Fludarabine Cyclophosphamide Research Articles

PF642 REDUCED INTENSITY ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IS A SAFE AND EFFECTIVE TREATMENT OPTION IN HIGH RISK MYELOMA PATIENTS – A SINGLE CENTRE EXPERIENCE

Background:The role of allogeneic hematopoietic stem cell transplantation (AHCST) remains controversial in myeloma, with myeloablative regimens associated with an unacceptable transplant‐related mortality (TRM). Despite this, even in an era of increasing drug treatments, AHCST remains one of the only curative options. Previous studies have included a mixture of different conditioning regimens in a variety of patients. Here we report our results using a non‐myeloablative (NMA) approach in a selected higher‐risk myeloma patient population at our institution.Aims:We report the outcomes of 37 patients with myeloma, transplanted using an NMA Fludarabine/Cyclophosphamide (FC) conditioning regimen without T cell depletion.Methods:We reviewed all patients receiving AHSCT at our centre between November 2000 and October 2017 All patients received fludarabine 25 mg/m2/day for 5 days and cyclophosphamide 1 g/m2/day for 2 days. Short course methotrexate and ciclosporin were used for GVHD prophylaxis without T‐cell depletion. Standard supportive care was employed.Results:37 myeloma patients (median age 52 years, range 31–63) underwent AHCST with 28 (76%) IgG, 5 (14%) IgA, 3 (8%) LC‐only and 1 (3%) non‐secretory disease. For those with recorded ISS (33), 8 (24%) were ISS1, 12 (36%) ISS2 and 13 (39%) ISS3. For those with recorded cytogenetics (19), high risk features (defined as t(4;14), t(14;16), t(14;20), 17p‐ or 1q+) were present in 14 cases (74%).At the time of transplant, patients had received a median of 2 prior lines of therapy (range 1–5), with 19 (51%) in 1st remission, 16 (43%) in 2nd, and 2 (5%) in 3rd. Status at the time of transplant was as follows: CR 27 (73%), VGPR 1 (4%), PR 2 (5%), SD 3 (8%), PD 4 (11%). 34 (92%) had a received previous autograft. All patients received peripheral blood stem cells from either HLA‐matched sibling (59%) or unrelated (41%) donors.TRM was very low (3% at 1 year and 9% at 5 years) precluding analysis of specific risk factors. Incidence of acute GvHD (including late onset acute GvHD with cessation of ciclosporin up to day 180) was 38% (Grade 1–4) and 14% (Grade 3–4). The incidence of chronic GvHD was 55%.Incidence of progression was 26% at 1 year and 49% at 5 years, and was significantly higher in patients who had received >1 prior line of therapy (p = 0.05, Log Rank test) and those in less than a VGPR at the time of transplant (p = 0.05). Patients who developed aGvHD had a significantly lower incidence of relapse (p = 0.05) consistent with a graft‐versus‐myeloma effect.Progression‐free and overall survival were 74% and 91% at 1 year, and 57% and 66% at 5 yearsrespectively, with worse outcome in those who received >1 prior line of treatment (p = 0.04) and in those without aGvHD (p = 0.03).Summary/Conclusion:NMA T‐replete AHSCT using a low dose Fludarabine/Cyclophosphamide platform is a safe approach with very low TRM. In this group of carefully selected younger patients with predominantly high‐risk myeloma, PFS was achieved in > 50% of patients at 5 years which is likely to represent a cure. Less heavily pre‐treated patients in a deeper response had better outcomes, with GVHD associated with freedom from relapse, providing evidence for a graft‐versus‐myeloma effect. This approach should be considered as a treatment option in young, high‐risk patients.image

PF780 STEM CELL TRANSPLANTATION FOR ACQUIRED APLASTIC ANEMIA: THE ROLE OF THE CONDITIONING REGIMEN

Background:Hemopoietic stem cell transplantation (HSCT) remains the standard of care for eligible patients with acquired aplastic anemia (AA). Conditioning rfegimens have changed over the yearsAims:To asses the role of different conditioning regimens over the years in HSCT in patients with acquired AAMethods:We have analyzed the outcome of 179 patients with acquired aplastic anemia (AA) undergoing an HSCT in 3 consecutive eras: before year 2000, between 2001 and 2010 and beyond year 2010. The median age of the patients was 20,28,31 years in the three periods, and there has been an increased use of donors other than HLA identical siblings (6%, 45%, 62% respectively). The major change in the 3 periods, has been in the use of conditioning regimens: cyclophosphamide (CY) 200 mg/kg was used in 92%, 32% and 20% of patients respectively in the 3 periods; the combination of fludarabine (FLU), CY low dose (1200 mg/m^2) and total body irradiation 2 Gy (FLU‐LDCY‐TBI) was used in 5%, 58% and 20% of patients in the 3 periods; finally the combination of FLU CY 120 mg/kg and TBI 2 Gy (FLU‐CY‐TBI) was given to 0%, 9%, 58% of patients respectively. GvHD prophylaxis remained unchanged during the three transplant periods: cyclosporin methotrexate and ATG for all patients, with the addition of rituximab 200 mg on day+5, as of year 2002.Results:The 5 year survival has improved in three consecutive transplant eras, from 58% before year 2000, to 73% in the years 2001–2010, and 92% in the years 2011–2018.We then compared the outcome of transplants prepared with FLU‐LDCY‐TBI (n = 38) or with FLU‐CY‐TBI (n = 21): the 2 groups were comparable for patients age (31 years for FLU‐LDCY‐TBI, range 17–60, versus 39 years for FLU‐CY‐TBI, range 18–62, p = 0.2) and donor type (p = 0.2), with 44% and 55% of donors being unrelated. The 5 year survival was 62% for FLU‐LDCY‐TBI vs 95% for FLU‐CY‐TBI (p = 0.02). In the FLU‐LDCY‐TBI, 4 patients died of graft failure (11%), 7 died of infections (18%) and 3 (8%) of toxicity. In the FLU‐CY‐TBI, 1 patient died of rejection (4%) and 1 of GvHD (4%). No patient experience EBV‐driven post transplant lymphoproliferative disorders (PTLD)Summary/Conclusion:In conclusion CY200 mg/kg remains standard of care for young patients grafted from identical siblings. The combination of FLU‐CY 120 mg/kg and TBI2 Gy appears to allow a better engraftment as compared to FLU‐LDCY‐TBI, and may be preferred for older patients and patients grafted from unrelated donors. We recommend low dose rituximab on day+5, which will effectively prevent PTLD.

CYP2B6 polymorphism and lipoprotein lipase expression in chronic lymphocytic leukemia: impact on the outcome of fludarabine–cyclophosphamide regimen

Background Chronic lymphocytic leukemia (CLL) is the most common type of leukemia and has a highly variable clinical course. Cyclophosphamide (CPA)-containing regimens are the standard of care for patients lacking the 17p deletion. CYP2B6 is a polymorphic cytochrome P450 isoform that converts CPA to its active form. Lipoprotein lipase (LPL) catalyzes the hydrolysis of triacylglycerol. Remarkably, a growing body of data emphasizes its role in the biology of different tumors. Objectives This study aimed to study CYP2B6 polymorphism and LPL expression in fludarabine cyclophosphamide (FC)-treated CLL patients lacking 17p deletion. Methods 46 treatment-naive CLL patients negative for 17p deletion and indicated to receive chemotherapy were enrolled. CYP2B6 genotyping and lipoprotein lipase mRNA expression were assayed by Realtime PCR. FC-protocol was given then treatment-related toxicities, response, and event free survival were traced. Results CYP2B6*6 allele was associated with lower rates of treatment-related anemia and hospital admission. The response to FC was affected only by CYP2B6 polymorphism. The event-free survival of responders was significantly higher in patients having low LPL expression. Conclusion CYP2B6*6 infers lower CPA efficacy with lower treatment-induced side effects and increased risk of nonresponding to FC chemotherapy in CLL. LPL expression is a predictor of outcome in CLL, indicating poor survival.

Outcomes of second-line treatment after fludarabine cyclophosphamide and rituximab in patients with chronic lymphocytic leukemia outside clinical trials.

To evaluate disease characteristics and long-term outcomes in patients requiring second-line treatment following fludarabine, cyclophosphamide, and rituximab (FCR), for relapsed/refractory disease (R/R), or following discontinuation due to toxicities. A retrospective analysis of 126 chronic lymphocytic leukemia patients treated with frontline FCR: 63 received second-line treatment (41 relapsed, nine refractory [SD/PD], 13 prior toxicity). Time to next treatment (TTNT) was calculated from beginning FCR to initiation of second-line therapy. Overall and event-free survival was calculated from initiation of salvage treatment (OS2/EFS2). Median follow-up for the entire cohort was 67 and 37months from second-line therapy. TTNT<24months was associated with shorter OS2 and EFS2 similar to those observed with primary refractory disease (OS2 19 and 23months; EFS2 12 and 9months for TTNT<24months and SD/PD, respectively). TTNT≥24months (71% chemotherapy-based second-line), had longer OS2 and EFS2 (48 and 20months). Among the 13 patients receiving second-line therapy after discontinuing FCR due to toxicity EFS2 was 41months (59months from initiation of FCR). With limitations of sample size and treatment heterogeneity, patients progressing <24months following FCR have poor outcomes, similar to refractory patients, while longer remissions are indicative of a chemoimmunotherapy sensitive disease. Patients who discontinue FCR for toxicities may achieve excellent outcomes with subsequent treatment.

CHRONIC LYMPHOCYTIC LEUKEMIA INVOLVEMENT OF CENTRAL NERVOUS SYSTEM: A SINGLE CENTRE EXPERIENCE

Introduction: Chronic lymphocytic leukemia (CLL) involvement of central nervous system (CNS) is reported to be rare, mainly due to only occasional appear of predominantly non-specific neurological symptoms. Neurologic complications arising from direct leukemic involvement of CNS is stated in only 1% of patients (pts) with CLL. There is no treatment consensus with similar results of intrathecal chemotherapy or whole-brain irradiation, but some more recent studies reported more encouraging data with application of immunochemotherapy or tyrosine kinase inhibitor, ibrutinib. CLL with CNS involvement is related with poorer outcome, especially for pts with unfavorable cytogenetic (17p deletion). Methods: We presented a small series of four pts that were diagnosed and treated in our Institution. All pts met the International Workshop on CLL diagnostic criteria (2008). Diagnosis of CNS involvement was established via neuroimaging methods such as MRI, as well as cerebrospinal fluid (CSF) cytology, and CSF multiparameter flow cytometry immynophenotyping method (CSF FCM). Results: All pts were men with average age of 55.25 years (yrs). On CNS onset, all had disseminated disease and 17p deletion was registered in one case. Average latency period from CLL to CNS onset was 2.91 yrs. We registered heterogeneous neurological symptoms on CNS onset, including bradypsyhia, headaches, nausea, vomiting, dysphasia, repeated unconsciousness, urinary incontinence, dyslexia, lack of fine motor control, diplopia and bilateral eyelid swelling. Diagnostics included positive CSF cytology in three cases, CSF FCM was performed in all of our cases. MRI scan was performed in all cases and was conclusive in three (75%) cases. On CLL onset, two pts were treated with systemic chemotherapy, FC (fludarabine, cyclophosphamide) in one case and CHOP (cyclophosphamide, doxorubicine, vincristine, prednisolone) in other, third was initially treated with corticosteroid therapy due to immunological thrombocytopenia and fourth was on “watch and wait” policy, due to comorbidities. Two of our pts were treatment naïve on CNS onset. When CLL in CNS was diagnosed, systemic chemotherapy was applied in all cases. First patient received high-dose methotrexate with intrathecal therapies, second R(rituximab)-FC, and two received DHAP regimen (dexametasone, high-dose cytarabine, cisplatin) in two cases. Average and median OS from CNS onset was 4 and 3.5 months, respectively, with lethal outcome in 75% of cases in our follow-up. Conclusions: CLL in CNS is still rarely diagnosed, primarily due to the presence of heterogeneous, non-specific neurological symptoms, or their absence. The most effective diagnostics includes MRI, CSF-FCM, and if it is possible PCR detection of CLL cells in CSF. Our results confirm the poor therapeutic outcome and short survival in our group of pts. Keywords: chronic lymphocytic leukemia (CLL); flow cytometry; immunochemotherapy.

Results from Hemato-Oncology Latin America Observational Registry (HOLA) Providing Real World Outcomes for the Treatment of Patients with CLL

Introduction: There are few reports of standard of care and outcomes in Latin America. The HOLA study is a retrospective chart review of patients with B-cell malignancies in Latin America (LATAM).Methods: The objective of this registry is to describe patient characteristics, diagnostic and treatment patterns, and clinical outcomes in patients with Chronic Lymphocytic Leukemia (CLL) from a mix of public and private sites in Brazil, Mexico, Chile, Argentina, Colombia, Guatemala, and Panama. We report 472 patients with CLL diagnosed in the period from January 2006 to March 2016.Results: Median age at diagnosis was 66 years (range 23 - 95). Male gender predominance (53.6 vs 46.4%). Twenty-three percent of the patients (n=103) were dead, median time from diagnosis to death of 2.4 years (range 0-6.6 years). Seventeen percent (n=19) died before frontline treatment, 35%(39) after first-line treatment, 19%(21) in second-line, 27%(30) at or after third-line treatment.Anemia reported on 34%. Of the 34% (n=162) patients with COOMBS test, it was positive on 13%.Frequent comorbidities were high blood pressure (46%), heart disease (17%) and diabetes (15%).Binet status reported on 63% of patients, Rai status on 55%. (Table 1)Flow cytometry missing on 27% of patients (not performed/missing report). Diagnostic markers were positive as follows: CD23, 94% and CD5, 92%. Prognostic markers: 52% tested for CD38 and 10% ZAP 70, positivity on 24% and 26% of tested patients, respectively. Cytogenetic/FISH test performed on 21% (102), del(17p) was present on 7.4% of tested patients at diagnosis.Seventy two per cent of patients were considered for watch- and-wait approach. Median time from diagnosis to treatment initiation was 113 days (range 1 -2808).Sixty one per cent (288/472) receive front line treatment at any time. Frequent reasons to start treatment were B symptoms (25%), anemia (21%) and lymphocyte doubling time <6 months (17%). (Table 2)Response was assessed by clinical exam and blood count in 95% of patients, CT scan 24 %, abdominal ultrasonography 12%.Twenty-eight per cent of patients (135) relapsed and received second-line treatment. The most frequent second-line treatments were Chlorambucil (Chl) 37%; Fludarabine + Cyclophosphamide (FC) 16%, Cyclophosphamide + Vincristine + Prednisone (CVP) 9%. Clinical complete responses were as follows: FC = 4.5%, FCR= 25%.Sixty-five out of 472 patients (14%) received third-line treatment. Most frequently used treatments at this line were: Chlorambucil 23%, FC 20%, CVP 13%, FCR 9.2%, BR 4.6 %, and other chemotherapies 4.6%.Only 7% of patients in the registry relapsed and received fourth-line treatment.Conclusions:HOLA registry describes patterns of demographics, diagnosis and treatments in the real world in Latin America. CLL diagnosis in Latin America is made based on flow cytometry for the majority of the patients. Cytogenetic and FISH test are scarcely performed.For the deceased patients, median time from diagnosis to death was 2.4 years. This could be related to the high risk, but since prognostic tests were not always present this merits further investigation.Watch-and-wait was the most frequent approach. Time elapsed from diagnosis to treatment initiation was less than a year. Lymphocyte doubling time as reason to start treatment was frequent.Chlorambucil remains the most frequently used treatment for elderly in newly diagnosed and relapsed /refractory patients, use is also frequent in the young/fit patient population. Access barriers to innovative drugs and monoclonal antibodies could explain this situation. [Display omitted] [Display omitted] DisclosuresChiattone:Janssen: Membership on an entity's Board of Directors or advisory committees; roche: Membership on an entity's Board of Directors or advisory committees; abbvie: Membership on an entity's Board of Directors or advisory committees. Gomez-Almaguer:Bristol: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pavlovsky:Janssen: Speakers Bureau; Novartis: Speakers Bureau; Bristol Myers Squib: Speakers Bureau. Tuna-Aguilar:Janssen: Speakers Bureau. Farias:Janssen: Consultancy. Galvez:Novartis: Consultancy. Santos:Janssen: Employment. De La Mora Estrada:Janssen: Employment, Membership on an entity's Board of Directors or advisory committees.

Maintenance Therapy for Patients with Mantle Cell Lymphoma (MCL) - a Systematic Review and Meta-Analysis of Randomized Controlled Trials (RCTs)

Background:MCL is characterized by a dismal long term prognosis with a median overall survival of 3-5 years. Rituximab maintenance treatment (MR) improves survival of patients with follicular lymphoma, and its effect was assessed for MCL patients in several trials with inconsistent results. Other agents as bortezomib were also evaluated as maintenance therapy for MCL.Aims:We performed a systematic review and meta-analysis of RCTs in order to assess the effect of maintenance therapy on clinical outcomes of patients with MCL.Methods:We included RCTs that compared any type of maintenance to no maintenance or a different maintenance for patients with MCL, either in first line or relapsed disease. In July 2016 we searched The CochraneLibrary, MEDLINE, conference proceedings, and databases of ongoing trials. Two reviewers independently assessed the qualityof the trials and extracted data. The primary outcome wasall cause mortality. Secondary outcomes included progression free survival (PFS) and infectious adverse events. Relative risk (RR) for dichotomous data and hazard ratio (HR) for time to event datawere estimated and pooled using random-effects model.ResultsWe identified 6 trials that reported relevant outcomes, conducted between the years 1998 to 2012 and randomizing 857 patients with MCL. Most patients were males, with a median age ranging from 57 to 70 years, and predominantly good performance status. Ninety-six percent of the patients received their first line of treatment. MIPI score was reported in three trials: 20 to 42 percent of patients had a high MIPI score. Induction therapy included rituximab in all trials. In five trials chemotherapy induction was applied and consisted of fludarabine, cyclophosphamide (FC) and mitoxantrone (Forstpointner, Blood 2006), cyclophosphamide, vincristine, adriamycin, prednisone (CHOP) or FC in one trial (Kluin-Nelemans et al.), bendamustine (Rummel et al.), DHAP followed by autologous stem cell transplantation (ASCT) (Le Gouill et al.), and CHOP/cytarabine followed by ASCT (Doorduijn et al.); in one trial rituximab was given alone (Ghielmini et al.). Maintenance consisted of rituximab in five trials and bortezomib in one trial (Doorduijn et al.). The control group received no maintenance in two trials and interferon alfa in one trial. All included trials were judged at low risk of selection bias, none were blinded.No statistically significant effect on mortality rate was shown with rituximab maintenance therapy compared to no maintenance or interferon alfa RR 0.72, 95% CI 0.50 to 1.04, I2 of heterogeneity 57%, 751 patients. The RR of mortality with bortezomib maintenance was 0.67, 95% CI 0.12 to 3.71, but that is based on only 60 patients.PFS improved with rituximab maintenance compared to no maintenance or interferon alfa: HR 0.59, 95% CI 0.46 to 0.75. With bortezomib maintenance vs. no maintenance the HR of event free survival was 0.84, 95% CI 0.32 to 2.20.There was no statistically significant difference in infection rate with or without maintenance (RR 0.80, 95% CI 0.37 to 1.69, 419 patients).ConclusionsMaintenance therapy improved PFS of patients with MCL, but no survival benefit could be shown. The pooled analysis is based mainly on the results of rituximab maintenance as data of the effect of bortezomib maintenance is scarce. The absence of significant increase of infection rate as opposed to maintenance rituximab in follicular lymphoma might be attributed to the small sample size. Based on these results patients treated for both first line and relapsed/refractory MCL should receive rituximab maintenance after achieving response to induction. [Display omitted] DisclosuresDreyling:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial

AbstractDespite promising results with targeted drugs, chemoimmunotherapy with fludarabine, cyclophosphamide (FC), and rituximab (R) remains the standard therapy for fit patients with untreated chronic lymphocytic leukemia (CLL). Herein, we present the long-term follow-up of the randomized CLL8 trial reporting safety and efficacy of FC and FCR treatment of 817 treatment-naïve patients with CLL. The primary end point was progression-free survival (PFS). With a median follow-up of 5.9 years, median PFS were 56.8 and 32.9 months for the FCR and FC group (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.50-0.69, P < .001). Median overall survival (OS) was not reached for the FCR group and was 86.0 months for the FC group (HR, 0.68; 95% CI, 0.54-0.89, P = .001). In patients with mutated IGHV (IGHV MUT), FCR improved PFS and OS compared with FC (PFS: HR, 0.47; 95% CI, 0.33-0.68, P < .001; OS: HR, 0.62; 95% CI, 0.34-1.11, P = .1). This improvement remained applicable for all cytogenetic subgroups other than del(17p). Long-term safety analyses showed that FCR had a higher rate of prolonged neutropenia during the first year after treatment (16.6% vs 8.8%; P = .007). Secondary malignancies including Richter's transformation occurred in 13.1% in the FCR group and in 17.4% in the FC group (P = .1). First-line chemoimmunotherapy with FCR induces long-term remissions and highly relevant improvement in OS in specific genetic subgroups of fit patients with CLL, in particular those with IGHV MUT. This trial was registered at www.clinicaltrials.gov as #NCT00281918.

Comparison of Phase 3 Ibrutinib Results Versus Standard of Care in Sweden in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)

BackgroundIbrutinib (Ibr), an oral, first-in-class covalent Bruton's tyrosine kinase inhibitor, showed in the Phase 3 RESONATE trial significantly improved progression-free survival (PFS, hazard ratio [HR] =0.22, p<0.001) and overall survival (OS, HR=0.39,p=0.001) compared with ofatumumab (ofa) in patients with previously treated CLL who were not eligible for chemoimmunotherapy (Byrd et al, NEJM 2013). Long-term follow-up data from a single arm Phase 2 study have also demonstrated that patients treated with ibrutinib have long durable responses with a PFS at 2.5 years of 69% (Byrd et al, Blood 2015). While ofatumumab is a licensed comparator and included in treatment guidelines, some Health Technology Assessment (HTA) bodies require comparisons with a wider range of treatments. In the absence of direct head-to-head comparison of single-agent ibrutinib with other frequently used treatments in this patient population, additional comparative evidence against standard of care as observed in clinical practice can provide useful insights on the relative efficacy of ibrutinib. Naïve (unadjusted) comparisons of outcomes from different sources are prone to bias due to confounding, as treatment assignments were not randomly assigned, and populations can vary in important prognostic factors.The objective of this analysis was to compare the relative efficacy of Ibr versus physician's choice in R/R CLL-patients based on patient-level data from RESONATE pooled with an observational cohort, adjusting for confounders using multivariate statistical modelling.MethodsPatient-level data from the Phase 3 RESONATE trial (Ibr: n=195; ofa: n=196) were pooled with data from a retrospective observational study conducted in the Stockholm area in Sweden. This retrospective study collected efficacy and safety data from a detailed, in-depth retrospective review of individual patient files from 148 consecutively identified patients with R/R CLL initiated on second or later line treatment between 2002 and 2013 at the four CLL-treating centers in Stockholm, Sweden, with complete follow-up. Longitudinal follow-up in subsequent treatment lines was available for patients in 3rd (n=91), 4th (n=51), 5th (n=29), and 6+ (n=15) line, and as such individual patients could contribute information to the analysis for multiple lines of therapy, with baseline defined as the date of initiation of the actual treatment line. A multivariate cox proportional hazards model was developed to compare PFS and OS between treatments, including line of therapy, age, gender, Binet stage, ECOG, and refractory disease as covariates. Adjusted HRs and 95% CIs are presented vs. Ibr.ResultsAcross all treatment lines, fludarabine-cyclophosphamide (FC) (n=64), chlorambucil (n=59), alemtuzumab (n=33), FC+rituximab (FCR) (n=30), bendamustine+rituximab (BR) (n=28), and other rituximab-based combination chemotherapy (n=28) were the most frequently used treatments. Line of therapy, age and gender, Binet stage, ECOG performance status, and refractory disease were all independent risk factors for worse outcome on both PFS and OS. The adjusted HR for PFS and OS pooled observational data versus Ibr were 6.80 [4.72;9.80] (p<0.0001) and 2.90 [1.80;4.69] (p<0.0001). HR's for PFS/OS versus most frequent treatment regimens ranged between 2.50/1.82 (FCR) and 14.00/5.34 (anti-CD20 Mab). Baseline adjusted results for the Ofa-arm in RESONATE were comparable for both PFS and OS to outcome data from the consecutive historical cohort, however OS outcomes for Ofa were partly confounded by cross-over to Ibr.ConclusionsComparison of results from the Phase 3 RESONATE study with treatments used as part of previous standard of care in a well-defined cohort of consecutive Swedish patients shows that ibrutinib is superior to physician's choice in patients with relapsed/refractory CLL, suggesting a more than 6 fold improvement in PFS and almost 3 fold improvement in OS. Results were consistent across all different physician chosen treatments and provides further evidence that ibrutinib improves both PFS and OS vs current and prior standard of care regimens. [Display omitted] DisclosuresÖsterborg:Janssen Cilag: Research Funding. Asklid:Janssen Cilag: Research Funding. Diels:Janssen: Employment. Repits:Janssen Cilag: Employment. Söltoft:Janssen Cilag: Employment. Hansson:Jansse Cilag: Research Funding. Jäger:Janssen Cilag: Research Funding.

Obinutuzumab (GA101) is highly effective against chronic lymphocytic leukemia cells in ex vivo B-cell depletion irrespective of high-risk prognostic markers

The anti-CD20 monoclonal antibody rituximab has revolutionized the management of B-cell non-Hodgkin's lymphoma and chronic lymphocytic leukemia (CLL). Addition of rituximab to the frontline standard chemotherapy (fludarabine–cyclophosphamide, FC) within the rituximab fludarabine cyclophosphamide regimen has recently shown to statistically increase both progression-free survival (PFS) and overall survival (OS) in the randomized CLL8 phase III trial of the German CLL Group.1 This was the first example of improved OS in first-line CLL, although restricted to those patients fit enough to receive FC chemotherapy. However, the translation of these results into the clinical setting is hampered by the fact that ca. one half of CLL patients are 72 years at the time of first therapy, 40% being aged more than 75 years2 with increased burden of comorbidities (for example, kidney function impairment) and thus not eligible for FC chemotherapy.

Bendamustine in combination with rituximab for elderly patients with previously untreated B-cell chronic lymphocytic leukemia: A retrospective analysis of real-life practice in Italian hematology departments

The front-line therapy for CLL young and fit patients is chemo-immunotherapy with fludarabine–cyclophosphamide–rituximab (FCR). FCR regimen results in a significant myelosuppression and high rates of early and late infections especially in elderly patients. German CLL study group compared FCR vs. bendamustine–rituximab (BR) in fit untreated patients. The response rates with BR or FCR were comparable, BR could be an alternative 1st-line treatment for elderly patients.Here we report retrospective data of 70 elderly (≥65 years) CLL patients from 12 Italian centers treated with BR as front-line therapy. The primary end points were overall response rate (complete remission/partial remission) and safety.Forty-seven males and 23 females, with a median age of 72 years, were included in the study. Eight patients were unfit for CIRS. The OR rate was 88.6% (31.4% CR and 57.2% PR). Progression free survival, treatment free survival and overall survival rates at 2-years were 79%, 90.3% and 89.6%, respectively. Only del17 was independent unfavorable parameter on the response rate and PFS. Our results indicate that BR front-line at standard dose provides a high response rate with a good safety profile, even if more than 50% of patients experienced a bendamustine dose reduction until 70mg/m2.

Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial

AbstractObinutuzumab is a type 2, glycoengineered, anti-CD20 antibody recently approved with chlorambucil for the initial therapy of chronic lymphocytic leukemia (CLL). In this nonrandomized, parallel-cohort, phase 1b, multicenter study, we explored the safety and preliminary efficacy of obinutuzumab-bendamustine (G-B) or obinutuzumab fludarabine cyclophosphamide (G-FC) for the therapy of previously untreated fit patients with CLL. Patients received up to 6 cycles of G-B (n = 20) or G-FC (n = 21). The primary end point was safety, with infusion-related reactions (88%, grade 3-4 20%) being the most common adverse event and grade 3-4 neutropenia in 55% on G-B and 48% on G-FC. Mean cycles completed were 5.7 for G-B and 5.1 for G-FC, with 2 and 7 early discontinuations, respectively. The objective response rate (ORR) for G-B was 90% (18/20) with 20% complete response (CR) and 25% CR with incomplete marrow recovery (CRi). The ORR for G-FC was 62% (13/21), with 10% CR and 14% CRi, including 4 patients not evaluable. With a median follow-up of 23.5 months in the G-B cohort and 20.7 months in the G-FC cohort, no patient has relapsed or died. We conclude that obinutuzumab with either B or FC shows manageable toxicity and has promising activity. This study was registered at www.clinicaltrials.gov as #NCT01300247.

High-Resolution Genomic Copy Number Analysis on Sequential Samples from the CLL8 Trial: Relation Between Clonal Evolution and Defects in DNA Damage Response?

Genomic abnormalities have strong prognostic impact in chronic lymphocytic leukemia (CLL). However, clonal evolution has been studied in a limited number of cases and not within the setting of current standard therapy. It was therefore our aim to study changes in the composition of copy number alterations (CNA) over time with and without the influence of chemo(immuno)therapy.Sequential samples of 92 patients enrolled on the CLL8 trial of the GCLLSG were analyzed by Affymetrix® 6.0 single nucleotide polymorphism (SNP) arrays. Since procurement of a relapse sample was a prerequisite for this study, the cohort was not representative for the CLL8 trial [21% CR (N=19), 63% PR (N=58), 13% non response (N=12), 3% missing response (N=3)]. 48 patients received Fludarabine / Cyclophosphamide (FC), 44 patients FC plus Rituximab (FCR). Samples were taken at 3 time points: pre-treatment [N=27], time of first treatment in CLL8 [N=92] and post treatment at relapse / progressive disease [N=74]. The median observation period between samples was 35 months [range: 6-127] for the pre-treatment vs. first treatment and 41 months [range: 5-87] for the first treatment vs. post treatment (relapse) comparisons.The majority of cases maintained genomic stability over time. This applied in particular for the comparison between pre-treatment and first treatment [N=21 of 27; 78%] but also for the comparison between first treatment and relapse [N=49 of 74; 66%].The cohort was characterized by a high proportion of high-risk genomic abnormalities [30% del(11)(q22.3), 22% TP53 loss and/or mutation in the pre-treatment cohort; 36% del(11)(q22.3), 24% TP53 loss and/or mutation in the post treatment cohort]. The acquisition of novel clonal CNAs was associated with these: In the pre-treatment to first treatment comparison [N=27], only 6 [22%] cases had novel CNAs emerging over time and all of them carried an ATM loss by del(11)(q22.3). Eight cases with ATM and/or TP53 alteration and all cases without high-risk genomic aberrations [N=13] showed no evidence of clonal evolution. In the first treatment to relapse comparison [N=74], 25 [34%] cases had newly acquired CNAs at relapse and 20 of them [80%] carried high-risk genomic abnormalities [44% del(11)(q22.3), 36% TP53 loss and/or mutation]. Only 5 cases lacking ATM or TP53 alteration had newly acquired CNAs. In contrast, genomic stability was observed in 25 cases with high-risk genomic abnormalities [15 cases with del(11)(q22.3), 10 with TP53 loss and/or mutation) and 24 cases without high-risk abnormalities. No statistically significant increased incidence of clonal evolution was observed in IGHV unmutated cases [N=66 of 92] [24 (80%) cases with clonal evolution vs. 42 (70%) cases without clonal evolution, p=0.3].Nine patients had samples available from all 3 time points. While mainly genomic stability could be observed prior to treatment, 3 cases acquired 3 novel CNAs each after therapy.Comparing both treatment arms in the post treatment cohort [N=74] revealed a higher incidence of clonal evolution after treatment with FCR [FCR: N=16 of 35, 46%; FC: N=9 of 39, 23%; p=0.04] at a similar median observation period [36 and 35 months, respectively]. Also, the mean number of newly acquired CNAs at relapse was higher in the FCR treated group [3.3 vs. 2.6]. With regard to response no statistically significant differences were observed between cases with and without clonal evolution [cases with clonal evolution: 6 (24%) CR, 17 (64%) PR, 2 (8%) non-response; without: 8 (17%) CR, 31 (66%) PR, 8 (17%) non-response, p=0.5].Loss of clonal lesions was rare, occurring only under the selection pressure of therapy: 16 CNAs in 11 cases were not observed anymore at relapse. 3 of these CNAs were subclonal at time of first treatment [10-20% allelic burden] and might not yet have re-emerged after relapse. 5 CNAs in 4 cases were lost at relapse. The remaining 8 CNAs were del(13q) [N=5] and del(11q) [N=3] that were lost for a probably more advantageous del(13q) / del(11q) clone. The appearance of a more advantageous del(13q) / del(11q) clone was linked to a larger deletion size [N=3] or a larger discontinuous deletion very likely resulting from chromothripsis [N=3].The results of this study support previous data of a high genomic stability in CLL cases lacking alterations of TP53 and/or ATM. However, application of chemo(immuno)therapy did slightly increase the number of cases acquiring novel clonal CNAs. DisclosuresStilgenbauer:Pharmacyclics, Janssen: Honoraria, Research Funding.

Rituximab Maintenance (MR) for Patients with Mantle Cell Lymphoma (MCL) – a Systematic Review and Meta-Analysis of Randomized Controlled Trials (RCTs)

BackgroundMCL is characterized by a dismal long term prognosis with a median overall survival of 3-5 years. The addition of rituximab to induction chemotherapy improved significantly response rates of patients with MCL. MR treatment for these patients has the potential to further improve disease control and overall survival (OS). The few trials that addressed that question showed inconsistent results.AimsWe performed a systematic review and meta-analysis of RCTs in order to assess the effect of MR on clinical outcomes of patients with MCL.MethodsWe included RCTs that compared MR to no treatment or other treatment for patients with MCL, either in first line or relapsed disease. In March 2014 we searched The Cochrane Library, MEDLINE, conference proceedings, and databases of ongoing trials. Two reviewers independently assessed the quality of the trials and extracted data. The primary outcome was all cause mortality. Secondary outcomes included progression free survival (PFS) and infectious adverse events. Relative risk (RR) for dichotomous data and hazard ratio (HR) for time to event datawere estimated and pooled using random-effects model.ResultsWe identified 3 trials, conducted between the years 1998 to 2010 and randomizing 434 adult patients with MCL. Most patients were males, with a median age ranging from 61 to 70 years, and predominantly good performance status. Seventy-nine percent of the patients received their first line of treatment. MIPI score was reported in one trial. Induction therapy included rituximab in all three trials. In two trials additional chemotherapy induction was applied consisting of fludarabine, cyclophosphamide (FC) and mitoxantrone in one trial (Forstpointner, Blood 2006), and cyclophosphamide, vincristine, adriamycin, prednisone (CHOP) or FC in the other (Kluin-Nelemans, NEJM 2012); in the third trial rituximab was given alone (Ghielmini, JCO 2005). The control group received no maintenance in two trials and interferon alfa in one trial. All included trials are judged at low risk of selection bias, none were blinded.Mortality rate decreased with MR compared to no MR or interferon alfa RR 0.67, 95% CI 0.46 to 0.98, I2 of heterogeneity 54%, 392 patients (Figure).PFS improved with MR compared to no MR or interferon alfa: HR 0.60, 95% CI 0.44 to 0.82, I2 of heterogeneity = 0.There was no statistically significant difference in infection rate with or without MR (RR 0.80, 95% CI 0.37 to 1.69, 419 patients).ConclusionsThe results of this meta-analysis support a survival benefit of MR in patients with first line or relapsed/refractory MCL who responded to induction therapy. Additionally, there is a significant improvement of PFS benefit of MR. The absence of significant increase of infection rate as opposed to MR in follicular lymphoma may be attributed to the small sample size. Based on these results patients treated for both first line and relapsed/refractory MCL should receive MR after achieving response to induction. [Display omitted] DisclosuresVidal:Roche: unrestricted grant Other. Ghielmini:Roche: Research Funding, Speakers Bureau. Unterhalt:Roche: Travel Support Other. Shpilberg:Roche: Consultancy, Research Funding.

Safety and Efficacy Of Obinutuzumab (GA101) With Fludarabine/Cyclophosphamide (G-FC) Or Bendamustine (G-B) In The Initial Therapy Of Patients With Chronic Lymphocytic Leukemia (CLL): Results From The Phase 1b Galton Trial (GAO4779g)

BackgroundChemoimmunotherapy (CIT) is the standard of care to treat fit patients (pts) with CLL. These CIT regimens include the use of rituximab, an anti-CD20 monoclonal antibody (mAb), with standard chemotherapy such as fludarabine/cyclophosphamide (FC) or bendamustine (B). GA101 is a novel, glycoengineered, type II CD20 mAb designed to increase direct and antibody-dependent cellular cytotoxicity. Early phase 1/2 GA101 studies in pts with CLL demonstrated single-agent activity with treatment-related neutropenia. GALTON (NCT01300247) is a non-randomized, parallel group, phase 1b study of the safety and preliminary efficacy of GA101 plus FC or B in the initial therapy of pts with CLL. MethodsUntreated CLL pts requiring therapy who had a performance status ≤2 were treated with GA101 1000 mg (100 mg IV d1, 900 mg d2, 1000 mg d8 and d15 of cycle 1; 1000 mg d1 in cycles 2–8) with either FC (25/250 mg/m2 IV on d2–4 of cycle 1, then d1–3 of cycles 2–6; G-FC) or B (70 mg/m2 IV on d2–3 of cycle 1, then d1–2 of cycles 2–6; G-B). Each cycle was 28 days. Pts received acetaminophen and an antihistamine before each infusion of GA101. Pts also received methylprednisolone or dexamethasone prior to the 1st and 2nd GA101 infusions. Each center chose to participate in either the G-FC or G-B arm, and physicians could reduce the dose of FC or B after the 1st cycle if there was concern about tolerance to chemotherapy. The primary endpoint was to evaluate safety and tolerability of GA101 with chemotherapy. Secondary endpoints included response rates per iwCLL criteria, including required CT scans to confirm response. Complete response (CR) required resolution of all disease, and single lymph nodes (LNs) needed to be ≤ 1.5 cm in long axis by CT. Partial response (PR) required a ≥ 50% decrease in lymphocyte count, ≥ 50% reduction in sum of product diameter (SPD) of LNs, ≥ 50% reduction of liver and/or spleen, and either neutrophil, platelet or hemoglobin recovery. ResultsWe enrolled 41 pts (Table 1) with a median follow-up time of 11.9 months. The most common adverse events (AEs) (any grade) occurring in ≥ 9 pts in the G-FC arm were GA101 infusion–related reactions (IRRs) (91%), nausea (76%), fatigue (57%), constipation (48%), and neutropenia (43%); in the G-B arm, they were GA101 IRRs (90%), nausea (65%), neutropenia (55%), diarrhea (50%), and pyrexia (45%). The most common Grade (Gr) 3/4 AEs are in Table 1. In both cohorts, Gr 3/4 GA101 IRRs only occurred with the 1st dose. Fourteen pts experienced serious AEs (6 pts in G-FC, 8 pts in G-B), with events including febrile neutropenia (n=5 events); infections (n=4); IRRs (n=3); nausea, vomiting, pyrexia (n=2 each); and diarrhea, fatigue, tachycardia, tumor lysis syndrome, syncope, mental status changes, neutropenia, face swelling, and hypertension (n=1 each). Nine pts (7 in G-FC, 2 in G-B) had AEs leading to treatment discontinuation, including Gr 3/4 neutropenia (3 in G-FC [1 of 3 pts also had Gr 4 cellulitis], 2 in G-B), Gr 3 thrombocytopenia (2 in G-FC), Gr 4 pancytopenia (1 in G-FC), and Gr 4 AST/Gr 3 ALT elevation (1 in G-FC). [Display omitted] The overall response rate was 62% (2 CR, 3 CRi, 8 PR) in the G-FC arm, and 90% (4 CR, 5 CRi, 9 PR) in the G-B arm, including 6 pts (4 in G-FC, 2 in G-B) not evaluable due to inadequate response evaluation. Four pts in the G-FC arm (0 in G-B) had stable disease during and after therapy. No pt progressed during the study. ConclusionsGA101 plus chemotherapy can be administered safely to pts requiring initial therapy for CLL. IRRs were the most common AE, but typically occurred during the initial infusions of GA101 and were not dose-limiting. The AE rates observed in pts treated with G-FC or G-B did not appear to be greater than those in pts treated with standard CIT. Our data show GA101 plus FC or B has clinical activity in the initial therapy of pts with CLL, warranting further clinical study. Disclosures:Brown:Pharmacyclics, Genentech, Celgene, Emergent, Onyx, Sanofi Aventis, Vertex, Avila, Novartis: Consultancy; Genzyme, Celgene: Research Funding. Off Label Use: GA101 is a novel, glycoengineered, type II anti-CD20 monoclonal antibody that is designed to enhance direct cell death and antibody-dependent cellular cytotoxicity. It is being investigated in chronic lymphocytic leukemia, Non-Hodgkin's Lymphoma and other hematologic indications. O'Brien:CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead Sciences, Infinity, MorphoSys, Pharmacyclics, Talon: Research Funding; Teva/Cephalon, Celgene, Emergent, Genentech, Gilead Sciences, Infinity, Pharmacyclics, Talon: Consultancy. Eradat:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lymp:Roche: Stock options, Stock options Other; Genentech: Employment. Hirata:Roche: Stock options, Stock options Other; Genentech: Employment. Kipps:Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Updated Follow-Up In The CLL2007FMP Trial Supports The Non Superiority Of The Association Fludarabine-Cyclophosphamide (FC) Plus Campath Compared To FC Plus Rituximab and Points Out The Importance Of Minimal Residual Disease, By 6-Color Flow Cytometry Technique, On Progression Free Survival

▪ IntroductionCLL2007FMP (fit medically patients) is a Randomized Phase-III Trial conducted by the French Cooperative Group on CLL and WM (FCGCLL/WM) and the “Groupe Ouest-Est d'Etude des Leucémies et Autres Maladies du Sang” (GOELAMS), comparing FC plus Rituximab (FCR) to FC plus Campath (FCCam) in previously untreated fit patients with chronic lymphocytic leukemia (CLL). Early results showed that the FCCam regimen was associated with an unfavourable safety profile limiting significantly its use in this indication (Blood 2012). We present here the results of the extended follow up of the CLLFMP2007 trial, with particular emphasis on survival data, minimal residual disease (MRD) and late adverse events. MethodsIn this trial, 178 younger (<65) fit patients (pts) (cumulative illness rating scale (CIRS) score of up to 6), were enrolled between November 2007 and January 2009. Cases with del(17p) were excluded. Pts were randomly assigned to receive 6 oral courses of FCR (n=83) or FCCam arm (n=82). The primary endpoint of the study was 3-year progression-free survival (PFS). Secondary endpoints were safety, response to treatment, overall survival (OS) and MRD. MRD evaluation was performed by 6-color flow cytometry in an oligocentric manner. MRD testing was scheduled before therapy initiation and at final evaluation, (i.e. 3 months after completion of immunochemotherapy) where it was to be assessed for all responding patients in both peripheral blood (PB) and bone marrow (BM). Recruitment was interrupted in January 2009 after 165 pts had been randomized due to an excess of mortality in the FCCam arm. ResultsPFS and OS were not significantly different between the two arms. With a median follow-up of 55.5 months (interquartile range, 50-60), 57 pts in the FCCam arm were free of disease progression compared with 50 in the FCR arm, with a 3-year estimated PFS at 81% in both arms (p=0.80). Fourteen pts died in the FCCam arm (7 from progression and 7 from toxicity) and 9 died in the FCR arm (all from progression), with a 3-year estimated survival at 90% vs. 88% (p=0.85). PFS was significantly impacted by IGHV mutational status (p=0.001), Binet stage (p=0.0002) and MRD level. At final evaluation, MRD was established using the result in PB samples (available for 120 patients) and was determined in 103 pts by combining the results from blood and BM samples. Interpretation was based firstly on the use of the classical 10-4 threshold as reference and secondly on the limit of detection of the technique (0.7x10-5). In MRD-positive patients, the median PFS was 44.7 months (PB) whereas it was not reached in the group with MRD lower than 10-4 (p<0.0001, figure 1) ; similar data were found in MRD-positive PB+BM patients with a median PFS of 46 months whereas it was not reached in the group with MRD lower than 10-4 (p=0.002). No significant difference was found regarding OS but follow-up is still short for this evaluation. Similar results were observed when considering the limit of detection of the MRD technique (data not shown). Late toxicities (occurring after the final evaluation at 3 months after the end of treatment or at the ninth month when treatment was prematurely stopped) included : 1 bile duct cancer, 1 myelodysplastic syndrome, 1 transient ischemic attack, 1 lung adenocarcinoma and one prostate cancer in the FCR arm and 3 febrile neutropenia, 3 pneumonia (1 due to legionella), 1 pneumococcal sepsis, 1 bronchitis, 1 toxoplasma eye infection, 1 pyelonephritis, 2 herpes zoster, 1 acrodermatitis, 1 subdural hematoma, 1 autoimmune thrombocytopenia, 1 agranulocytosis, 1 autoimmune haemolytic anaemia in the FCCam arm. [Display omitted] ConclusionResults of this extended follow-up of the CLL2007FMP trial confirm the absence of superiority of the FCCam regimen on OS and PFS. Interestingly, longer follow-up did not reveal a higher rate of late toxicity in FCCam arm, notably in terms of secondary malignancies; Similarly to early toxicity, late was adverse events were mainly infectious. Finally, MRD status determined by 6-color technique in PB and/or BM at post-treatment evaluation was predictive of PFS whatever the treatment arm. This finding is in line with recent reports in other studies pointing out to the powerful value of MRD as prognostic factor, supporting its use as PFS surrogate primary endpoint in clinical trials. Disclosures:Feugier:roche: Honoraria. Cazin:roche: meeting invitation Other, Membership on an entity's Board of Directors or advisory committees; GSK: meeting invitation, meeting invitation Other, Membership on an entity's Board of Directors or advisory committees.

Comparison Of Umbilical Cord Blood and Haploidentical Donor Grafts In Adults With High Risk Hematologic Diseases After Fludarabine Cyclophosphamide and TBI 2 Gy Based Reduced-Intensity Conditioning Regimen Stem Cell Transplantation

IntroductionHuman leukocyte antigens (HLA)-matched sibling or unrelated donor are available for around only 50-60% of patients. However, for patients without a suitably matched related donor, Alternative donors such as mismatched unrelated, cord blood and mismatched family donors could be searched. The aim of this retrospective study was to compare the results of graft source on outcome of patients after haploidentical related donor (Haplo), and the unrelated umbilical cord blood (UCB) transplantation in the setting of Non myeloabalative conditioning regimen (NMA). Patients and methodsWe retrospectively analyzed outcomes in 150 adult patients with high risk hematologic diseases who received Allo-SCT from alternative donors from two centers (Institut Paoli-Calmettes at Marseille France and Humanitas cancer center at Rozzano, Italy): These two centres have been applying common transplant approaches and procedures during the study period. 69 patients received Haplo and 81 patients received UCB. In the UCB group, the NMA regimen consisted of fludarabine (Flu), cyclophosphamide (Cy) and low dose TBI (2 Gy) combination in the two groups. The GVHD prophylaxis consisted of Cyclosporine A (CsA) and MMF in all patients in the two groups. In the Haplo group all patients received also 50 mg/kg Cy at day 3 and 4 post transplant. Of note, supportive care was the same during the whole study period. CMV infection management was also homogeneous. Patient characteristics are shown in Table 1.Table 1Patient and transplantation characteristics:Characteristic Total =150 patientsHaplo transplant (n = 69)CB transplant (n = 81)P valuePatients Age years (median) [range]44 (19-68)47 (18-66)Patients sexnsMale39 (57)46 (57)Female30 (43)35 (43)Disease typeAML3 (4)37 (46)<0.0001ALL1 (1)14 (17)<0.0001NHL24 (35)14 (17)nsHL30 (43)2 (2)<0.0001MM4 (6)2 (2)nsCLL5 (7)4 (5)nsCML01 (1)nsMDS/ MPS2 (3)7 (9)nsStatus of diseaseCR37 (54)56 (69)nsPR/SD24 (35)12 (15)0.04PD8 (11)13 (16)nsDonor typeSibiling32 (46)Parent18 (26)Child18 (26)cousin1 (2)Donor/recipient sex mis-match34 (49)56 (69)nsABO incompatibility24560.02Conditioning regimenFlu 5+Cy 1+ TBI075 (93)Flu 5+Cy 2+ TBI69 (100)6 (7)Stem cell sourcePeripheral Blood19 (28)Bone Marrow50 (72)Stem cell dose median [range] CD34+ x 106/kg3,96 (0,8-14)0,9 (0,08-1,28)GvHD prophylaxisCSA+MMF69 (100)81 (100)nsCy post transplant69 (100)0Days with ANC< 500 x 109/l20 (14-39)22 (6-67)nsDays with platelets<20 x 109/l29 (14-50)41 (18-80)ns ResultsWith a median follow-up of 59 months (8-101) and 18 months (3-51), in the UCB group versus the Haplo group, respectively. Nine patients (11%) in the UCB and 8 patients (12%) in the Haplo group had a spontaneous autologous reconstitution subsequent to primary graft failure. The median times to neutrophil and platelet recovery were 20 d (14–39) and 29 d (14–50) after Haplo and 22 d (6–67) and 41 d (18–80) after cord blood. All supportive care measures included red blood cell, and platelet transfusions were significantly increased in cord blood transplantation group. The cumulative incidence of transplant related mortality (TRM) at one year was 23% in the UCB group versus 17% in the Haplo group (P=0.39). Grade 2-4 acute graft-vs.-host disease (GVHD) and extensive chronic GVHD incidences were 52% versus 29% (P=0.05), and 12% versus 6% (P<0.0001), in the UCB group versus the Haplo group, respectively. The Kaplan-Meier estimate of overall survival at 2 years was 45% (95%CI, 34-56%) in the UCB group versus 69% (95%CI, 58-80%) in the Haplo group, (P=0.10). The estimate of progression-free survival at 2 years was 36% (95%CI, 25-47%) in the UCB group versus 65% (95% CI, 53-77%) in the Haplo group (P=0.01). Figure 1 ConclusionIn this study, relapse and PFS was lower in Haplo group than in UCB transplants. The main difference between the 2 groups was the significantly higher incidence of acute and chronic GVHD in the UCB group. Surprisingly, this did not translate into a decrease of the cumulative incidence of OS nor increase of the TRM, which may be explained by a slightly shorter follow-up in this group. Our results suggest that haploidentical transplants are a good and promising alternative option for patients with high risk hematological diseases who lack an HLA-matched donor (sibling or unrelated donor). This should be now investigated in prospective comparative studies. Disclosures:No relevant conflicts of interest to declare.

Allogeneic Stem Cell Transplantation for Accelerated/Blastic Phase Philadelphia-Chromosome Negative MPN

AbstractAbstract 4532Myeloproliferative Neoplasm (MPN)-Leukaemic Transformation (LT) uniformly carries a dismal prognosis. Effective therapy for such patients are currently lacking with no established evidence base to guide Allogeneic Haematopoietic Stem Cell Transplant (AHSCT) regimen. We report the outcome of a cohort of patients undergoing AHSCT at our 2 institutions over a 6-year period (2006–2012).24 patients underwent AHSCT following diagnosis of MPN transformed to an accelerated phase (5–9% blasts on bone marrow (BM), n=9 & 10–19% BM blasts, n=2) or blastic phase (>20% blasts on peripheral blood or BM, n=13). Disease subtypes were: Polcythaemia Vera (PV, n=4), Essential Thrombocythaemia (ET, n=6), Primary Myelofibrosis (PMF, n=8), Myelodysplastic/Myeloproliferative neoplasm-Unclassified (MDS/MPN-U, n=6). Median age at diagnosis was 50 years (range 29–67) and median time to transformation was 50 months (range 0–271). Cytogenetics were abnormal at transformation in 11 patients (46%), with 6 (25%) demonstrating abnormalities of chromosomes 5, 7 or complex karyotype, and 5 displaying trisomy 8, whilst 1 had isolated chromosome 17p deletion. 13 patients harboured the JAK2V617F mutation.Patients received a median of 3 (range, 1–5) lines of therapy for chronic and acute phase prior to AHSCT, of which 20 patients received intensive AML-type induction therapy. Disease status at time of AHSCT was complete remission (CR) in 13 cases, partial response (PR) in 7, and 4 patients had persisting AML. Conditioning regimes were Reduced Intensity with T-depletion (Alemtuzumab or Anti-Thymocyte globulin) in 23/24 cases (Fludarabine/Busulfan-based n=12, FLAMSA (Fludarabine, Ara-C and Amsacrine, followed by TBI/Cyclophosphamide or Busulfan) n=9, Fludarabine Cyclophosphamide TBI haploidentical protocol n=1, Fludarabine/Melphalan n=1). Median CD34 dose was 6.48 × 10∧6 cells/kg (range 1.17 {BMH} −10.71). Stem cell source was Peripheral Blood in all but one case, from unrelated (n=17) or related (n=7) donors. Median time to both neutrophil and platelet engraftment was 13 days (range 9–25 and 7–68 respectively); 2 patients including the haploidentical transplant had Primary Graft Failure (8%). The incidence of severe (grade 3&4) acute GVHD was 3/24 (12.5%) and 10 patients developed NIH-defined chronic GVHD (8 moderate, 1 severe). Day 100 Non-relapse mortality was 12.5%.Patients underwent sequential chimerism monitoring. Median OS for the entire cohort was only 10 months with a median progression free survival (PFS) of only 6.5 months. 5 patients received therapeutic Donor Lymphocyte Infusion (tDLI) for relapse at a median dose of 1×10∧6 CD3+/kg. 2 patients received DLI alone for chronic phase relapse, of whom 1 achieved remission. 3 patients received chemotherapy + DLI and 1 achieved 2ndCR. At last follow-up, 11/24 patients were alive with median surviving patient follow-up of 25 months.The percentage of BM blasts at progression from chronic phase had a highly significant impact upon outcome post AHSCT, median OS 23 vs. 10 months for 5–9% BM blasts compared to 310% BM blasts (p=0.011) & PFS 11 vs 6 months respectively (p=0.033, Fig 1). This effect was replicated when considering disease response immediately prior to AHSCT, with a median OS of 28 months for those in CR, compared to 10 months for those with excess blasts (p=0.017) and median PFS 11 vs 6 months, p=0.019 (Fig 2). Disease duration, subtype, Jak2 status and age at allograft did not significantly affect survival.Of note for the 3 surviving patients with follow-up over 6 months, all received FLAMSA-RIC conditioning (n=9). 5 patients who received FLAMSA TBI; 2 died of treatment-related complications, and 2 with residual disease at time of AHSCT relapsed early. Of 4 patients who have received a hybrid FLAMSA-Busulfan regimen, 2 remain alive in CR and 2 achieved a relapse free period of 12 months. Interestingly, PFS for FLAMSA-Bu patients appears significantly improved compared to conventional RIC regimens (median PFS 12 vs. 6 months, p=0.035) on univariate analysis, although conclusions are limited by cohort size.Further work into optimising transplantation regimens for accelerated and blastic phase MPN is warranted. Early use of FLAMSA-Busulfan hybrid protocol, before transformation to overt blastic phase, in conjunction with early weaning of immunosuppressive therapy and prophylactic DLI may improve the proportion of long-term survivors. [Display omitted] [Display omitted] Disclosures:Harrison:Sanofi Aventis: Honoraria; Shire: Honoraria, Research Funding; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau.

PRM12 Joint Estimation of Progression Free Survival and Overall Survival

In cancer, treatments often aim to extend time to progression. The implications on overall survival are often inconclusive, as trials are too short and the majority of patients are still alive at the end of the trial. However, for decision making, it is important to estimate both the treatment effect on Progression Free Survival as well as the treatment effect on Overall Survival. This poster shows how the estimation of Overall Survival benefit can be improved by the use of Progression Free Survival data. The developed Network Meta-Analysis model uses the tested hypothesis that treatments provided until progression in general do not change the length of the post-progression period. This hypothesis is tested in detail based on systematic literature reviews concerning 4 different types of cancer. A test for equal lengths of the post-progression periods is described too. A network meta-analysis model is described, which can be used to obtain estimates for OS from PFS data for treatments for which no OS data or insufficient OS data are available. This informs decision making in situations where otherwise no conclusion can be drawn. The methodology is applied to an indirect comparison of Chlorambucil, Fludarabine and Fludarabine Cyclophosphamide. Comparable DIC were obtained to individual fitting of OS and PFS for the situation that OS data were available. Therefore, the methodology both enables the fitting of OS when OS data are not available as well as potentially improves OS fitting when data are limited available. Based on systematic literature reviews, a method is developed to use PFS as surrogate outcome for OS. In addition, a test is developed to justify the assumption of equal post-progression periods among treatments, which can be used to assess whether the translation of PFS time differences in OS time differences is appropriate.

Economic Analysis of Alemtuzumab (MabCampath®) in Fludarabinerefractory Chronic Lymphocytic Leukemia

Objective: The objective of this economic analysis is to determine the cost-effectiveness of alemtuzumab in the treatment of B cell chronic lymphocytic leukemia (B-CLL) patients who have progressed despite fludarabine therapy. Method: This model was developed according to the Canadian public payer health system considering only direct medical costs. Effectiveness information was obtained from the published literature. Resource utilization was based on guidelines, literature and expert opinion. Cost information was obtained from provincial costing sources and presented in 2008 Canadian dollars. The primary comparators for this analysis were alemtuzumab, Various Treatments (VT) (combination of agents), fludarabine+cyclophosphamide (FC), fludarabine+cyclophosphamide+rituximab (FCR) and best supportive care (BSC). Results: Estimated mean survival for alemtuzumab was 22.68 months (1.89 years). Mean survival for VT was estimated from the literature at 16.32 months (1.36 years). The mean survival for FC was 17.44 months (1.45 years) and FCR 20.06 months (1.67 years). The incremental cost-effectiveness ratio (ICER) for alemtuzumab vs VT was $43,615/life year gained (LYG); $52,536/LYG for the alemtuzumab vs FC; $21,818/LYG vs FCR; and less costly and more effective vs BSC. ICERs were sensitive to three variables: treatment duration of alemtuzumab; treatment duration of FCR; and additional survival due to rituximab for FCR patients compared to FC. Conclusion: The results showed that the ICERs for alemtuzumab in B-CLL patients who have failed fludarabine ranged from $21,818/LYG to $52,536/LYG compared to active treatment, and was less costly and more efficacious compared to BSC.