Time Of First Relapse Research Articles

Survival outcomes of patients with germ cell tumors treated with high-dose chemotherapy for refractory or relapsing disease.

IntroductionMale patients with metastatic germ cell tumors can be cured in up to 96% of cases depending on stage and IGCCCG prognosis group. Treatment in relapse consists of conventional or high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) combined with local treatment modalities.ResultsMost patients were classified as poor risk according to IGCCCG (n = 24; 52%) and as intermediate (n = 12), high (n = 16), or very high risk (n = 9) at time of first relapse according to IPFSG criteria. In 67% of patients (n = 31) HDCT/ASCT was performed as first salvage treatment in relapse or for primary refractory disease following first line chemotherapy. In 46% of patients (n = 21) progressive disease was documented after mobilization and prior to HDCT/ASCT. Median progression free survival (mPFS) was 7.4 months (95% confidence interval (CI): 1.3–13.6) while median overall survival (mOS) was 22.2 months (95% CI: 8.9–35.5). When stratified for IPFSG risk group, mPFS (p < 0.001) and mOS (p = 0.009) differed significantly between risk groups (very low vs. low vs. intermediate vs. high vs. very high). Metastases to liver/bone/brain and platinum refractory disease were independent risk factors for inferior PFS (p = 0.024; p = 0.008) but not OS.Materials and MethodsForty-six patients treated with HDCT/ASCT at the university clinics in Heidelberg and Nuremberg between 2000–2016 were identified and analyzed. Data was collected retrospectively.ConclusionsHDCT/ASCT offers a potential curative strategy for patients with relapsed GCT. Improvement is still needed in patients with intermediate, high, and very high IPFSG risk group.

Outcomes of Stage I-II Squamous Cell Carcinoma of the Oral Tongue Managed With Surgery Including an Elective Nodal Dissection: Potential Indications for Postoperative Radiation Therapy

Patients with pathologic T1-2N0 oral tongue squamous cell carcinoma (OTSCC) are considered “low risk” and typically do not receive adjuvant treatment. We sought to characterize the outcomes of patients managed with surgery alone, their recurrence patterns, and any prognostics factors predictive of recurrence and/or survival. We retrospectively reviewed the records of 84 consecutive patients with newly diagnosed, early-stage pT1-2N0 OTSCC who underwent partial glossectomy and ipsilateral elective neck dissection from 2007-2013 at our institution. Patients who received PORT were excluded as well as those who had positive margins, pathological nodal involvement, or a history of prior or synchronous head and neck primaries. The cohort was 60% male and was comprised of 62% pT1 and 65% grade 2-3 tumors. Of the patients, 51% were current or former smokers. Median age was 58.5 (range: 20-87 years). With a median follow-up of 58 months (range: 3-131 months), 13 (16%) patients developed a relapse. The site of first relapse was isolated local in 5 patients, isolated regional in 2 patients, and combined locoregional in 6 patients. No patients developed a distant recurrence, either isolated or combined, at the time of first relapse. Regional recurrences were ipsilateral in 75% and contralateral in 25% of patients. Overall, the 5-year rates for local control (LC), regional control (RC), locoregional control (LRC), disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS) were 89%, 91%, 86%, 80%, 93%, and 87%, respectively. Pathologic T2 status was a predictor for worse outcomes across all endpoints. Perineural invasion (PNI) was a predictor for worse RC (P=.04), DSS (P=.001), and OS (P=.001). Margin ≤2 mm was a predictor for worse LC (P=.0001) and PFS (P=.0011). Nine of the 49 (18%) patients with depth of invasion (DOI) ≥4 mm suffered locoregional relapses (LRR). Of the 5 patients with pT2 and PNI, 2 (40%) developed isolated regional relapses. Of the 24 patients with pT2 and DOI ≥4 mm, 5 (21%) had regional failures. Patients who developed neck recurrences experienced a significantly worse DSS (5-year: 38% vs 100%; P<.0001) and OS (5-year: 38% vs 92%; P<.0001) compared to those who did not. All relapses underwent further salvage treatment; 8 (62%) patients were successfully salvaged with no evidence of disease at last follow-up. At our institution, patients with early-stage, pT1-2N0 OTSCC exhibited relatively low rates of LRR and good overall prognosis. Regional relapse, however, significantly impacts OS adversely. Patients with pT2 disease who have PNI and/or DOI ≥4 mm appear to be at considerable risk of regional relapse and should be counseled regarding PORT. When feasible, wider margins >2 mm should be obtained surgically.

A randomized study on a 3-month versus a 7-month prednisolone regimen for the initial episode of childhood idiopathic nephrotic syndrome at a large Saudi center.

Background and objectivesThe standard International Study of Kidney Disease in Children (ISKDC) regimen of prednisolone of 2 months duration for the treatment of the initial episode of Idiopathic Nephrotic Syndrome (INS) was associated with a high relapse rate. The long prednisolone protocols were introduced in order to reduce the relapse rate and steroid toxicities. The main objective of this study was to assess the efficacy and safety of a 3 months protocol of prednisolone versus a 7 months protocol for the first episode of idiopathic nephrotic syndrome.Design and settingThe study took place in the Pediatric Nephrology Department of King Saud Medical City, Riyadh which is a large referral center all over Saudi Arabia. The study was a randomized control trial using 2 groups. Group A received the 3 months protocol and Group B received the 7 months protocol.Patients and methodsAll children with a confirmed diagnosis of Idiopathic Nephrotic Syndrome were included. The patients were randomized by simple randomization using sealed envelopes into two groups; group A comprised of 60 children using the daily regimen prednisolone 60 mg/m2 OD X 1 ½ months then 40mg/m2 on alternate day for 1 ½ months (total = 3 months) and group B also comprised of 60 children using the 7 months protocol, Prednisolone 60mg/m2 OD x 1 month then 40mg/m2 EOD x 2 months then 30mg/m2 EOD for 2 months then 20mg/m2 EOD for 2 months. The efficacy and safety of these two prednisolone regimens were recorded. The follow-up period was two years. Statistical analysis was done using the SPSS progress version 16 (Chicago, USA) P < .05 was taken as a significant result. Consort guidelines for randomized controlled trials (RCTs) were followed. The hospital ethical committee approved the study. The parents gave an informed consent.ResultsGroup B protocol was found to be significantly better than the group A protocol in both years of follow-up. The mean time of first relapse was significantly better in group B than in group A (P < .0001). The relapse rate reduced significantly in group B vs group A in both the first year (P = .0031) as well as in the second year (P = .00002). The cumulative dose of steroids was significantly less in group B vs group A both in the first year of follow-up (P = .0039) as well as in the second year (P = .0026). The incidence of frequently relapsers was significantly less (P = .049) in group B as compared to group A. The risk of relapse was better in group B as compared to group A (RR 0.8039; 95% CI 0.6566 to 0.9843 significance (P = .0346). The side effects of corticosteroids were significantly less in group B protocol as compared to group A.ConclusionWe concluded that the long 7 months protocol was significantly better than the 3 months prednisolone regimen in both efficacy and safety for the initial episode of childhood INS.

Carfilzomib, Cyclophosphamide and Dexamethasone (KCD) Versus Bortezomib, Cyclophosphamide and Dexamethasone (VCD) for Treatment of First Relapse or Primary Refractory Multiple Myeloma (MM): First Final Analysis of the Phase 2 Muk Five Study

Carfilzomib, Cyclophosphamide and Dexamethasone (KCD) Versus Bortezomib, Cyclophosphamide and Dexamethasone (VCD) for Treatment of First Relapse or Primary Refractory Multiple Myeloma (MM): First Final Analysis of the Phase 2 Muk Five Study

Prognostic Model to Predict Post-Autologous Stem-Cell Transplantation Outcomes in Classical Hodgkin Lymphoma

Purpose Our aim was to capture the biology of classical Hodgkin lymphoma (cHL) at the time of relapse and discover novel and robust biomarkers that predict outcomes after autologous stem-cell transplantation (ASCT). Materials and Methods We performed digital gene expression profiling on a cohort of 245 formalin-fixed, paraffin-embedded tumor specimens from 174 patients with cHL, including 71 with biopsies taken at both primary diagnosis and relapse, to investigate temporal gene expression differences and associations with post-ASCT outcomes. Relapse biopsies from a training cohort of 65 patients were used to build a gene expression-based prognostic model of post-ASCT outcomes (RHL30), and two independent cohorts were used for validation. Results Gene expression profiling revealed that 24% of patients exhibited poorly correlated expression patterns between their biopsies taken at initial diagnosis and relapse, indicating biologic divergence. Comparative analysis of the prognostic power of gene expression measurements in primary versus relapse specimens demonstrated that the biology captured at the time of relapse contained superior properties for post-ASCT outcome prediction. We developed RHL30, using relapse specimens, which identified a subset of high-risk patients with inferior post-ASCT outcomes in two independent external validation cohorts. The prognostic power of RHL30 was independent of reported clinical prognostic markers (both at initial diagnosis and at relapse) and microenvironmental components as assessed by immunohistochemistry. Conclusion We have developed and validated a novel clinically applicable prognostic assay that at the time of first relapse identifies patients with unfavorable post-ASCT outcomes. Moving forward, it will be critical to evaluate the clinical use of RHL30 in the context of positron emission tomography-guided response assessment and the evolving cHL treatment landscape.

Moderate/severe Depression (MADRS) Can Affect the Quality of Life and Outcome Among Patients Admitted to Breast Cancer Diagnosis Unit.

The Montgomery-Asberg Depression Rating Scale (MADRS) is one of the most widely used examiner rating instruments for screening, diagnosis and measuring the severity of depression. However, the long-term predictive value of the MADRS in patients admitted to the breast cancer diagnosis unit (BCDU) is unknown. In the Kuopio Breast Cancer Study women with breast symptoms were evaluated for the total MADRS score before any diagnostic procedures. The relapse-free survival (RFS) was calculated from the time of diagnosis to the time of first relapse including local relapse, contralateral breast cancer (BC) or metastatic disease. The overall survival (OS) was assessed as the time from the date of diagnosis to the date of last follow-up or death of the patient. The effect of the MADRS on the RFS and on the OS were calculated by Kaplan-Meier survival analysis and the difference between groups was assessed by the log-rank test. The RFS and OS were estimated for the study groups with the low MADRS score (<25) versus the high MADRS score (≥25). The end-point of our study was to determine differences in long-term outcome and in MADRS score in breast cancer (BC), benign breast disease (BBD) and healthy study subjects (HSS). In the Cox proportional hazard model the total MADRS score significantly predicted the 25 year RFS and OS in the HSS, BBD and BC groups combined (HR=2.26, p=0.006; HR=2.46, p=0.008, respectively), and in the Kaplan-Meier survival analysis with the log-rank test the total MADRS score predicted the 25 year RFS and OS in the HSS, BBD and BC groups combined (p=0.005; p=0.006, respectively). The moderate/severe depression (MADRS) can affect the quality of life and outcome among patients admitted to the BCDU.

Beck Depression Inventory as a Predictor of Long-term Outcome Among Patients Admitted to the Breast Cancer Diagnosis Unit: A 25-year Cohort Study in Finland.

The Beck Depression Inventory (BDI) is one of the most widely used instruments for measuring the severity of depression. However, there has been no prospective study to investigate the long-term outcome in patients admitted to Breast Cancer Diagnosis Units. In the Kuopio Breast Cancer Study, women with breast symptoms were evaluated for total BDI score before any diagnostic procedures were carried out. The relapse-free survival (RFS) was calculated from the time of diagnosis to the time of first relapse including local relapse, contralateral breast cancer (BC) or metastatic disease. The overall survival (OS) was assessed as the time from the date of diagnosis to the date of last follow-up or death of the patient. The effect of the BDI on the RFS and on the OS were calculated by the Kaplan-Meier survival analysis and the difference between the groups was assessed by the log-rank test. The RFS and OS was estimated for the study groups with a low BDI score (<8) versus those with a high BDI score (≥8). The end-point of our study was to determine differences in long-term outcome and in BDI score in individuals with BC, benign breast disease (BBD) and in healthy study subjects (HSS). In the Cox proportional hazard model, the total BDI score significantly predicted the 25-year RFS and OS in the HSS, BBD and BC groups combined (Hazard Ratio=1.87, p=0.039; Hazard Ratio=1.98, p=0.048, respectively), and in the Kaplan-Meier survival analysis with the log-rank test, the total BDI score predicted the 25-year RFS and OS in the HSS, BBD and BC groups combined (p=0.043; p=0.036, respectively). The BDI is a significant predictor of long-term outcome among patients admitted to the Breast Cancer Diagnosis Unit in Finland.

A Phase I/II Study of Vaccination By Autologous Leukemic Apoptotic Corpse Pulsed Dendritic Cells for Elderly Acute Myeloid Leukemia Patients in First or Second Complete Remission (LAM DC trial)

Introduction: A number of approaches have been explored to prevent relapse in AML setting, including immune-strategies such as dendritic cells (DC) vaccination. There is no report so far of the use of autologous apoptotic leukemic cells as a source of tumor antigen for DC vaccine.Methods: The main objective of this prospective monocentric Phase I/II study was to explore the feasibility to produce autologous leukemic apoptotic corpse-pulsed DC for elderly AML patients in first or second complete remission (CR) and to report the toxicity of such a vaccine. Inclusion criteria were AML (except promyelocytic) patients older than 59 years with a good performans status (ECOG <=2), not eligible for allogeneic transplantation or another trial, with >=50% of leukemic blasts in bone marrow (BM) or peripheral blood, and with no contra-indications to apheresis. Vaccines were produced by Nantes UTCG according to good manufacturing practices for cell and gene based therapies in order to comply to the French AFSSAPS (currently ANSM) agency guidelines. Patients had to be pre-included (refractory or not) at diagnosis or at time of first relapse in order to collect sufficient leukemic cells (>2.4 108) prior to chemotherapy after 1 or 2 days of collection. After blasts collection, the choice of chemotherapy regimen was at the discretion of the investigator. Few courses of chemotherapy were allowed before vaccine production but not after. Patients were definitively included only in case of CR to allow collecting autologous non-leukemic peripheral monocytes by apheresis to generate the DC vaccine. Patients were programmed to receive up to 5 doses of vaccine (days +1 +7 +14 +21 and +35 +2) which consisted of 10 millions pulsed DC, including 9 millions administered subcutaneously (1 mL) and 1 million administered intradermally (0.1mL). Minimal residual disease (MRD) was studied after vaccines using flow cytometry.Results: Between November 2009 and March 2015, 23 patients were pre-included but 2 patients were excluded for analyses because blast collection was finally not performed. Thus, overall, 21 elderly AML patients (male n=14; median age: 74 years (range: 65-84), secondary AML n=8) were considered either at time of diagnosis or at time of first relapse. The median % of BM blasts was 63% (range: 20-92), including 3 and 4 cases with less than 40% and between 40-49%, respectively (protocol deviation). Although it was not the case for one patient with >50% of BM blasts, all patients between 40-49% of BM blasts reached the threshold of 2.4x108blasts required for the study. Two patients out of 3 with less than 40% BM blasts had insufficient blast collection to pursue the protocol. After blast collection, the majority of patients (n=19) received non-intensive chemotherapy. 5/21 (24%) cases achieved CR, a rate that was expected for this very old population. All of CR patients could proceed to apheresis after 2 (n=4) or 4 (n=1) courses of non-intensive consolidation. Production of the 5 vaccines was possible for all of them and first infusion was made at a median of 25 days (range: 20-28) from the apheresis. However, a median of 27 vaccines (range: 8-85) could have been theoretically produced in CR patients, suggesting the possibility to realize a longer maintenance therapy to prevent relapse in the future.All patients received as expected the 5 vaccines and no adverse events were documented. Durations of response from CR were: +8.5, +8, +4.5, +4, +12 months and from first vaccine: +5.5, +4.5, +1.8, +1.8, and +9 months. Two patients had relapsed before day+55. At this time, the 3 other patients were documented with negative MRD. In July 2016, 2 patients are still alive, 1 at +30 months from CR in relapse and 1 at +13 months in CR. The 3 other cases died of relapse at +15.5, +8 and +5.5 months from CR. The median OS from pre-inclusion was significantly higher for vaccinated CR patients (13 months (9-41) vs 4.75 months (1-24), p=0.009).Conclusion: Our strategy seems promising for elderly AML patients achieving CR in terms of relapse prevention. Vaccine production is reproducible and compliant for clinical use. Larger Phase 2 studies are required to confirm our results in younger and older AML population. The trial is registered at Clinicaltrials.gov NCT01146262. This study was supported by a grant from the French National Cancer Institute. DisclosuresMoreau:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria; Takeda: Honoraria; Amgen: Honoraria.

Efficacy of Brentuximab-Vedotin (BV) in Peripheral T-Cell Lymphomas (PTCLs) Other Than Anaplastic Large Cell Lymphoma (ALCL)

Background. BV, an anti-CD30 antibody-drug conjugate, has been approved for the treatment of Hodgkin lymphoma (HL) and ALCL. Of interest, BV has shown activity in PTCLs other than ALCL that express low or even undetectable levels of CD30. In particular BV has been reported effective in angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma not otherwise specified (PTCL-nos). Here, we report 4 cases with relapsed/resistant PTCLs (1 AITL, 1 NK-T nasal type, 1 PTCL with T-helper follicular phenotype-PTCL-TFH and 1 PTCL-nos) who responded to BV therapy.Results. On August 2014, a 53-y-old caucasian male was diagnosed with 5% CD30-positive AITL. The final stage was IIIA, because of a single left axillar node was documented at the PET-TC scan in addition to the excised inguinal lymphadenopathy. A complete metabolic PET remission (PET-CR) was documented after the 3th and confirmed after the 6th cycle of cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone (CHOEP). However, relapsing disease was documented 6 mths later. At that time, diffuse over and under-diaphragm nodal involvement was observed. A PET-CR was achieved after 2 cycles of dexamethasone, cytarabine, and cisplatin (DHAP), but disease progressed shortly after the 4th cycle before the planned autotransplantation (ASCT). A 3th line chemotherapy, consisting of mitoxantrone and high dose ARA-C (modified HAM), was performed and failed to control the disease. Furthermore HAM chemotherapy was associated with severe infectious complications (sepsis from MDR S. Epidermidis and pulmonary aspergillosis). On December 2015, BV was begun. A PET-CR was documented after the 4th and confirmed after the 8th cycle of therapy. The patients is still in CR, in continuous therapy (12th cycle), waiting for HLA matched unrelated donor.On July 2012 a 62-y-old caucasian man was diagnosed with extranodal NK/T-cell nasal type lymphoma. Both Epstein Barr virus (EBV) and CD30 molecule were not expressed by neoplastic cells. Weekly cisplatin and radiotherapy were concomitantly given followed by 3 cycles of etoposide, ifosfamide, cisplatin and dexamethasone. This treatment resulted in PET-CR. At the time of first relapse (Nov 2013), 3 cycles of methotrexate, L-asparaginase and dexamethasone, followed by ASCT (fotemustine, etoposide, cytarabine, melphalan), induced a 2nd PET-CR. However, two subsequent PET evaluations suggested the presence of active disease shortly after (December 2015) a biopsy proven relapse was documented. A PET-CR was observed after 2 and confirmed after 7 cycles of single agent BV. The patient is still undergoing treatment.On September 2015, a 49-y-old african man was diagnosed with PTCL-THF, showing AITL signs, with both EBV and CD30 positive (50-75%) Hodgkin/Reed-Sternberg cells. A progressive disease was documented after the 4th cycle of CHOEP. At that time, patient was not candidate to receive further chemotherapy, because of worsening of perfomance status (PS). BV, given as salvage therapy, resulted in a rapid control of all signs and symptoms after the 6th administration. Because of improved PS and a partial metabolic remission, the DHAP combination was begun on June 2016 and ASCT is now planned as consolidation.On November 2009, a 46-y-old caucasian man was diagnosed with classical HL. The final stage was IEA. The disease was refractory to doxorubicin, bleomycin, vinblastine, dacarbazine and radiotherapy. A PET-CR was achieved in response to ifosfamide, gemcitabine, vinorelbine and prednisone chemotherapy. After 3 yrs, a lymph node biopsy confirmed a relapsed HL. Four cycles of DHAP followed by ASCT resulted in a 2nd PET-CR. After 3 mths, a PTCL-NOS associated with blastic lymphoid B EBV positive cells was diagnosed on an excisional lymph node biopsy. On May 2014 BV as single-agent was started. A PET-CR lasted for 8 mths. Relapsing disease was documented on January 2015. The patient refused further chemotherapy and died because of disease progression on July 2015.Conclusion. In this experience BV, regardless of CD30 expression, has shown significant clinical activity in recurrent or refractory T-cell lymphomas and no significant toxicity, even in heavily pretreated patients. In consideration of the BV activity in PTCLs, combination studies with other molecules, such as romidepsine, are desirable. DisclosuresNo relevant conflicts of interest to declare.

Single Centre Experience in Treating Newly Diagnosed t(4;14) Multiple Myeloma with and without Planned Front-Line Autologous Stem Cell Transplant

Introduction: The optimal management of multiple myeloma (MM) patients (pts) with t(4;14) is not certain. Before the introduction of novel agents, the progression-free (PFS) and overall survival (OS) outcomes with autologous stem cell transplant (ASCT) were disappointing (median PFS 9.9 months [mos]; Chang H, et al. Bone Marrow Transplant 2005;36:793). Subsequently, early experience with bortezomib (btz) in relapsed myeloma showed its efficacy in t(4;14) disease, and led to the prospective Canadian trial of 12 cycles of btz-based therapy (DBD = Doxorubicin + btz + dexamethasone) x 4, followed by CyBor-P (Cyclophosphamide + btz + prednisone) x 8 and then dexamethasone maintenance, without planned ASCT, in newly diagnosed pts with this cytogenetic abnormality by FISH (Reece D, et al; Blood 2010;116: abstract 1968). After completion of this trial, particularly with the absence of provincial funding for long-term upfront btz, we adopted a standard approach of btz-based induction followed by ASCT. We now report the results of newly diagnosed t(4;14) pts treated at our centre with these 2 approaches. Methods: We analysed consecutive patients with newly diagnosed MM harbouring t(4;14), who were transplant-eligible and treated at Princess Margaret Cancer Centre with btz-based therapy between July 1, 2006 and June 30, 2014. Patients lost to follow-up (F/U) before completion of front-line treatment or transferred to another centre after first-line treatment were excluded. Statistical analyses were performed using IBM SPSS version 20. Results: A total of 58 patients were analysed with a median F/U of 41.5 mos. The median age at diagnosis was 56.5 years, and 62.1% were male. Concomitant del(17p) was noted in 10.3% of the patients. Thirty-two of these pts (Group A) were enrolled onto the prospective phase II study described above; the other 26 pts (Group B) received the subsequent standard of care, which involved btz-based induction (usually CyBor-D) for 4-6 months, followed by planned ASCT. Amongst these 26 patients, 11 received single ASCT, 13 received tandem ASCT and 2 failed to respond to btz-based induction. The only significant difference in pt characteristics between these 2 groups was a higher median haemoglobin level in group A (116 g/L vs 106 g/L; p=0.003). The median OS was 54.7 months for Group A and 47.6 months in Group B (HR = 1.095, p = 0.817). Median PFS for Group A was 24.2 months and was 30.0 months for Group B (HR = 0.874, p = 0.680). No difference in OS and PFS was noted between those who received single and tandem ASCT as planned front-line treatment (OS HR = 1.105, p = 0.895; PFS HR = 1.723, p = 0.317). Amongst those in Group A, 25 patients have relapsed to date. Eight received single ASCT, 6 received tandem ASCT, and 11 received chemotherapy only as salvage therapy. In Group B, 15 patients have relapsed, and 11 of these went on to receive lenalidomide-based salvage treatment. The PFS and OS from the time of first relapse in this group of relapsed patients in Group A was similar between those who received ASCT as front-line treatment in Group B (median PFS 12.5 vs 11.1 months, p = 0.842; median OS 27.5 vs 21.6 months, p = 0.985). Amongst those who relapsed in Group A, those who received salvage ASCT had a better PFS and OS from the time of relapse than those who did not received salvage ASCT (median PFS 22.4 vs 1.7 months, p Conclusions: Newly diagnosed MM pts with t(4;14) treated with btz-based therapy with or without ASCT as part of first-line therapy have a median OS in the range of 4-4.5 years; 2) the use of ASCT at some time point in the course of t(4;14) disease is likely beneficial; 3) however, there was no obvious benefit for tandem ASCT as part of initial or salvage therapy in this analysis, although we cannot exclude an effect of pt bias in the ability to perform 1 or 2 ASCT; 4) the integration of an IMiD, particularly lenalidomide, in more pts either in combination with btz or as maintenance therapy, may have improved the outcome but was not available for all pts in this analysis; 5) as observed in other centres, the co-existence of del 17p and t(4;14) identifies a particularly high risk group of MM pts. Disclosures Chen:Takeda: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Kukreti:Amgen: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria. Prica:Janssen: Honoraria; Celgene: Honoraria. Tiedemann:Celgene: Honoraria; Janssen: Honoraria; BMS Canada: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Takeda Oncology: Honoraria. Trudel:Celgene: Honoraria; Glaxo Smith Kline: Honoraria, Research Funding; Oncoethix: Research Funding; Novartis: Honoraria. Reece:Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Research Funding; BMS: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Time to Relapse in Children with Crohn's Disease Treated with Azathioprine and Nutritional Therapy or Corticosteroids.

The duration of remission has been shown to be longer in patients initially treated with exclusive enteral nutrition (EEN) compared to corticosteroids (CS). However, no published studies required concurrent immunomodulator [6-mercaptopurine or azathioprine (AZA)] use at the time of diagnosis. The aims of this retrospective study were to compare the duration of remission between patients initially treated with AZA in combination with CS or EEN and identify predictors of early relapse in these patients. Data from 65 newly diagnosed children with CD in clinical remission on either EEN or CS and commencing AZA at diagnosis were included. We compared duration of remission using physician global assessment and carried out Cox regression analysis to identify predictors of early relapse. Patients were followed up to the time of first relapse or for at least 12months. There were no differences in the duration of remission between patients initially treated with EEN or CS (p=0.978). We identified younger age at diagnosis [hazard ratio (HR) 0.87, 95 CI 0.78-0.98, p=0.016], lower height Z score at diagnosis (HR 0.61, 95 CI 0.44-0.85, p=0.003), involvement of the upper gastrointestinal tract (HR 2.69, 95 CI 1.27-5.66, p=0.009), and elevated platelet count at remission (HR 1.004, 95 CI 1.001-1.008, p=0.021) as independent predictors of early relapse. Neither induction regime demonstrated longer duration of remission of CD in patients treated with immunomodulators since the time of diagnosis.

Nelarabine Alone or in Combination in High Risk Childhood / Adolescent and Young Adults (AYA) T- Cell Acute Lymphoblastic Leukemia

▪Introduction: T-cell acute lymphoblastic leukemia (T-ALL) represent 15-20% of childhood/adolescent young adults (AYA) ALL. An intensive chemotherapy is generally needed to obtain the same results than in B-lineage ALL. Day 8 Poor Prednisone Response (PPR) and early resistant disease (refractoriness after induction course or MRD level >10-3 at time point 1 (TP1) and/or TP2) remain particularly challenging as relapses are very difficult to treat especially if they occur early. Nelarabine is a water-soluble prodrug of araG (9-B-arabinofuranosylguanine) which is cytotoxic to T lymphoblasts due to the accumulation of araG nucleotides, especially araGTP, which result in inhibition of ribonucleotide reductase and inhibition of DNA synthesis. Nelarabine was shown to be effective and safe in phase II-III adult and pediatric ALL trials. We describe here a 7 consecutive years experience of nelarabine in “real life” in 3 pediatric / AYA centers.Methods: All children and AYA who received nelarabine in first line therapy or after relapse between 2006 and 2013 were reviewed retrospectively. Classical initial prognostic factors were collected: age, leucocytosis, CNS status, day 8 prednisone response, complete remission (CR) or not, minimum residual disease (MRD) level at TP1 and TP2. Eighty two % of the patients (pts) followed the French FRALLE 2000-T recommendations. Nelarabine, alone or in combination, was used in two groups of pts: group 1: pts in whom nelarabine is given in first line therapy because of high MRD level >10-3 at TP1 and/or TP2 (whatever the level at time of nelarabine infusion) and pts refractory to induction course, and group 2: pts in relapse. Group 1 and 2 are compared for MRD level after nelarabine, number of patients able to go to allogeneic HSCT and overall survival. Finally the safety profile was assessed.Results: 33 T-ALL patients received nelarabine alone (n= 22) or in combination (n= 11, most often with cyclophosphamide and etoposide) from 2006 to 2013. At initial diagnosis, median age was 11.6 y old [3-24], sex ratio 4.5 (M/F 27/6) and median leukocytosis 184.7.109/L [0.1-914]. These patients shared poor risk factors: CNS3 (n=8, 24.1%), D8 PPR (n=23, 69.7%), day 21 M3 bone marrow (n=13, 36.4%), no CR after one induction course (n=6, 18.2%) and MRD level > 10-3 at CR1 (n=15, 42.4%). Regarding group 1 (high MRD level at TP1 and/or TP2 n= 11, refractoriness to induction course n= 5), the status just before nelarabine was: 6 in CR1 with finally MRD <10-3, 5 in CR1 but MRD >10-3 and 5 refractory. Nelarabine was given alone in 12 patients and in combination in 4 patients. MRD level after nelarabine was <10-3 in 12/16 patients. Overall, 11 pts received an allogeneic HSCT and 13/16 (81%) are alive in CR1 at the time of the analysis with a median FU from first nelarabine infusion of 13.7 months [0.8-58.3]. Overall survival is 79.8%+/-10.5 at 5 years. Regarding group 2 (relapsed patients, n= 17), nelarabine was infused at the time of first relapse in 4 patients and in refractory first relapse or more than first relapse in 13 patients. Among these heavily pretreated patients, only 6 obtained a MRD level <10-3 leading to allogeneic HSCT but none of 6 survived. Only one patient survived in CR3 after a success of nelarabine alone and received other chemotherapy without allogeneic HSCT. Regarding toxicities, the only WHO grade III-IV observed side effects are cytopenias (n= 25, 75.8%). Others reported side effects are limited (grade I-II): fever of undetermined origin or infections (n= 7, 21.2%), neurological (n= 6 pts, 18.2%; some of them with more than one side effect: sensory neuropathy in 4, motor neuropathy in 2, headaches in 2, motor-facial neuropathy in 1, ataxia in 1) or muscular (n= 4, 12.1%; 2 myalgia, 1 myositis, 1 amyotrophia), liver toxicities (n= 4, 12.1%; 3 transaminase increases, 1 hyperbilirubinemia).Conclusions: In a non selected population of childhood / AYA high-risk T-ALL, nelarabine was very useful for poor risk patients in first line therapy. The majority of patients received nelarabine as a monotherapy. By contrast nelarabine mostly failed to improve the survival in heavily pretreated relapsed patients. Overall, this study conforts the use of nelarabine in first line T-ALL and high-risk features with acceptable tolerance. The evaluation of nelarabine in selected high-risk patients in a first line setting should be evaluated prospectively to confirm these results. DisclosuresBaruchel:JAZZ: Membership on an entity’s Board of Directors or advisory committees; ARIAD: Membership on an entity’s Board of Directors or advisory committees; Seattle Genetics: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees.

Salvage Therapy for Multiple Myeloma with Lenalidomide-Based Regimens: Impact of Single Nucleotide Polymorphisms Related to miRNA Pathways

Introduction: Multiple myeloma (MM) remains an incurable disease for most patients. Thus, sequential therapy when relapse or progression after first line is almost always needed. Immunomodulatory agents derived from thalidomide such as lenalidomide, has several antitumoral effects including anti-proliferative and immune-modulation by binding the intracellular protein cereblon. Lenalidomide has been approved for the treatment of relapsed or refractory MM in Europe and USA. The possibility of using biological predictors of response with this regimen could be promising. A group of genetic normal variations in DNA, mainly single nucleotide polymorphisms (SNPs), have been described in association with response to treatment in MM. A distinctive group of polymorphisms is constituted by SNPs in microRNAs (miRNA) processing machinery in miRNA precursor molecules and in miRNA binding sites, known as miRSNPs, that we have associated with response to autologous transplantation and bortezomib. The aim of this study was to ascertain the outcome of patients with relapsed myeloma treated with lenalidomide in a tertiary hospital as to investigate the prognostic impact of 9 miRSNPs located either in MM related miRNAs target genes or in miRNA biogenesis pathway proteinsMethods: One hundred and three patients (54M/49F; median age 65 years, range 30 to 86) with relapsed MM after at least one treatment regimen were treated from November 2003 to January 2014 with lenalidomide plus dexamethasone. Median follow-up for alive patients was 3 years. Patients had received a median number of 2 treatment lines (range 1 – 6), but with no lenalidomide-based regimens.Genomic DNA was isolated from bone marrow slides using a commercial kit (Qiagen). The genes and SNPs evaluated in genomic DNA by allelic discrimination (TaqMan assays) were KRT81 (rs3660), FAM179b (rs1053667), MIR146A (rs2910164), MIR196A2 (rs11614913), MIR149 (rs2292832) and MIR423 (rs6505162) for miRNA target genes, and RAN (rs14035), TRBP (rs784567) and XPO5 (rs11077) for miRNA biogenesis pathway. These genes were selected based on their potential impact on prognosis in solid tumors in previous reports.Results: Overall response (OR) was achieved in 55.4% of the patients (complete remission 6.8%, partial response 40.8% and minor response 7.8%), while 16 (15.5%) and 26 (25.2%) showed no response (NR) or progressive disease (PD), respectively. 4 patients (3.9%) died before response could be evaluated. The median progression-free survival (PFS) after lenalidomide therapy was 8.1 months (95% CI 7.3 to 8.9), with a median overall survival (OS) of 2.3 years (95% CI 1.5 to 3.2). OS was significantly shorter in those patients not reaching at least MR (1 vs. 3.7 years; p<0.0001). Six patients did not progress during the first 5 years of treatment: two have died for unrelated causes; two progressed biologically but no requiring further treatments and the remaining two are in continued response while on therapy. Only 8 responding patients (7.8%) in whom therapy with lenalidomide was discontinued received re-treatment with lenalidomide at progression.OS was significantly longer in patients with SNP in FAM179b (p=0.041) (Figure 1) and MIR196A2 (p=0.01) (Figure 2), with a trend for MIR149 (p=0.117). In the two first SNPs, there were also a significant impact in PFS after lenalidomide regimen (p=0.024 and p=0.018). Interestingly, these miRSNPs have not shown the same impact as previously reported when autologous transplantation or bortezomib are used, where XPO5 is the crucial gene. Other factors associated with longer OS included lenalidomide at first relapse vs. subsequent lines (p=0.002), IgG isotype (p=0.044), normal serum LDH (p=0.032) and a trend for creatinine lower than 2 mg/dL (p=0.08) at diagnosis. In a multivariate analysis for OS, only the use of lenalidomide at first relapse (HR 2, 95% IC 1.04-3.9; p=0.039) and SNP in MIR196A2 (HR 1.86, 95% IC 1.03-3.4; p=0.04) remained at significant level.Conclusions: Lenalidomide plus dexamethasone is a very active regimen when used in daily clinical practice, particularly at the time of first relapse. A small subgroup of patients can remain disease-free for more than 5 years. Some SNPs in miRNA target genes (FAM179b and, particularly, MIR196A) could be useful as potential predictors of response. [Display omitted] DisclosuresFernández de Larrea:Celgene: Consultancy, Honoraria. Cibeira:Celgene: Consultancy, Honoraria. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Jiménez:Janssen: Honoraria. Bladé:Janssen: Grant support Other, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Grant support, Grant support Other, Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Outcome in Unselected Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) Following R-CHOP When Stem Cell Transplantation Is Not Feasible

Introduction: While R-CHOP has improved survival for DLBCL, outcome in patients (pts) with relapsed/refractory disease remains dismal and may have worsened since the introduction of immunochemotherapy. High-dose chemotherapy and stem cell transplantation (SCT) offers the best chance of secondary cure, but the majority of patients are ineligible due to age, co-morbidities or disease refractory to salvage chemotherapy. Novel agents will address this unmet medical need; however, their impact is difficult to assess without a reliable historical comparator. Herein, we evaluate the outcome in an unselected population with relapsed/refractory DLBCL following R-CHOP in whom SCT is not feasible.Methods: The BC Cancer Agency Lymphoid Cancer Database was used to identify all pts diagnosed with de novo DLBCL between Dec 2000 to Jan 2013 who were treated with curative intent R-CHOP and subsequently progressed or relapsed. Patients were excluded if they were HIV positive, had CNS involvement at diagnosis, PMBCL, composite/discordant histology or transformed lymphoma. Clinical information at baseline and at relapse/progression was compiled. Overall survival (OS) from relapse was calculated from the date of 1st relapse/progression to death or last follow-up. Progression-free survival (PFS) from relapse was defined as interval from 1st relapse/progression to the date of 2nd relapse, initiation of next line of therapy, death or last follow-up.Results: 379 pts with relapsed/refractory DLBCL were identified. 53 underwent SCT and were excluded from analysis. The remaining 326 (274 SCT-ineligible and 52 SCT-eligible pts who did not receive SCT due to toxicity or chemo-refractoriness) were analyzed. Response to primary treatment was: 44% CR; 20% PR; 2% SD; 34% PD. 174 (53%) were primary refractory (progression during or within 3 mos of primary R-CHOP). Median time from diagnosis to first recurrence was 7.8 mos (range 0 – 116). Patient characteristics at relapse: median age 70 y (range 21-93); 55% male; 59% elevated LDH; 58% ECOG PS >1; 55% stage III/IV; 18% >1 extra-nodal site; 53% IPI score at relapse > or = 3. 14 (4%) relapsed with an indolent histology only and 74 (23%) exhibited CNS involvement at relapse (54 isolated, 20 concurrent systemic). Treatment at initial relapse: 78 supportive care; 77 radiotherapy (RT) alone; 2 single agent rituximab (for indolent relapse); 168 (R)-chemo +/- RT (79 single agent, 89 multi-agent). (R)-GDP was the most commonly used multi-agent regimen (75%). 1 pt had missing information. Median follow-up for living pts from the time of first relapse was 3 y. Median OS and PFS from relapse for the entire cohort were 3.9 and 2.1 mos, respectively. Outcome was worse for pts with primary refractory disease (median OS 2.5 mos, median PFS 1.7 mos). On multivariate analysis elevated LDH, ECOG PS >1, Stage III/IV and primary refractory status were independent predictors of OS and PFS from relapse. Pts who relapsed > 2 y from diagnosis had a better median OS and PFS from relapse (11 mos and 5.7 mos, respectively). Excluding pts with CNS involvement, pts who received chemo +/- RT (median OS 6.1, median PFS 3.1 mos) or RT alone (median OS 5.7, median PFS 3.3 mos) had a marginally better outcome. Disease control was similar between pts who received multi-agent vs single agent chemotherapy (median PFS 3.3 vs 2.9 mos). Median OS and PFS from relapse for the 74 pts with CNS involvement were 3.3 mos and 2.2 mos, respectively; this was similar compared to the entire cohort. Outcome was also similar between those with isolated CNS recurrence and concurrent systemic disease but 10 pts with isolated CNS relapse survived > 2 yrs. The 14 pts with indolent histology-only relapse had a significantly better outcome (median OS 36 mos, median PFS 12 mos).Conclusion: The outcome in pts who relapse or progress following R-CHOP is exceedingly poor with standard therapy, with median OS less than 4 mos. Pts who receive treatment at initial relapse fare slightly better, but this may reflect more favorable pt characteristics. Disease control was equivalent for multi-agent vs single agent treatment. While CNS relapse is a rare event in DLBCL, a high proportion of relapsed/refractory pts have CNS disease. The presence of CNS disease did not negatively impact outcome, as outcome was dismal in the entire cohort. Novel treatments are greatly needed and these survival estimates may serve as a comparator to assess their benefit. [Display omitted] [Display omitted] DisclosuresSavage:F Hoffmann-La Roche: Research funding to support BCCA Lymphoid Cancer Database Other. Villa:F Hoffmann-La Roche: Other. Shenkier:F Hoffmann-La Roche: Research funding to support BCCA Lymphoid Cancer Database Other. Gerrie:F Hoffmann-La Roche: Other. Klasa:F Hoffmann-La Roche: Other. Connors:F Hoffmann-La Roche: Other. Sehn:F Hoffmann-La Roche: Research funding to support BCCA Lymphoid Cancer Database Other.

P07.03 * RECURRENT MEDULLOBLASTOMA AND CNS PNET IN ADULTS - RESULTS OF VIP CHEMOTHERAPY

INTRODUCTION: Medulloblastoma and central nervous system (CNS) primitive neuroectodermal tumor (PNET) are rare embryonal brain tumors in adults. Surgery and radiotherapy are an important part of the initial treatment, however, the role of (neo)adjuvant chemotherapy or chemotherapy at relapse is still unclear. In our center, etoposide/ifosfamide/cisplatin (VIP) chemotherapy is the standard of care for patients with a first relapse of medulloblastoma or CNS PNET. We reviewed the outcome in a consecutive series of patients treated with VIP chemotherapy at first relapse in our center between 2004 and 2012. MATERIALS AND METHODS: Patients were treated with 3 weekly cycles consisting of etoposide 75 mg/m2 d1-5, ifosfamide 1200 mg/m2 d1-5, and cisplatin 20 mg/m2 d1-5, followed by pegfilgrastim 6 mg s.c. d6, for a maximum of 4 cycles. We assessed toxicity using the CTCAE version 4 criteria (CTC), response, progression-free survival and overall survival measured from the day of start of chemotherapy. RESULTS: Twelve adult patients diagnosed with medulloblastoma (n = 6) and CNS PNETs (n = 6) were treated. The median age at first diagnosis was 34.6 years. After resection of the tumor eleven patients received craniospinal radiotherapy with a boost on the primary tumor site(n = 11); One patient received craniospinal radiation only because of adverse side effects. One patient had been treated with (neo)adjuvant chemotherapy (vincristine/carboplatin/cyclophosphamide) at the time of first diagnosis. The median time from diagnosis until time of first relapse was 18.5 months. At start of VIP, the median performance score was WHO 1. Nine patients were treated with the maximum number of 4 cycles VIP, in 3 patients VIP was stopped prematurely because of progressive disease (PD). Grade 3-4 CTC adverse effects were described in 8 patients: thrombocytopenia (n = 6); anemia (n = 6); leukopenia (n = 4); neutropenia (n = 4), and ototoxicity (n = 2). Three patients showed a partial response (PR) after VIP, 5 patients showed stable disease (SD) and 4 patients PD. After treatment with VIP chemotherapy median progression-free survival (PFS) was 5.3 months (medulloblastoma 10.5 months; CNS PNET 4.3 months) and median overall survival (OS) was 7.5 months (medulloblastoma 27 months; CNS PNET 5.3 months). These differences are not significant. Five of all patients (42%) were still alive one year after receiving VIP therapy. CONCLUSION: The results of this study underline the poor prognosis of adult patients with recurrent medulloblastoma or CNS PNETs. VIP chemotherapy accomplishes a disease stabilization or response in 75% of the patients but of short duration. There is a trend showing a better response to VIP therapy in medulloblastoma patients compared to CNS PNETs.

Predictors of response to infliximab in paediatric perianal Crohn's disease.

It is reported that 27-54% of paediatric patients with perianal Crohn's disease (CD) do not respond to infliximab (IFX). To identify predictors of response to IFX in paediatric perianal CD. A retrospective cohort study of 101 paediatric patients treated with IFX between 2000 and 2011 for perianal CD in 22 French hospitals of the GETAID pédiatrique network was performed. Response was monitored after induction therapy and at 1 year. Complete response was defined by closure of all fistulas and complete healing of ulcers. Associations between baseline characteristics and (i) 1-year response and (ii) time of first relapse among initial responders were tested by logistic regression and Cox model respectively. Eighty-nine patients (88%) responded to induction therapy (36 partial/53 complete). At 1 year, 76 patients (75%) were responders (22 partial/54 complete). Predictors of 1-year response were: number of fistulas ≤1 (OR: 3.76, 95% CI: 1.20-11.77, P = 0.03) and baseline Harvey-Bradshaw index <5 (OR: 3.72, 95% CI: 1.10-12.60, P = 0.03). Predictors of relapse among initial responders were: CD duration <10 months (OR: 3.31, 95% CI: 1.34-8.19, P = 0.0097) and number of fistulas >1 (OR: 2.79, 95% CI: 1.12-6.95, P = 0.028). Combined therapy with an immunomodulator was not associated with 1-year response or time of relapse. Those patients with perianal Crohn's disease have better outcomes if they have less fistulas, a low baseline Harvey-Bradshaw Index or a longer duration of Crohn's disease.

Peripheral blood lymphocyte/monocyte ratio at the time of first relapse predicts outcome for patients with relapsed or primary refractory diffuse large B-cell lymphoma.

BackgroundDespite the use of modern immunochemotherapy regimens, a significant proportion of diffuse large B-cell lymphoma (DLBCL) patients will relapse. We proposed absolute lymphocyte count/absolute monocyte count ratio (ALC/AMC ratio) as a new prognostic factor in relapsed or primary refractory DLBCL.MethodsWe retrospectively analyzed 163 patients who have been diagnosed with relapsed or primary refractory DLBCL. The overall survival (OS) and progression-free survival (PFS) were measured from the time of first relapse. The Cox proportional hazards model was used to evaluate ALC/AMC ratio as prognostic factors for OS and PFS.ResultsOn univariate and multivariate analysis performed with factors included in the saaIPI, early relapse, prior exposure to rituximab and autologous stem-cell transplantation (ASCT), the ALC/AMC ratio at the time of first relapse remained an independent predictor of PFS and OS (PFS: P < 0.001; OS: P < 0.001). Patients with lower ALC/AMC ratio (<2.0) had lower overall response rate, 1-year PFS and 2-year OS rate compared with those with higher ALC/AMC ratio (≥2.0). Moreover, the ALC/AMC ratio can provide additional prognostic information when superimposed on the saaIPI.ConclusionsLower ALC/AMC ratio at the time of first relapse is a adverse prognostic factor for OS and PFS in relapsed or primary refractory DLBCL, and leads to the identification of high-risk patients otherwise classified as low/intermediate risk by the saaIPI alone.

Central Nervous System Relapse In Adults With Acute Lymphoblastic Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation

▪ IntroductionCentral nervous system (CNS) recurrence after allogeneic hematopoietic stem cell transplantation (HSCT) confers a poor prognosis in adult patients with acute lymphoblastic leukemia (ALL). Preventing CNS recurrence after HSCT remains a therapeutic challenge, and criteria for post-HSCT CNS prophylaxis have not been addressed. Our goal was to investigate the post-HSCT outcome of ALL patients and identify patient groups who may benefit from post-HSCT CNS prophylaxis. MethodsIn this two-center retrospective study, we studied all adult (age≥18) ALL patients who underwent HSCT at MD Anderson Cancer Center or Fred Hutchinson Cancer Research Center between 1997 and 2011. We included all adult ALL patients who were transplanted in the first or second complete remission (CR) and who received any prophylactic or therapeutic CNS therapy before HSCT. We assessed the cumulative incidence of systemic and CNS relapses in a competing risks framework with a competing risk of non-relapse death. Since data from second and subsequent relapses were not available, patients whose first relapse did not include CNS involvement were censored at the time of relapse. To analyze the association between post-HSCT CNS prophylactic therapy and CNS relapse, we used a landmark analysis, including only patients who had not relapsed or died by 3 months post HSCT. ResultsWe included 415 adult ALL patients (239 in CR1 and 176 in CR2) who were transplanted with a myeloablative total body irradiation based (MA-TBI, n=252), myeloablative non-TBI based (MA-nonTBI, n= 130), or reduced intensity conditioning regimen (RIC, n=33). Median age at HSCT was 37 years (range 18-70; 59% male). Sixty seven patients (16%) had a history of pre-HSCT CNS involvement either at diagnosis or at time of first relapse, while 339 patients (81%) had no CNS disease at any time before HSCT. Overall 175 patients (42%) received CNS prophylaxis after HSCT. CNS prophylaxis included intrathecal methotrexate, cytarabine, or both agents. Two patients received prophylactic cerebrospinal radiotherapy.The median follow-up for the 189 surviving patients was 4.2 years. Sixteen patients (3.8% of all patients, 13.2% of all relapses) developed CNS relapse (11 isolated and 5 combined with marrow relapse) at a median of 231 days (range 38-1397) after HSCT. Seven of these patients had pre-HSCT CNS disease. The 4-year cumulative incidence of relapse after HSCT among all patients was 31.7% and 28.2% for patients with and without CNS prophylaxis after HSCT, respectively (P=0.51). The 4-year cumulative incidence of CNS relapse was 6% and 2.6% for patients with and without CNS prophylaxis after HSCT, respectively (P=0.16) (Figure 1). When the analysis was limited to the patients without prior CNS involvement, there was still no benefit to post-HSCT CNS prophylaxis (P=0.63). Patients with a prior history of CNS involvement with leukemia had a significantly higher rate for CNS relapse, 11.6% vs. 2.7% (P=0.003) (Figure 2). The 4-year rate of CNS relapse was not impacted by intensity of the HSCT conditioning regimen and was 3%, 4%, and 6.5% for RIC, MA-TBI, and MA-nonTBI, respectively. ConclusionCNS relapse is an uncommon event following HSCT for ALL in CR1 or CR2. Furthermore, neither the intensity of the HSCT conditioning regimen nor the routine use of post-HSCT CNS prophylaxis made a significant difference in the rate of post-HSCT CNS relapse in patients who had received CNS prophylaxis prior to HSCT. Not surprisingly, patients with a pre-HSCT history of CNS involvement had a significantly higher risk of CNS relapse after HSCT. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Phase III Trial Of Bortezomib, Melphalan, and Prednisone (VMP) Versus Bortezomib, Thalidomide, and Prednisone (VTP) In Elderly Multiple Myeloma (MM) Patients: Update Follow-Up, Patterns Management Of First Relapse/Progression

BackgroundInitial results of the Spanish GEM2005mas65 phase III trial comparing VMP versus VTP as induction therapy in elderly patients with newly diagnosed MM did not show any difference in terms of OS or PFS. The purpose of this study was to update clinical results with a longer follow-up. Secondary objectives were to know the patterns of symptomatic relapse and response to therapy in patients previously exposed to novel agents. MethodsGEM2005mas65 trial lasted from March, 2006, and October, 2008. Overall, 260 patients with untreated MM, 65 years and older, from 63 Spanish centres, were randomly assigned to receive six cycles of VMP (n=130) or VTP (n=130) as induction therapy followed by maintenance therapy with bortezomib plus prednisone (n=87) or bortezomib plus thalidomide (n=91). ResultsWith a median follow-up of 53.2 months, median OS of the entire cohort of patients was 42.45 months. Median OS was 62 months in patients receiving VMP versus 42.6 months in patients receiving induction with VTP (P = 0.045) (Figure 1). No differences were observed in PFS, being 31 and 24.4 months in the VMP and VTP groups, respectively.At the time of the study, 167 patients had relapsed or progressed and 92 of them received some kind of post relapse treatment. Front-line therapy and clinical and biological characteristics at the time of relapse in this subgroup of patients are summarized in Table 1.Initial induction treatment consisted of VMP in 40 (43.4%) patients and VTP in 52 (56.5%) patients. Overall, after induction and maintenance therapy 66 (71.7%) patients had been exposed to bortezomib and thalidomide and 26 (28.2%) patients received bortezomib-based therapy without immunomodulatory agents before relapse.At symptomatic relapse, median age was 74 years (range 65-87) and 43 (46.7%) were male. Serum creatine level > 2 mg/dL was present in 11.9% of the patients and 4.3 % had hypercalcemia. Extramedullary disease and plasma cell leukemia was present in 17% and 4.4% of patients, respectively. Finally, severe bone disease was observed in 39 the patients.Management of relapse was very heterogeneous. Subsequent drugs used in first clinical relapse included lenalidamide combinations in 40 (43.4%) patients, bortezomib-based therapy in 19 (20.5%) patients, different chemotherapy combinations in 25 (27.1%) patients and bendamustine-prednisone in 2 (2.1%) patients. Six (6.5%) patients received only supportive at time of first relapse. Overall, 45 (52%) patients achieved partial response or better after rescue therapy. Response rates were higher after lenalidomide-based therapy (62.5%) when compared with bortezomib (42.1%) and conventional chemotherapy-based regimens (40.7%),although this difference did not translate into significant PFS advantage.After a median follow-up of 16.4 months (range 0-50.2) from clinical relapse,58 (63%) patients had died. Median PFS and OS were 10 (CI95%; 10.7-50.2) and 15.6 months (CI95%; 8.5-16.5%), respectively. In patients initially treated with VMP (n = 40) and VTP (n =52) median survival from start of subsequent therapy was 15.6 and 15.4 months, respectively. Among characteristics at relapse, only ISS stage had an impact on survival (P= 0.03).There was no difference in OS or PFS from front-line induction and/or maintenance therapies or salvage therapy. ConclusionsThis updated analysis of the GEM2005mas65trial shows a survival advantage of the VMP arm when compared with patients receiving VTP. Patterns of relapse were similar regardless previous induction and maintenance therapy. Finally, and when analyzing the subgroup of patients receiving active therapy at relapse, only ISS stage seemed to have a prognostic impact on OS. [Display omitted] Group A: VMP, group B : VTD Disclosures:Mateos:Janssen, Celgene, Onyx, Millennium, Mundipharma: Honoraria. Oriol:Celgene: Consultancy. Off Label Use: Bendamustine, bortezomib and prednisone is a combination not approved for newly diagnosed myeloma patients.

Skeletal-Related Events In Patients With Multiple Myeloma In The Era Of Novel Agents: Low Incidence Of Pathological Fractures After Treatment

Skeletal-related events (SREs) which include pathological fractures, spinal cord compression (SCC) and a need for radiotherapy or surgery to bone are frequent complications of multiple myeloma (MM). Although, the frequency and characteristics of SREs in MM patients who received conventional chemotherapy (CC) or thalidomide-based regimens along with bisphosphonates (BPs) have been described, there are no data available in the era of proteasome inhibitors or novel IMiDs. Thus, we retrospectively evaluated the records of 400 consecutive patients with symptomatic MM (207M/193F, median age: 63 years) who were diagnosed, treated and followed in a single center. All patients had a whole body skeletal survey using conventional radiography at diagnosis and then at the time of relapse or whenever clinically indicated, while MRI of the spine and pelvis at diagnosis was available for 223 patients. Furthermore, we tested 125 patients for SNPs in genes that are involved in the biology of bone destruction: LRP5 (rs4988321), GC vitamin D (rs4588), TNFRSF11A (rs3018362), DKK1 (rs1569198), RANKL (rs9594759), OPG (rs6469804) and ERS1 (rs1038304).At diagnosis, the skeletal survey detected osteolytic disease in 284 (71%) patients. In MRI, 34.5% of the patients had focal, 40.5% diffuse, 21% normal, and 4% a variegated pattern of marrow involvement. SREs were observed in 167 (41.7%) patients at diagnosis: 104 (26%) patients presented with pathological fractures (87 with vertebral fractures, 18 with rib fractures and 17 with fractures of the long bones; 22 patients had both vertebral and long bone or rib fractures), while 22 (5.5%) patients required surgery to bone, 21 (5.2%) radiotherapy and 20 (5%) patients presented with SCC. The incidence of SREs was higher in patients with osteolytic lesions (49.5% vs. 24%, p<0.001) or abnormal MRI pattern (49.7% vs. 23.3%, p=0.001). However, we noted that approximately 1/4 patients without lytic lesions in plain X-rays or with normal MRI pattern presented with a SRE at diagnosis. Patients homozygous for RANKL polymorphism had lower incidence of osteolysis at diagnosis (14/28, 50%) versus all others (76%, p=0.009), suggesting that this polymorphism may protect bone loss in MM, as it has been suggested for normal population.Frontline therapy with IMiD-based regimens was given in 172 (43%) patients, while 80 (20%) patients received bortezomib-based regimens, 111 (27.7%) both IMiD and bortezomib (VTD or VRD) and 37 (9.2%) patients CC. BPs were given in all but 86 patients (21.5%) at diagnosis, mainly due to renal insufficiency; however, almost 60% of them (n=51) received BPs later in the course of their therapy. The vast majority (91%) of patients received zoledronic acid (ZA). Due to renal impairment, ZA was discontinued in 6 patients, while the dose was reduced in 44. During first line treatment, 7 (1.75%) patients developed a SRE: 2 on bortezomib- and 5 on IMiD-based regimens. The rate of SREs was higher in patients who did not receive upfront BPs (4.7% vs. 1%; p=0.021).The median follow-up was 39 months. At the time of first relapse (data available for 176 patients), 3 patients presented with fractures and 35 patients required local radiotherapy to bone (SRE incidence: 21.6%). Patients who had received only bortezomib-based regimens (VD or VCD, n=20) had lower SRE rate (2/20, 10%) vs. all others (36/156, 22%, p=0.173); the 3 patients with fractures had received MPT (n=2) or RD (n=1). In total, during the course of their disease, 52.8% of the patients presented with at least one SRE. Presentation with SREs at diagnosis did not predispose for SREs during the disease course, regardless of anti-myeloma treatment, possibly due to the low number of fractures and the higher number of radiation needed after frontline therapy.In summary, our data from the first systematic report on the incidence and characteristics of SREs in the era of novel agents indicate that SREs remain a significant complication in MM. Importantly, despite high response rates after first line therapy more than 20% of patients required radiotherapy at the time of relapse. The fracture rate was very low during first line therapy and at first relapse probably due to the extensive use of potent BPs and bortezomib, which has bone anabolic effects. The use of modern imaging techniques (i.e. PET/CT or LDWBCT) that can detect bone masses earlier and lead to earlier initiation of treatment may reduce the SRE incidence in the near future. Disclosures:No relevant conflicts of interest to declare.