN 6. Otherwise it was grade 1–2 (n=3). Cutaneous toxicity (skin rash, responsive to steroid therapy) was seen in five patients (33%: grade 3 n=1; grade 1–2 n=4). Mucositis was seen in nine patients (60%). It was grade 3 (n=1); grade 1–2 (n=8). Other organ toxicities were not seemingly markedly different from the ones seen with FM140 only. Three patients expired (graft rejection n=1, in UPN 6; CMV pneumonia n=1; PD n=1). Twelve patients are alive (ten progression-free, eleven in CR/CRU) with a median follow-up of 18 months (range 2–33). Actuarial rates of overall survival (OS) and progression-free survival (PFS) at 24 months are 87% (95% CI: 56–96) and 49% (95% CI: 18–74), respectively (see Figure). While a formal comparison with our historical experience with the FM140 regimen is clearly not possible, OS and PFS (actuarial estimates) at 24 months were 64% (95% CI: 49–76), and 32% (95% CI: 20–45), respectively (Anderlini et al, Haematol 2008; 93 :257). Conclusions: The addition of G to FM140 is feasible. Pulmonary, cutaneous toxicities, as well as mucositis, while clinically significant, were manageable and did not contribute to mortality in the patients treated with only one G dose. While quite encouraging, these data remain preliminary. The G-FM regimen deserves further study in a larger cohort of patients. [Display omitted] Disclosures:Off Label Use: Gemcitabine, fludarabine and melphalan as part of conditioning regimen for allogeneic stem cell transplantation.

The effect of SGN-75, a novel antibody–drug conjugate (ADC), in treatment of patients with renal cell carcinoma (RCC) or non-Hodgkin lymphoma (NHL): A phase I study.

3071 Background: SGN-75 is an ADC composed of a humanized anti-CD70 mAb conjugated to the antimicrotubule agent MMAF, via a plasma-stable linker. Upon binding to CD70, SGN-75 internalizes and releases cys‐mcMMAF, which binds tubulin and induces G2/M arrest and apoptosis. Methods: A phase I, dose-escalation, multicenter study was initiated to investigate the safety, tolerability, PK, pharmacodynamic effects, and antitumor activity of SGN-75 monotherapy in pts with CD70-positive metastatic RCC or relapsed/refractory NHL. SGN-75 was administered IV in cohort-specific doses using 2 schedules (q3wk or q1wk). Pts were eligible to receive cycles of SGN-75 until progression. Results: A total of 26 pts, 14 RCC and 12 NHL, have been treated. Median age was 60 years (range 30–70); all pts had an ECOG status of 0/1. RCC pts had a median 3.5 prior regimens (range 1–7), and all had prior nephrectomy. NHL pts had a median 3 prior regimens (range 1–6), and 2 had prior autoSCT. Doses up to 3 mg/kg q3wk and 0.6 mg/kg q1wk have been tolerated; MTD has not been reached in either dosing schedule. The most common AEs were fatigue (31%), nausea (23%), dyspnea, peripheral edema, and thrombocytopenia (19% each). AEs ≥ Gr 3 observed in >1 pt were thrombocytopenia, dyspnea, and fatigue (3, 2, and 2 pts). Related serious AEs were Gr 2 iridocyclitis and Gr 4 ITP. Preliminary PK analysis demonstrated dose-proportional exposure; mean SGN-75 terminal half-life ranged from 6–13 days across dose levels. Best responses in RCC were 2 PR, 5 SD, 6 PD, and 1 not evaluated (NE); in NHL, responses were 1 CR, 6 SD, 3 PD, and 2 NE. Objective responses were observed at 1 mg/kg q3wk (CR - mantle cell lymphoma; 31 wk duration), 2 mg/kg q3wk (PR - RCC; 7+ wk duration), and 3 mg/kg q3wk (PR - RCC; 2+ days duration). CD70 expression was variable among all patients; the 3 responding pts had nearly uniform CD70 expression on malignant cells. Conclusions: SGN-75 has generally been well tolerated in pts with RCC or NHL; MTD has not been reached in 2 dosing schedules under investigation, and dose escalation is ongoing. Encouraging antitumor activity has been observed in both heavily pretreated RCC pts and in relapsed/refractory NHL pts.

A Phase IB, Multi-Center, Open-Label Dose-Escalation Study of Oral Panobinostat (LBH589) and I.V. Bortezomib in Patients with Relapsed Multiple Myeloma.

Abstract 3852Poster Board III-788 IntroductionPanobinostat (LBH589) is a highly potent pan-deacetylase inhibitor (pan-DACi), inclusive of HDAC6, which disrupts aggresome function, promotes accumulation of cytotoxic misfolded protein aggregates and triggers myeloma cell death. Combination of pan-DAC and protease inhibition by co-treatment with panobinostat (PAN) and bortezomib (BTZ) has demonstrated synergistic cytotoxicity in vitro and in vivo in multiple myeloma (MM) cell lines and may provide increased efficacy in patients with MM. The primary objective of this Phase Ib trial is to determine the maximum tolerated dose (MTD) of oral PAN when combined with BTZ in patients with relapsed or refractory MM. Safety, tolerability, PK/PD, and preliminary efficacy are the secondary objectives. ResultsA total of 29 patients have been enrolled into four completed dosing Cohorts: (I) 10 mg PAN (TIW) + 1 mg/m2 BTZ (i.v., Days 1, 4, 8, 11) during a 21-day cycle; (II) 20 mg PAN + 1 mg/m2 BTZ; (III) 20 mg PAN + 1.3 mg/m2 BTZ; (IV) 30 mg PAN + 1.3 mg/m2 BTZ. Enrollment into Cohort V is ongoing at 25 mg PAN + 1.3 mg/m2 BTZ with 6 patients accrued to date. In Cohorts I– IV, the median number of prior therapies was 3 (range 1–6); 25 patients had at least one prior auto-SCT. Of 16 BTZ pretreated patients, 11 were refractory to their last prior BTZ-based therapy (9 with PD, 2 with SD on BTZ). Median time on study has been 97 days (range 7–424). Overall, the combination of PAN and BTZ was safe and tolerated in Cohorts I - III with one dose-limiting toxicity (DLT) (Gr 4 afebrile neutropenia) in Cohort II. In Cohort IV, four DLTs were reported: two Gr 4 thrombocytopenias,(requiring platelet transfusions), Gr 3 pneumonia, and Gr 3 fatigue. In the subsequent Cohort V, PAN dose was de-escalated. Hematologic adverse events (AEs) have been frequent, including Gr 3/4 thrombocytopenia (25), neutropenia (18), and anemia (6). Non-hematologic AEs included: diarrhea (18), fever (15), nausea (14), fatigue (14), and asthenia (11). A total of 1,778 ECGs were centrally, reviewed with neither QTcF prolongation from baseline >60 msec nor absolute QTcF duration >480 msec noted. Gr 3/4 thrombocytopenia was manageable by dose modification and platelet transfusion; two patients only discontinued for this AE in Cohorts I – III and no hemorrhagic events were reported in association with thrombocytopenia. Encouraging clinical efficacy was observed in all four Cohorts, with 14 responders (partial response [PR] or better) in 28 evaluable patients (50%), including 4 with immunofixation (IF) negative complete response (CR). Four additional patients achieved minor responses, resulting in 64% overall response rate. Responses were also seen in the subset of patients refractory to prior BTZ, suggesting a strong clinical correlate for synergism of the PAN/BTZ combination: 6 of 10 (60%) BTZ-refractory evaluable pts responded, including 4 PR and 2 MR (see Table for details). Dexamethasone (DEX) was introduced at Cycle 2 (or 3) in 9 pts; 11 of 18 pts with a response did not receive DEX, including several pts refractory to BTZ. All 15 patients in Cohorts III and IV treated with the full registered dose of BTZ (1.3 mg/m2) in combination with PAN 20 mg experienced a clinical benefit; however, toxicity in Cohort IV was not acceptable.Cohort I10 mg PAN + 1.0 mg/m2 BTZCohort II 20 mg PAN + 1.0 mg/m2 BTZCohort III 20 PAN + 1.3 mg/m2 BTZCohort IV 30 mg PAN + 1.3 mg/m2 BTZTotal (n=6)BTZ refractory (n=3)Total (n=7)BTZ refractory (n=5)Total (n=8)BTZ refractory (n=2)Total (n=7)BTZ refractory (n=0)CR*--1-2-1-VGPR1-------PR--33313-MR11--211-SD----1-2-PD4232----*CR: IF negative CR; VGPR, very good partial response ConclusionThe encouraging clinical anti-myeloma synergism of the PAN and BTZ combination in this trial warrants further clinical investigation in patients with refractory and relapsed MM. Given the frequency of thrombocytopenia and dose adjustments, the dosing schedule in subsequent Phase II/III studies will be modified to take the safety profile and dose-reduction/-interruption pattern into account. Disclosures:San-Miguel:Novartis: Advisory Board, Consultancy, Honoraria; J&J: Advisory Board, Consultancy, Honoraria; Millenium: Advisory Board, Consultancy, Honoraria; Celgene: Advisory Board, Consultancy, Honoraria. Sezer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Siegel:Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Speakers Bureau. Guenther:Novartis: Consultancy, Research Funding. Mateos:Ortho Biotech: Speakers Bureau; Novartis: Honoraria. Cavo:Novartis: Honoraria. Blade:Novartis: Honoraria; Janssen-Cilag: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Boccadoro:Celgene: Honoraria; Janssen Cilag: Honoraria. Bengoudifa:Novartis Pharma AG: Employment. Klebsattel:Novartis Pharma AG: Employment. Bourquelot:Novartis Pharma AG: Employment. Anderson:Millenium: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Allogeneic Stem Cell Transplantation (SCT) for Multiple Myeloma (MM) - What Has Changed? : A CIBMTR Analysis From 1989 – 2005.

Abstract 54Despite its curative potential, the role of allogeneic stem cell transplant (allo-SCT) in MM has been limited by high treatment related mortality (TRM). Autologous stem cell transplant (auto-SCT) thus remains the standard of care for eligible patients (pts) with MM. Recently interest in allo-SCT has been increasing due to the incurable nature of MM, better risk stratification models, improved supportive care and finally the increasing experience with less toxic reduced intensity conditioning. We analyzed the trends in practice of allo-SCT for MM over the past two decades. A total of 1211 pts undergoing allo-SCT for MM between 1989 and 2005, reported to the CIBMTR were analyzed in three cohorts based on year of allo-SCT: 1989–1994 (n=346), 1995–2000 (n=285), and 2001–2005 (n=580). Probabilities of progression-free survival (PFS) and overall survival (OS) and cumulative incidence estimates of TRM and relapse were calculated.Patient characteristics are summarized in table 1. Patients transplanted in the later cohort (2001–2005) were of higher age with 53% above age 50 years (vs. 12% in 1989–1994). There was decreasing use of myeloablative regimens and bone marrow grafts over time (82% vs. 62% vs. 9% for myeloablative regimens and 99%, 62% and 13% for marrow grafts respectively). Increasing number of pts in the later cohort received an auto-SCT prior to allo-SCT (Table 1). The proportion of unrelated allo-SCTs increased over time (5% vs. 21% vs. 33%). Graft versus host (GVH) prophylaxis changed over time with increasing use of cyclosporine with agents other than methotrexate and increasing use of ATG in the recent years. Median survival increased over the three time periods from 1989 – 2005: 11.1 months (mos.) vs. 12.2 mos vs. 20.3 mos. The 100 day mortality decreased steadily over successive time periods; 35% (95% CI; 29–31), 29% (24–35) and 19% (16–23) respectively. Similarly, the TRM at 5 years remained steady between the first two periods, but decreased in the last period (40 & 48% vs. 29%). The incidence of chronic GVHD increased in the later cohort but the incidence of acute GVHD was similar over the years. While PFS was the lowest for the most recent group (15% at 5 years), the overall survival at 5 years was similar among the groups (30, 32, and 29 mos). Long term PFS at 10 years was 18% in the 1989–1994 cohort and 17% in 1995–2000. Long term OS at 10 years was 23% in 1989 – 1994 and 1995–2000 cohorts. Results are summarized in table 1. A clear trend towards reduced intensity conditioning, unrelated donor SCT, use of PBSC grafts and selection of older patients was noted. There was increasing use of tandem auto-allo SCT with an increasing proportion of patients with a prior auto-SCT. While the TRM has decreased significantly in the last cohort, this did not translate into an improvement in survival primarily because of increased risk of relapse in the latter cohort. Long term (>10yr) progression free survival which may approach a cure has remained unchanged over the past two decades at <20%.Table 1Variables1989–1994 N (%)1995–2000 N (%)2001–2005 N (%)Number of patients346285580Age at transplant, yearsMedian (range)44 (24 – 59)46 (22 – 62)51 (24 – 70)50–5942 (12)83 (29)234 (40)60–69—3 (1)75 (13)Male196 (57)181 (64)358 (62)Time from diagnosis to transplant, Median (range), months15 (2 – 169)12 (1 – 216)15 (1 – 233)Prior auto transplant10 (3)45 (16)355 (61)First allo336 (97)240 (84)225 (39)Bone Marrow Graft345 (99)178 (62)76 (13)Donor type Unrelated16 (5)60 (21)192 (33)ATG given as conditioning or GVHD prophylaxis8 (2)31 (11)108 (19)Median follow-up of survivors, range, months123 (3 – 204)96 (3 – 135)37 (<1 – 92)OutcomesProbability (95% CI)TRM@ 1 yr36 (31 – 41)43 (37 – 48)24 (21 – 28)@ 5 yrs40 (35 – 45)48 (42 – 54)29 (26 – 34)Relapse/Progression@ 1 yr27 (22 – 32)16 (12 – 20)33 (29 – 36)@ 5 yrs39 (34 – 44)28 (22 – 33)55 (50 – 61)PFS@ 1 yr37 (32 – 42)42 (36 – 47)43 (39 – 47)@ 5 yrs21 (17 – 26)25 (20 – 30)15 (11 – 20)Overall survival@ 1 yr50 (45 – 55)50 (44 – 56)60 (56 – 64)@ 5 yrs30 (25 – 35)32 (27 – 38)29 (24 – 34) Disclosures:Lonial:Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding.

Related Vs Unrelated Donors After Auto-Allo Tandem Stem Cell Transplantation for Newly Diagnosed Patients with Multiple Myeloma.

Abstract 1201Poster Board I-223 Introduction:Autologous stem cell transplantation followed by a dose-reduced conditioning and allogeneic stem cell transplantation from HLA-identical siblings has become a treatment option for patients with multiple myeloma. However, only a minority of the patients with multiple myeloma has an HLA-identical sibling and the experience using unrelated donor in this setting is limited. Patients and Methods:From 1997 to 2007, 73 patients (male:45; female:28) with multiple myeloma stage II/III and a median age of 49 years (r, 29-64) were included in a prospective trial to determine the efficacy of a tandem auto-allogeneic stem cell transplantation SCT) from HLA-identical sibling (n=24) or unrelated donors (n=45). Unrelated donor were either fully HLA matched (n=29) or had one mismatch (n=16).Deletion 13q14 could be analyses in 64 pts was found to be positive in 66% of the pts. Del13q14 was more present in patient with unrelated (n=42) than with related (n=22) donors. Stem cell source was PBSC (n=69) or bone marrow (n=4). Induction-chemotherapy consisted of a median of 4 cycles anthracycline-based therapy in 60 pts, or of thalidomide- (n=3) or bortezomib- (n=8) based regimen. 6 pts did not respond to induction therapy and received salvage chemotherapy before autologous SCT. Conditioning prior auto SCT consisted of melphalan 200mg/m2. After a median of 110 days (range 39-228) patients received a reduced intensity regimen with melphalan (140 mg/m2)/fludarabine regimen followed by allogeneic SCT from related (n=24) or unrelated (n=45) donors. GvHD prophylaxis consisted of anti-lymphocyte globulin (ATG-Fresenius®), cyclopsorin A and short course of MTX. Results:No primary or secondary graft failure was observed and leukocyte engraftment was achieved after a median of 15 days (range, 9-27), respectively. Acute graft-versus-host disease (GvHD) grade II to IV occurred in 38% and chronic GvHD in 22% of the patients. Limited GvHD was seen in 16 % and extensive GvHD was seen in 6 % of the patients. There was no difference regarding incidence of GvHD between HLA-identical sibling and unrelated donors. Overall response rate at day 100 was 94% including 55% complete remission (CR) and did not differ between related and unrelated SCT. Cumulative incidence (CI) of non-relapse mortality at one year was 20% (95% CI:11-29%) and did not differ between MUD and MRD (21 vs 17%, p 0.35). The cumulative incidence of relapse at 3 and 5 years was 30% (95% CI:19-41%) and 42% (95% CI: 29-55%), respectively with no difference between related and unrelated SCT at 5 years: 36 vs 44%(p= 0.6). The only significant factor for higher relapse incidence at 5 years was the presence of del13q14 (60 vs 20%, p= 0.007). After a median follow up of 40 months (r., 26-100), the estimated 5-year progression-free (PFS) and overall survival (OS) rates were 31% (95%CI: 19-43%) and 54% (95% CI: 42-64%), respectively, with no difference between related and unrelated SCT. Due to the higher relapse incidence only presence of del13q resulted in a significant worse 5- year OS and DFS (45 vs 77%, p=0.02 and 18 vs 57%, p=0.04). Conclusions:Unrelated donors as stem cell source for auto-allogeneic tandem stem cell transplantation for newly diagnosed myeloma patients resulted in similar NRM, relapse-incidence, DFS and OS than HLA-identical sibling transplantation and can therefore be used as alternative stem cell source. Outcome after transplantation is better for patients lacking del 13q14. Disclosures:No relevant conflicts of interest to declare.

A Retrospective Comparison of Autologous Vs. Allogeneic Transplantation for Peripheral T-Cell Lymphoma: A Single Institution Experience

Peripheral T-cell Lymphomas (PTCL) are a heterogenous group of malignanices that represent 10–15% of non-Hodgkin lymphoma (NHL). This group has a worse prognosis with conventional chemotherapy compared to B-cell lymphomas. Both autologous (AutoSCT) and allogeneic stem cell transplantation (AlloSCT) have been used as consolidation in first remission and at relapse, but the role of transplantation has not been clearly defined.We report a retrospective analysis of 42 patients with PTCL who underwent AutoSCT (24) or AlloSCT (18) between 8/1997 and 12/2007. The AlloSCT group consisted of 4 PTCL unspecified (PTCLu), 3 angioimmunoblastic T-cell lymphomas (AITL), 2 panniculitic T-cell lymphomas, 2 cutaneous T-cell lymphomas (CTCL) with large cell transformation, 2 NK-cell lymphomas, 2 anaplastic large cell lymphomas (ALCL, 1 Alk+, 1 Alk unknown), 1 hepatosplenic T-cell lymphoma, 1 enteropathic T-cell lymphoma, and 1 refractory CTCL. The AutoSCT group consisted of 6 PTCLu, 12 ALCL (5 Alk+, 5 Alk−, 2 Alk unknown), 4 AITL, 1 CTCL with transformation, and 1 T-lymphoblastic lymphoma. The median age of the AlloSCT and AutoSCT groups was 51 (range 29–72) and 52 years (range 19–67), respectively.The median number of prior treatments of the AlloSCT and AutoSCT groups were 3 (range 1 to 5) and 1 (range 1 to 5), respectively. Within the AlloSCT group there were 14 matched-related donor transplants, and 4 matched-unrelated donor transplants; 7 were ablative and 11 were reduced-intensity transplants; the AlloSCT conditioning regimens varied. The AutoSCT group predominantly received BEAM as their conditioning regimen. Median time from diagnosis to AlloSCT or AutoSCT was 18.4 (range 6.9 to 109) and 7.5 (range 3.9 to 25) months, respectively. Median follow-up times for the AlloSCT and AutoSCT groups were 28.6 and 23.5 months, respectively.The day 100 transplant-related mortality rates in the AlloSCT and AutoSCT groups were 11% and 0%, respectively. Within the AlloSCT group the relapse and non-relapse mortalities were 11% and 33%, respectively. In the AutoSCT group, the relapse mortality was 33%. The 1- and 2-year overall survival (OS) rates were similar within the AlloSCT and AutoSCT groups (78% vs 74%, and 67% vs 60%, respectively). The 1- and 2-year progression-free survival (PFS) rates for the AlloSCT vs AutoSCT groups were 68% vs 52%, and 53% vs 45%, respectively (p = 0.28). Within the AutoSCT group, 14 patients (58%) were transplanted in first complete remission (CR1), and 10 (42%) in second complete remission (CR2), beyond CR2, or partial remission (PR). Patients in CR1 had significantly better PFS (57 vs 17 months, p=0.007) and OS (76 vs 29 months, p=0.004) than those in CR2, PR2, or beyond. Within the AlloSCT group, there was a trend toward poorer OS in 6 patients (33%) who had prior AutoSCT (32 vs 60 months, p=0.15). One patient (6%) was transplanted in CR1, and is still alive.We conclude that outcomes for AutoSCT are best in CR1. For patients with resistant or relapsed disease, AlloSCT should be strongly considered rather than AutoSCT. Prior AutoSCT may affect the outcome of AlloSCT. These results suggest that a prospective randomized trial comparing AutoSCT and AlloSCT for aggressive PTCL in first remission is warranted.

Prognosis Value of [18f] FDG-PET Prior Versus after Autologous Stem Cells Transplantation in High Grade Non-Hodgkin's Lymphoma.

Positron emission tomography using fluorine 18-fluorodeoxyglucose (FDG-PET) is required in the assessment of therapeutic response in diffuse large B-cell lymphoma. Limited studies addressed the interest of FDG-PET prior autologous stem cells transplantation (auto-SCT) in High-grade non Hodgkin's lymphoma (HG-NHL). Between April 2002 and December 2005, 42 HG-NHL (DLBCL in 35 cases and aggressive transformation in 7 cases) patients underwent auto-SCT in our institution and were systematicaly explored prior and after auto-SCT using computed tomography (CT) and FDG-PET. The therapeutic strategy included R-CHOP or R-DHAP as induction chemotherapy followed by auto-SCT. In note, auto-SCT was always included in the initial strategy and scheduled after completion of induction chemotherapy for patients at least in partial response (PR) according CT assessment. Pre-auto-SCT FDG-PET results did not influence the scheduled strategy. Auto-SCT was performed as part of the first-line therapy in 35 cases (83 %) or at the time of relapse in 10 cases. Prior auto-SCT, 14 patients were in PR and 24 in CR/Cru. Conditioning regimen consisted of BEAM in all cases (except one patient). The median follow-up (calculated from the time of auto-SCT) for living patients was 34,5 months [19–74 months]. The 2-years EFS and OS estimates were 79,6 % [63,2%; 89,3%] and 90,5 % [76,6%; 96,3%], respectively. According to pre and post auto- SCT FDG-PET results, patients were classified into 3 groups: NEG/NEG (n=25) POS/ POS (n=8) and POS/NEG (n=9). The 2-years EFS and OS estimates for NEG/NEG, POS/ POS and POS/NEG patients were 88 % versus 19 % versus 100 % (p= 0,0001) and 92 % versus 75 % versus 100 % (p = 0,19), respectively. According to FDG-PET response after auto-SCT, the 2-years EFS estimates for NEG versus POS patients were 90, 9 % versus 19 % (p<0,0001). In contrast, pre auto-SCT FDG-PET status has no prognosis value on both EFS (2-years EFS: 88% versus 65%) and OS (2-years EFS: 92% versus 88%). We conclude that only post and not pre-auto-SCT FDG-PET results has a prognostic value in HG-NHL. This result suggests that an pre-transplant intermediate positive FDGPET should not delay a scheduled ASCT which could clean off the negative value of an intermediate positive FDG-PET.

A Phase IB, Multicenter, Open-Label, Dose-Escalation Study of Oral Panobinostat (LBH589) and I.V. Bortezomib in Patients with Relapsed Multiple Myeloma

Panobinostat (LBH589) is a pan-deacetylase inhibitor (pan-DACi), targeting epigenetic and multiple oncogenic pathways. Beyond numerous hematological cell lines being highly sensitive in vitro, panobinostat has shown to induce cytotoxicity at low nanomolar concentrations in multiple myeloma (MM) cell lines resistant to dexamethasone, melphalan, and doxorubicin. Additional in vitro and in vivo experiments have demonstrated potent synergistic MM cytotoxicity of panobinostat and bortezomib associated with blocking of aggresome and proteosome degradation of ubiquinated protein. Collectively, these data provide a strong rationale for the first clinical trial of this combination in MM patients. The primary objective of this Phase I study is to establish the maximum-tolerated dose (MTD) of panobinostat with bortezomib in a second-line setting. Safety, tolerability, pharmacokinetic/pharmacodynamic profiles, and preliminary efficacy of the combination will be assessed as secondary endpoints.. Patients with relapsed MM, who have received at least 1 prior line of therapy, are to be enrolled, if they are suitable for bortezomib therapy and have no primary refractory MM prior exposure to an HDACi, impaired cardiac function, or QTc prolongation. Dose-escalation started at 10 mg of panobinostat (po thrice weekly) in combination with 1 mg/m2 of bortezomib (i.v on Days 1, 4, 8 and 11) over a 21 day cycle. In any cohort, dexamethasone can be added after Cycle 1, in case of worsening disease. A 6-parameter, adaptive Bayesian logistic regression model guides the escalation to MTD with each dose-combination being studied in cohorts of at least 6 patients. At the confirmed MTD, additional patients will be enrolled to obtain further safety and tolerability information. As of 21 July 2008, a total of 14 patients have been enrolled in 2 cohorts: Cohort 1 (10 mg panobinostat + 1.0 mg/m2 bortezomib, n=7,), and Cohort 2 (20 mg panobinostat + 1.0 mg/m2 bortezomib, n=7). Patients are 10 males and 4 females, with median age of 57 (range 46–78). Median number of prior therapies is 3 (range 1–7). All patients had at least one prior auto-SCT, and bortezomib was listed among prior therapies in 8 pts. Disease status included 9/14 pts refractory at entry, defined as progressing within 60 days of last therapy. 1 patient (Cohort 2) with a borderline entry ANC value experienced an early Grade 4 afebrile neutropenia, which met DLT criteria. Grade 3/4 hematological AEs were the most frequent and included anemia in 2 pts, thrombocytopenia in 11 pts, and neutropenia in 3 pts. G-CSF treatment was required by 2 patients. Non-hematological AEs have included lower grade diarrhea and fatigue. To date, with a total of 44 complete cycles received by 14 patients, 1 immunofixation negative (IF-) CR, 1 VGPR, and 3 PR were seen with dexamethasone added at 2nd cycle in 3 of these 5 pts (CR + 2 PR). The IF-CR response in a patient of Cohort 2, in relapse after Auto-SCT and observed after 3 cycles, was determined by negative IF and normalized serum-free light chain ratio (bone marrow evaluation refused by the patient). VGPR was observed in 1 patient in relapse after auto-SCT, after 7 cycles (Cohort 1); therapy was discontinued in Cycle 10 due to Grade 2 weight loss. PR was observed in 3 patients (1 in Cohort 1; 2 in Cohort 2), occurring early on after one to two cycles. 2 of these patients had received prior bortezomib, 1 had been treated with 4 prior lines of therapy, and the other received 6 prior lines of therapy, including autologous and allogeneic SCT, donor lymphocyte infusion, cyclophosphamide/thalidomide, and lenalidomide. These responses, observed at early/low dose levels of the trial drugs, show a potential activity of panobinostat in combination to bortezomib in patients who had not responded to bortezomib. The combination of panobinostat and bortezomib shows promising activity and a good safety profile. Enrollment into Cohort 3 (20 mg panobinostat + 1.3mg/mg/m2 bortezomib) is currently underway. Updated follow-up, as well as new patient data, will be presented.

Prior Treatment with Chemotherapy Associated to Gemtuzumab Ozogamicin (GO) Does Not Increase the Risk of Veno-Occlusive Disease (VOD) after Allogeneic Stem Cell Transplantation (all-SCT).

The combination of chemotherapy and GO is increasingly used for the treatment of CD33+ AML patients either at diagnosis or at time of relapse. GO is classically known to induce liver toxicity, that may significantly increase the risk of VOD, especially in patients receiving allo-SCT. A single study by Wadleigh et al (Blood, 2003) suggested an increased risk of VOD in patients who underwent myeloablative HSCT within a short interval from GO administration (<3.5 m.). However, no large series have comprehensively assessed this risk thus far. Here, we analysed the outcome of a cohort of 44 HSCT patients who had received previous combination of chemotherapy + GO in the course of their disease. This retrospective study included 44 patients (males, n=21) who received allo-SCT between Dec. 2001 and June 2008 after prior exposure to GO. Median age was 50 (range:3–67). There were 41 CD33+ AML, 2 CD33+ ALL and 1 CD33+ myeloid sarcoma. Before allo-SCT, 37 patients received the MIDAM regimen (GO: 9 mg/m², n=36; or GO 4.5 mg/m², n=1 at day 4 + Ara-C 1g/m²/12 hours day 1–5 + Mitoxantrone 12 mg/m²/day day 1–3). In 3 patients receiving MIDAM, Mitoxantrone was omitted. GO 9 mg/m² + other combinations of chemotherapy were used in the remaining 4 patients. Indications for the GO-based chemotherapy were as follow: first induction, n=3; second induction, n=4; primary refractory disease, n=14; first relapse, n=19; second relapse, n= 4. Only 1 patient developed VOD after receiving GO. In this series, 5 patients received an additional course of consolidation with GO+chemotherapy. Of note, 15 patients (34%) received prior auto-SCT. Median interval between last administration of GO and allo-SCT was 4.2 (range, 0.8–26.3) months, with 19 patients allografted <3.5 months from GO administration. At time of allo-SCT, 33 patients were in CR, and 11 remained refractory. The majority of patients (n=36; 82%) received a reduced intensity conditioning (RIC) regimen prior to allo-SCT, while 8 patients received a myeloablative regimen. The stem cell source was PBSC in 26, cord blood in 15, bone marrow in 2 and a CD34+ selected PBSC in 1 patient. Eleven patients received an allograft from an HLA matched related donor (MRD), 1 from an HLA mis-MRD, 16 from an HLA matched unrelated donor (MUD), and 1 from an HLA mis-MUD. All patients (but one who received defibrotide because of a prior history of VOD) received low-dose heparin as VOD prophylaxis. Engraftment was observed in 34 patients (77%) at a median of 15 (range, 8–43) days after allo-SCT. With a median FU of 15 (range, 1.1–63) m. for surviving patients, OS and DFS after allo-SCT were 45% (95%CI, 30–61%) and 38% (95%CI, 24–54%) at 3 years respectively. At time of analysis, 22 patients were still alive, while 22 patients died. The causes of death included: disease progression in 13, 1 fungal infection, 2 acute GVHD, 1 chronic GVHD, 3 multi organ failures, 1 ARDS, and one case of VOD, for an overall incidence of TRM of 20% in this high risk population. The incidence of Grade ¾ hyper-bilirubinemia was 13.5% (n=6), with this being 21% in patients with a short (<3.5 m.) GO-allograft interval (n=4/19) vs. 8% in all others (P=NS). In all, the incidence of VOD was 7% (n=3), with this being 10.5% (n=2/19) in patients with a short GO-allograft interval (<3.5 m.) vs. 4% (n=1/25) for all others (P=NS). Also, a myeloablative regimen was not associated with an increased risk of VOD (12.5%, n=1/8 vs RIC 5.5%, n=2/36, P=NS). Overall, these encouraging results suggest that GO-based (mostly salvage) therapy in combination with chemotherapy prior to allo-SCT is feasible and does not result in an excessive rate of toxicity, especially VOD, after allo-SCT.

Prolonged PFS after Autologous Stem Cell Transplantation in Follicular Lymphoma Patients: A Long-Term Retrospective Study.

Background: The course of follicular lymphoma (FL) is characterized by iterative relapses. Several reports have demonstrated that intensive chemotherapy followed by autologous stem cell transplantation (auto-SCT) is an attractive treatment. Because a subgroup of patients obtains prolonged complete remission after auto-SCT, some authors have postulated that auto-SCT may cure FL patients. In order to address this issue and to characterize long-term responders, we retrospectively studied the outcome of 80 FL patients who underwent auto-SCT in our institution.Patients characteristics: Between 1989 and 2004, 80 FL patients underwent auto-SCT in the Haematology Department of Nantes Medical University, France. All patients had a FL according to the WHO classification. Median age at diagnosis was 45.7 (range 27–62) and median age at the time of transplantation was 48.1 (range 27–69). Auto-SCT was performed upfront in 36 cases, at first relapse in 36 cases and at a subsequent relapse in 8 cases. Median time from diagnosis to auto-SCT was 53 months. At diagnosis, 25 patients presented with a FLIPI <2 and ≥ 2 in 34 cases (data missing =21). Prior to auto-SCT, 71 patients received a CHOP or CHOP-like regimen and 24 patients received a cytarabine-containing regimen. The conditioning regimens prior auto-SCT were TBI-cyclophosphamide (63 patients) or BEAM (17 patients). The source of stem cell was either bone marrow (19 patients) or peripheral blood stem cell (59 patients); 2 patients received both. In note, the graft was purged using a CD34+ selection in 30 cases or a B-depletion in 19 cases. In the course of their disease (prior or after transplantation), 35 patients received Rituximab.Results: Median follow-up (calculated from the time of auto-SCT) was 6.2 years (range 0.2–16.6) (data missing =1). No patient died during the auto-SCT procedure. After auto-SCT, 71 patients reached CR/CRu. Thirty-five patients relapsed and 10 patients experienced histological transformation (HT)(including 8 cases with HT at first relapse). Myelodysplasia/AML occurred in 5 cases. At the time of the analysis, 68 patients were still alive. Causes of death were: HT in 6 cases, AML in 3 cases, follicular lymphoma related in 2 cases and not related to lymphoma in one case. The 3-, 5- and 7-year progression free survival (PFS) estimates were 74.7%, 66.5% and 58.6%, respectively. In note, a plateau occurred on the PFS Kaplan-Meier curve after 8 years. The 3-, 5- and 7-year overall survival (OS) estimates were 92.9%, 86% and 79.7%, respectively.In univariate analysis, five variables (age at the time of auto-SCT < 50y, a purged graft, a Rituximab-containing therapy, an extra-nodal excluding bone marrow involvement at diagnosis and FLIPI <2 ) were found to be statistically significant at a p<0.15 level and were included in the multivariate analysis. In multivariate analysis, the PFS was significantly better for patients with a FLIPI<2 (p=0.043) and patients<50 years at the time of auto-SCT (p=0.03). A trend for a better PFS was observed for patients who received Rituximab in the course of the disease (p= 0.084).Conclusion: By multivariate analysis, we demonstrate that the FLIPI is a strong predictive index to predict PFS after auto-SCT. Moreover, our results confirm the major interest of auto-SCT in the treatment of FL and highlight that the opportunity to perform auto-SCT should not be jeopardize during the course of the disease. Finally, the plateau on the PFS curve suggests that some FL patients could be cured by auto-STC.

Second auto-SCT is safe and effective salvage therapy for relapsed multiple myeloma

Therapeutic options for patients with multiple myeloma whose disease has relapsed after a prior auto-SCT include novel biologic therapies, traditional chemotherapy or a second transplant, with no clear standard of care. Few published studies address the safety and efficacy of a second auto-SCT for relapsed disease. We reviewed the Abramson Cancer Center experience with salvage auto-SCT for relapsed multiple myeloma. Forty-one patients had received a salvage auto-SCT at our institution; the median time between transplants was 37 months (range 3-91). The overall response rate in assessable patients was 55%, and treatment-related mortality was 7%. With a median follow-up time of 15 months, the median PFS was 8.5 months and the median overall survival (OS) was 20.7 months. In a multivariate analysis of OS, independent prognostic factors were >or=5 prior lines of therapy and time to progression after initial auto-SCT of <or=12 months. We conclude that in well-selected patients, salvage auto-SCT is safe and effective for relapsed myeloma.

A Retrospective Single Institute Analysis of 127 Lymphoma Patients Who Underwent Allogeneic Stem Cell Transplantation: Impact on Peripheral T-Cell Lymphoma (PTCL) Including ATLL.

Background Clinical application of allogeneic stem cell transplantation (allo-SCT) for lymphoma patients (pts) has been hampered by its high mortality rate. In order to explore and establish safe and efficient procedures, reduced-intensity stem cell transplantation (RIST) has been incorporated in recent protocols for lymphoma. Here we retrospectively analyzed our single institute experiences of allo-SCT for lymphoma.Results Between 1999 and 2005, 127 allo-SCTs, including 94 RIST (74%), were performed for lymphoma in our single institute. The number of each pathological classification and the one in which RIST was used, which is shown in each parenthesis, were PTCL (non-ATLL) 15 (RIST 13), ATLL 25 (18), NK/T 3 (2), FL 36 (29), MCL 6 (5), DLBCL 23 (17), LPL 1(1), HL 5 (5) and LBL 13 (4). Most patients were not eligible for autologous transplantation (auto-SCT) because of relapse after auto-SCT or chemo-resistant disease. Transplant-related mortality (TRM) were 16% in RIST and 45% in conventional stem cell transplant (CST) (p<0.001), and it was as high as 54% in aggressive lymphoma pts treated with CST (n=26). 3-year OS and PFS of FL, PTCL including 2 ALCL and 1 AILT, and ATLL were 80.6±6.6% and 80.6±6.6%, 46.7±12.9% and 60.0±12.6%, 46.5±10.3 and 57.1±10.6%, respectively, with the median follow-up of 737 days (range, -4–2628) in all these pts. Pts with other histology had poor outcomes and the numbers of pts surviving more than 1 year were HL 1 (20%), MCL 2 (33%), DLBCL 7 (30%), NK/T 1 (33%) and LBL 3 (23%). 5 pts with DLBCL were treated with auto-SCT/RIST tandem transplantation according to in-house protocol, and 4 out of 5 were alive in current CR with median follow-up of 749 days (range, 580–1038).Discussion Since RIST was associated with lower TRM than CST, it could be applied safely in heavily treated pts with refractory lymphoma. Most pts with DLBCL, NK/T, and LBL relapsed or died of disease. However, pts with FL, PTCL and ATLL, even in chemo-refractory cases, had durable remissions after RIST. In refractory DLBCL, de-bulking of the tumor by prior auto-SCT might be promising.Conclusions RIST could be performed comparatively safely. Notably, PTCL, both ATLL and non-ATLL, were newly highlighted as a good indication of RIST and should be further investigated. [Display omitted]

Favourable Overall Survival with Myeloablative Allogeneic Stem Cell Transplantation for Follicular Lymphoma.

IntroductionAllogeneic stem cell transplantation (Allo-SCT) remains an option for patients with follicular lymphoma (FL). Our program employs a strategy using allo-SCT for patients (pts) with high risk disease based on clinical characteristics. We performed a retrospective analysis to examine long-term disease control and treatment-related mortality.Methods41 pts with indolent FL (follicular small cleaved [FSC], follicular mixed [FM] or FL grade 1,2 by WHO criteria) underwent allo-SCT at our institution between Jan 1989 and Dec 2005. Patients were in a chemosensitive remission at the time of SCT. The conditioning regimen consisted of busulfan (1 mg/kg PO q6h X4 days between 1989–200 and 3.2 mg/kg IV daily X 4days subsequently) and cyclophosphamide 60 mg/kg X 2 days. Cyclophosphamide 60 mg/kg X 2 days and TBI 12 Gy was used for unrelated donor SCT. GVHD prophylaxis was with cyclosporine A and methotrexate.ResultsThere were 21 males and 20 females. The median age at the time of transplant was 45 years (range 24 to 58). Histologic subtype was: unclassified indolent FL: 3, Grade 1 or FSC: 17, Grade 2 or FM: 21. The median number of prior chemotherapy regimens was 2 (range 1 – 6) and was unavailable in 5. Prior anthracycline: 37, prior purine analog: 9, prior platinum-based: 20, prior auto-SCT: 1, prior rituximab: 11. The median time from diagnosis to allo-SCT was 23 months (range 6 – 161). 38 pts received BuCy conditioning. 2 patients underwent RIC SCT. Graft source was: matched related (MRD) bone marrow (BM): 28, MRD peripheral blood stem cells (PBSC): 4, Mismatch related (MMRD) bone marrow (BM): 1, MMRD PBSC: 2, matched unrelated donor (MUD) BM: 1, MUD PBSC: 1, and syngeneic BM: 4. The five year overall survival is 77% (95% confidence intervals 73 – 91%) with a median follow-up of 48 months post-SCT. Treatment-related mortality was 5 of 41 pts (12%). Non-relapse mortality was seen in one patient (3%). One patient has relapsed at over 3 years post-SCT while all recipients of syngeneic SCT remain in remission.ConclusionsThese results demonstrate that in selected patients, a fully myeloablative allo-SCT utilizing Busulfan-Cyclophosphamide conditioning provides excellent overall survival and disease control with low TRM. Prospective comparisons of RICSCT with myeloablative SCT should be performed in order to better evaluate these strategies.

Long-Term Follow-Up of Allogeneic Stem Cell Transplantation for Chronic Lymphocytic Leukemia.

IntroductionAllogeneic stem cell transplantation (Allo-SCT) remains an option for patients with chronic lymphocytic lymphoma (CLL). Our program employs a strategy using allo-SCT for patients (pts) with high risk disease based on clinical characteristics and prior therapy. We performed a retrospective analysis to examine long-term disease control and treatment toxicity.MethodsA total of 52 patients (pts) are included who underwent allo-SCT at our institution between Aug 1989 and Dec 2005. Patients were in a chemosensitive remission at the time of SCT. The conditioning regimen consisted of busulfan (1 mg/kg PO q6h X4 days between 1989–200 and 3.2 mg/kg IV daily X 4days subsequently) and cyclophosphamide 60 mg/kg X 2 days. Cyclophosphamide 60 mg/kg X 2 days and TBI 12 Gy was used for unrelated donor SCT. Reduced intensity conditioning (RIC) SCT were typically performed with Fludarabine 50 mg/m2 for 4 days and 2 Gy TBI. GVHD prophylaxis was with cyclosporine A and methotrexate.ResultsThere were 34 males and 18 females. The median age at the time of transplant was 51 years (range 26 to 65). Histologic subtype was: CLL and/or small lymphocytic lymphoma (SLL); 48 and T-prolymphocytic leukemia (PLL): 4. The median number of prior chemotherapy regimens was 3 (range 1 – 10) and was unavailable in 16. Prior chemotherapies included: anthracycline-based: 24, prior purine analog: 32, prior platinum-based: 8, prior auto-SCT: 1, prior rituximab: 5. The median time from diagnosis to allo-SCT was 58 months (range 5 – 260). 10 pts underwent RIC SCT. Graft source was: matched sibling (MSD) bone marrow (BM): 18, MSD peripheral blood stem cells (PBSC): 20, Mismatch related (MMRD) bone marrow (BM): 1, MRD PBSC: 4, matched unrelated donor (MUD) BM: 8, MUD PBSC: 1. At 5 years, the overall survival of the entire cohort is 51% (95% confidence intervals: 34 – 68%) with two long-term survivors of 14 and 17 years. Treatment-related mortality (TRM) was 20 of 52 pts (38%). 4 pts have relapsed ((8% of total cohort) and non-relapse mortality was 1 pt (2%). Overall survival by intensity of SCT conditioning regimen was not significant (p=0.3). TRM was similar in pts who received fully myeloablative SCT (40% vs. 20% in RICSCT group, p=0.29).ConclusionsAcceptable survival post-SCT is possible using an allo-SCT strategy in CLL. However, TRM remains high in this group of heavily pre-treated patients with a median age of over 50 that predominantly received fully myeloablative allo-SCT. Due to small sample size, the potential benefit of reduced TRM with RICSCT cannot be demonstrated. Ideally, allo-SCT should be considered earlier in the course of the disease based on risk stratification utilizing traditional risk factors and modern prognostic factors such as FISH studies and novel markers.