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It has been proven that model predictive control (MPC) is an efficient method for closed-loop insulin delivery in clinical studies. This paper aims to design an observer-based fractional-order nonlinear MPC for type 1 diabetes mellitus (T1DM) patients. It is assumed that the proposed model is nonlinear and contains parametric uncertainty. To estimate unknown states, optimal non-fragile H∞ observer is designed for Lipschitz nonlinear fractional-order systems including parametric uncertainty and the existence of input disturbance. The min–max optimization-based robust fractional model predictive control (RFMPC) has been presented in the following for insulin delivery. Since sensor noise of continuous monitoring of interstitial glucose concentration is considered non-Gaussian, the performance of the proposed controller is improved under non-Gaussian measurement noise by selecting a proper cost function based on generalized correntropy, and as a contrast, the performance of the mean square error (MSE)-based controller is simulated. According to the results, not only is the performance of the proposed controller better under non-Gaussian situations but also effectively reaches the set point in the case of disturbance and uncertainty and provides higher control accuracy and robustness compared with the MSE-based MPC.

Autologous hematopoietic stem cell transplantation (AHCT) for relapsed/refractory aggressive non-Hodgkin lymphoma (NHL) results in long-term disease-free survival in 40-50% of patients. The incidence of and risk factors for second cancer development in these patients have not been well studied. We analysed 372 patients with relapsed/refractory aggressive NHL who underwent AHCT from 1987 to 2006. Median age at AHCT was 50 years (range 19-70). Most patients (74%) received two chemotherapy regimens before transplant. High-dose chemotherapy consisted of etoposide and melphalan in 95% of patients and 16% received total body irradiation. Thirty-two patients (9%) developed a second cancer (19 hematologic, 13 solid tumors). The probability of second cancer at 3 and 10 years post-AHCT was 4.4% and 12.9%, respectively. When compared with the general population, the relative-risk of acute myeloid leukemia and new solid tumor was 13.2 (p < 0.0001) and 2.3 (p = 0.0013). Salvage therapy using mini-BEAM was significantly associated with second cancer development (p = 0.004). In conclusion, second cancers are a significant cause of late morbidity and mortality patients treated with AHCT with curative intent, and appear increased in patients exposed to mini-BEAM chemotherapy.

Abstract 1217 Poster Board I-239 Background Single autologous stem cell transplant (ASCT) is considered the standard of care after induction therapy for younger multiple myeloma (MM) patients (pts). However, it is not curative and virtually all patients will ultimately relapse. As more options are available to treat relapsed disease, the role of a second ASCT as salvage therapy is unclear. Method Retrospective review of all MM pts who received a 2nd ASCT as salvage therapy at Princess Margaret Hospital. Results Between February 1997 and July 2009, 79 MM pts received a second ASCT for relapsed MM at our institution. Median age was 60 yrs (range 39-72) at second transplant. 48 pts (61%) were male. Immunoglobulin subtype included IgG (42), IgA (21), light chain (11), nonsecretory (3), IgM(1) and IgD (1). Transplant conditioning regimen for first transplant was high dose melphalan (MEL) 140-200 mg/m2 in 67, busulphan and cyclophosphamide in 1, and combinations of MEL with etoposide (E) or TBI in the rest. 2nd ASCT conditioning consisted of MEL alone in 76, the remaining 3 had MEL with either TBI or E. The median time to relapse after the first transplant was 2.72 years (0.81-8.26), with a median interval between transplants of 3.61 years (1.63-9.59). Response to first transplant in 78 evaluable patients was 13 CR/nCR (17%), 56 PR/VGPR (72%), 9 MR/SD (12%). Nineteen pts received maintenance therapy between transplants. Two transplant-related deaths occurred following 2nd ASCT. In 73 evaluable patients, response to second transplant was 11 CR/nCR (15%), 57 PR (78%), 6 MR/SD (8%). After 2nd ASCT, with median follow up 5.92 years (71 months), median progression-free survival (PFS) was 18.5 months and median overall survival (OS) was 4.4 years. Long term progression-free status based on the progression-free interval after 1st ASCT is summarized Table 1. PFS based on progression free interval after 1st ASCT is outlined in Figure 1. Conclusions 2nd ASCT is a feasible and safe salvage therapy in relapsed MM patients. It is effective in providing a median progression free survival of 18.5 months and median overall survival of 4.4 years (52.8 months) after 2nd ASCT. This is comparable if not better than modern salvage chemotherapies. The longer the disease free interval after 1st ASCT the more effective 2nd ASCT is at extending both progression free survival and overall survival. It is reasonable, therefore, to consider a 2nd ASCT if the time to progression is greater than 2 years after first ASCT. Disclosures Chen: Celgene: Honoraria, Research Funding; Ortho Biotech: Honoraria. Trudel:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria. Kukreti:Celgene: Honoraria.

BACKGROUND: Post transplant lymphoproliferative disorder (PTLD) is the commonest malignancy associated with pharmacologic immunosuppression after organ transplantation. Reduction in immunosuppression (RI) is a common initial strategy, but many pts require systemic therapy (ST) because of rapid disease progression. We evaluated the treatment and outcome of PTLD at a large multi-organ transplant programme to examine prognostic factors and predictors of outcome with RI and ST. METHODS: Patients (pts) were identified from the UHN Multi Organ Transplant Database and the Cancer Registry at Princess Margaret Hospital. Pts were included if they had a pathologic diagnosis of PTLD and adequate information to assess response to treatment. Variables evaluated for their influence on response to treatment and survival included age, organ transplanted, pathology, CD20+, time to PTLD from transplant, organ dysfunction, EBV+ lymphoma, stage, extranodal disease, B symptoms, CMV infection prior to PTLD, and LDH. RI was defined as a trial of „□10 days of reduction or discontinuation of calcineurin inhibitor (CNI), reduction or discontuation of mycophenolate mofitel or azathioprine and maintenance prednisone, with or without surgical resection of all known disease with repeat imaging to assess response. (Paya, Transplantation68(10):1517, 1999). Chemotherapy consisted of CHOP or equivalent regimens. Rituximab was given as a single agent 375 mg/m2 weekly ×4 doses. RESULTS: 80 pts were identified; 3 pts were excluded from the current analysis for a diagnosis of marginal zone lymphoma (2) or primary body cavity lymphoma (1). Of the 77 pts included 53 (69%) were males. 66% (51) of pts had monomorphic PTLD (44 diffuse large B cell lymphoma, DLBCL), 31% (24) had polymorphic PTLD, 3 (2%) pts had Hodgkin lymphoma-like PTLD; 79% were EBV positive by in-situ hybridization. Organ transplanted: liver 34 (44%), kidney 22 (29%), lung 16 (21%), heart 5 (7%). Fifty percent of pts presented with stage III/IV disease, 81% with extranodal disease, 52% with B symptoms and 69% with an elevated LDH. Initial therapy: RI 43 pts, chemotherapy 31 pts, RI + rituximab 1 pt, surgical resection and re-transplantation 1 pt. For those treated with RI, extent of reduction of CNI did not influence response rate, overall survival (OS) or rate of organ rejection. Overall response rate to RI was 74%; only CD20 expression on the lymphoma was associated with a higher rate of response (p=0.026). Inclusion of antiviral therapy (generally gancyclovir) reduced the risk of relapse in those responding to RI (p=0.026). Response to RI did not vary by time to PTLD diagnosis from transplantation (p=.355), however, the rate of relapse following RI was significantly higher in pts developing PTLD >1 year from transplantation (p=.017). OS in pts undergoing RI as initial treatment was 73% at 3 yrs and 66% at 5 yrs. Nine pts received single agent rituximab, either with RI or because of progression after RI; 4 of the 9 pts responded, and 3 are progression-free. Of the 31 pts treated with primary chemotherapy, 24 had a CR or PR (78%); 4 pts died of toxicity (13%). OS of pts undergoing chemotherapy as initial treatment was 62% at 3 yrs and 58% at 5 yrs. Pts who received RI +/− rituximab followed by chemotherapy for lack of response or relapse had no significant difference in OS compared to those who received frontline chemotherapy (p=0.36). Evidence of graft rejection during treatment was seen in 13 pts (30%) treated with first line RI, compared to 6 (19%) in pts treated initially with chemotherapy. The rate of graft loss was low in both groups at 7% (3) in the RI group and 3% (1) in the chemotherapy group. Median follow up of survivors is 92 months. Overall survival (OS) for the entire cohort was 110 months (95% CI: 67.6, 152.7). Investigation of independent variables affecting OS revealed that organ dysfunction at diagnosis was significantly associated with shorter survival (p=.028). CONCLUSIONs: The outcome of pts with PTLD managed with initial RI is similar to those receiving ST; however the latter is toxic and there are no reproducible variables predicting response to RI as primary treatment. OS is similar in pts receiving RI followed by ST, versus those that received first line chemotherapy, suggesting that a delay in ST for a trial of RI may be justified. Prospective controlled trials of antiviral therapy and the timing and addition of rituximab and chemotherapy are still needed to improve patient outcome and guide future therapy.

ASCT results in long-term disease free survival for approximately 40–50% of patients (pts) with relapsed−/− refractory aggressive NHL who respond to second-line chemotherapy. The incidence of second cancers (SC) in long-term survivors and risk factors in this pt population has not been well studied. We performed a retrospective analysis of 372 pts undergoing ASCT at our institution from May 1987 to Dec 2006 for relapsed−/− refractory aggressive NHL after primary therapy. Second-line chemotherapy was given to best response, followed by high dose therapy for pts with chemotherapy-sensitive disease. Intensive therapy was melphalan 180mg/m2 + etoposide 60mg/kg in 86%; regimens including total body irradiation (TBI) 12 Gy were received in 16%. Stem cell source: autologous bone marrow (27%), peripheral blood (63%) or both (10%); 7% received post-ASCT involved field RT to sites of bulky disease. Estimates of SC risk were determined adjusting for competing risks. The incidence of SC was compared to the general population in Ontario from 1987 to 2002. Of 372 pts, 59% had diffuse large B cell lymphoma, 24% transformed from prior indolent NHL, 16% T cell lymphoma, 1% undefined aggressive NHL. Median age at ASCT was 50 years (range 19–70); female 44%. The majority of patients (74%) received 2 chemotherapy regimens prior to ASCT (range 1–8); all pts with de novo DLCL received CHOP or equivalent regimen as primary therapy. For first salvage therapy cytarabine/platinum combinations were used in 205 (55%) pts, miniBEAM (melphalan, etoposide, cytarabine, BCNU) in 40 (11%), gemcitabine/dexamethasone/cisplatinum in 37 (10%); CHOP or equivalent was used in 42 pts (11%). Median follow up is 4.3 years and 27/185 (15%) have been followed more than 10 years. 184 pts (49%) have experienced disease relapse and 32 (9%) have developed a SC (17 MDS/AML, 13 solid tumors, 1 chronic lymphocytic leukemia and 1 acute lymphoblastic leukemia). During the follow up period 187 (50%) patients have died (126 from relapsed lymphoma, 30 from treatment-related toxicity, 14 from second cancer, 5 unrelated medical condition, 7 unknown). The probability of SC is 5% (95% CI: 3%-8%) 3 years post-ASCT and 14% at 10 years (95%CI: 10%-20%). Age at ASCT, sex, receipt of TBI, number of chemotherapy regimens, prior RT, graft source and lymphoma subtype were not associated with development of a second malignancy. Use of miniBEAM as part of salvage therapy was significantly associated with the development of a second cancer (p=0.001). The incidence of malignancy in survivors of ASCT is 32 per 1180 person years of follow-up. When compared to the general population (AML and solid tumors only) the relative risk (RR) for developing AML or a solid tumor is 13.5 (p

Background: Single autologous stem cell transplant (ASCT) is considered the standard of care for younger multiple myeloma (MM) patients (pts). However, it is not curative and virtually all patients will ultimately relapse. As more options, such as biological therapy, are available to treat relapsed disease, the role of a second ASCT as salvage therapy is unclear. Method: Retrospective review of all MM pts who received a 2nd ASCT as salvage therapy at Princess Margaret Hospital. Results: Between February 1997 and June 2007, 61 MM pts received a second ASCT for relapsed MM at our institution. Median age was 56 yrs (range 35–71) at second transplant. 37 pts (61%) were male. Immunoglobulin subtype included IgG (36), IgA (14), light chain (6), nonsecretory (3), IgM(1) and IgD (1). Transplant conditioning regimen for first transplant was high dose melphalan (MEL) 140–200 mg/m2 in 51, MEL/etoposide(E)/TBI in 4, and MELl/TBI in 2. 2nd ASCT conditioning consisted of MEL + TBI +/− E in 2, MEL alone in 58 and Busulfan/Cyclophosphomide in 1. The median time from diagnosis to first transplant was 9.7 months (2.0–74.2). The median time to relapse after the first transplant was 32.6 months (9.7–85.6), with a median interval between transplants of 45.1 months (19.7– 115). Two transplant-related deaths occurred (3%). Response to first transplant was 4 CR (8%), 34 PR (68%), 2 MR (4%) and 10 SD (20%). Nineteen pts went on to maintenance therapy between transplants. Response to second transplant was 4 CR (8%), 41 PR (80%), 5 SD (10%) and 1 PD (2%). Median progression-free survival (PFS) was 15.8 months (0–63.8) while median overall survival (OS) was 4.2 years (0–7.0) after 2nd ASCT. The relationship between progression-free interval after 1st ASCT and the outcome of the 2nd ASCT is summarized Table 1. Patients can be stratified into two groups, those with a disease free interval of less than or greater than 24 months. The use of maintenance therapy did not differ between the two groups, 6 (40%) in patients with PFS ≤24 months and 13 (28%) in patients with PFS >24 months. Conclusions: 2nd ASCT is a feasible and safe salvage therapy in patients with relapsed MM. 2nd ASCT is effective in providing a median progression free survival of 1.25 years and median overall survival of 4.2 years after 2nd ASCT - results that compare favourably with other salvage approaches. Patients with a longer disease free interval after 1st ASCT experience a better progression free survival and overall survival after 2nd ASCT. It is reasonable, therefore, to consider a 2nd ASCT if the time to progression is greater than 2 years after first ASCT. Outcomes Based on Time to Progression Post 1st ASCT PFS post 1st ASCT # of pts median PFS post 2nd ASCT PFS post 2nd ASCT1 Median OS post 2nd ASCT OS post 2nd ASCT2 1 p< 0.005, 2 p< 0.05 ≤24 months 15 12.7 months 1 year: 46% 3.5 years 1 year: 85% 2 year: 11% 2 years: 76% 3 years 0% 3 years: 63% 4 years: 31% > 24 months 46 19.8 months 1 year: 74% 5.9 years 1 year: 91% 2 year: 45% 2 years: 82% 3 year: 31% 3 years: 65% 4 years: 55%

BACKGROUND: Multiple myeloma (MM) only occurs in 2% of patients under the age of 40. It has been reported that this young cohort of patients have a superior overall survival when compared to those over the age of 40. OBJECTIVE: To evaluate the clinical and laboratory features of patients ≤40 years of age at diagnosis of MM and to compare survival outcomes to patients >40 years of age. METHODS: Retrospective institutional review of all patients ≤40 years of age at time of diagnosis of MM that had underwent upfront ASCT at PMH from January 1, 1990 to July 31, 2007. Outcomes were compared to patients >40 years of age who had also undergone ASCT as upfront therapy. RESULTS: 37 patients ≤40 years of age were identified. Twenty patients were male. Immunoglobulin subtype was as follows: 49% had IgG, 19% light chain,16% IgA, 8% IgD, and 5% IgG plasma cell leukemia. The main presenting clinical feature was bone pain (63%). 73% had radiological evidence of bony disease at diagnosis and 53% of these patients required radiation prior to ASCT. Clinical features included anemia in 81%, renal insufficiency in 39% and hypercalcemia in 28%. Conditioning regimens for ASCT were high dose melphalan (200mg/m2) alone in 25 pts, VP-16 & melphalan +/− TBI in 8 pts, bleomycin & cyclophosphamide in 3 pts, and in 1 pt it was unknown. Median time to engraftment of neutrophils (>0.5 x 109/L) and platelets (>20 x 109/L) was 11 days (range 8–18) and 12 days (range 0–54), respectively. Median duration of hospitalization was 17 days (range 10–54). No treatment related mortality was experienced. Response to ASCT was as follows in 29 evaluable pts: CR in 10 (34.5%), PR in 13 (44.8%), MR in 1 (3.4%), SD in 3 (10.3%), and PD in 2 (6.9%). Five patients underwent a tandem ASCT. Maintenance therapy was instituted in 11 pts. Median progression free survival (PFS) post ASCT was 23.0 months, which is similar to the PFS of 28.5 months in patients over 40 (p=0.559). There was also no difference in median overall survival (OS) from date of ASCT between the two groups (6.6 years in pts ≤40, 6.7 years in pts >40; p=0.797). CONCLUSION: Young patients with MM present with advanced disease as evidenced by anemia, bone involvement and hypercalcemia. ASCT yields high response rates, but PFS post ASCT is less than 2 years. Although young age has been historically been considered to be a positive prognostic marker, OS post ASCT is only 6.6 years, which is equivalent to those >40 years of age. Strategies to better the outcomes of young patients with MM are required.

8120 Background: The standard of care for chemosensitive relapsed or refractory DLBCL is autologous stem cell transplant (ASCT). There is no standard approach for patients (pts) whose disease fails to respond to platinum-based salvage chemotherapy (pSC) although pts who undergo further salvage chemotherapy to demonstrate chemosensitivity may benefit from ASCT (Chen, et al, BMT 2002). We analyzed the overall response rate (ORR) to each line of salvage therapy for pts with relapsed or refractory DLBCL and the impact of the number of salvage regimens necessary to demonstrate chemosensitivity on overall and progression-free survival (OS and PFS) post-ASCT. Methods: We retrospectively reviewed our computerized database and charts between Jan 1/99 - Dec 31/05 and identified 203 pts relapsed after or refractory to anthracycline-based chemo treated with pSC. Pts typically received 2–3 cycles of pSC to assess chemotherapy sensitivity. Responding patients received etoposide 60 mg/kg and melphalan 160 mg/m2 supported by autologous PBSCs. Pts with stable or progressive disease following first line salvage chemotherapy (SC1) were offered alternate non-cross resistant second-line salvage chemotherapy (SC2) and proceeded to ASCT if chemosensitive. Results: Pt characteristics: Median age at time of salvage chemotherapy: 52 years (range 21–65); primary refractory: 48%; advanced stage disease at salvage: 50%; prior rituximab: 17%; prior radiation 26%. 119/203 pts did not respond to SC1, 81 pts received SC2 and 10 pts received 3 salvage regimens (SC3). ORRs to salvage were: SC1: 40%, SC2: 14%, SC3: 10%. Pts able to proceed to ASCT were: SC1: 37%, SC2: 14%, SC3: 0. With a median follow-up of 1.8 years, the 2-year OS post ASCT for the SC1 and SC2 groups was 69% and 56% respectively. The 2-year PFS post ASCT for the SC1 and SC2 groups were 58% and 40%. Conclusions: The ORR to platinum-based SC is low in this cohort of primary refractory/relapsed patients (40%), and only 14% of pts who received SC2 after pSC responded. Although some have prolonged PFS following SC2 and ASCT, additional strategies should be investigated in these patients. No significant financial relationships to disclose.

INTRODUCTION: Results of the randomized Parma trial (Philip, NEJM 1995) demonstrated an overall survival (OS) advantage for patients aged ≤ 60 years who received an autotransplant for relapsed aggressive histology non-Hodgkin lymphoma (NHL). Autologous stem cell transplantation (ASCT) is the standard of care in this setting and trial results have been generalized to include patients up to age 65 years. Earlier results from our group (Gupta ASH 2003 abstract #2720) reported a treatment-related mortality (TRM) of 29% in a group of patients (pts) aged > 60 which included pts who had received bone marrow grafts and TBI-containing high dose therapy. We reviewed our results (overall [OS] and progression-free survival [PFS], TRM and non-relapse mortality (NRM) of ASCT in pts of age > 60 years (older group: OG) and compare these with patients aged ≤ 60 years (younger group: YG). METHODS: We retrospectively reviewed our computerized database and charts between Jan 1st 1986 until June 30th 2006 and identified 289 pts with relapsed or refractory aggressive NHL who underwent ASCT. 30 pts were aged > 60 years and 259 were age ≤ 60. All pts had disease that did not respond to or relapsed after initial anthracycline-based chemotherapy. Responses have been retrospectively assessed using International Workshop Criteria. Pts typically received 2–3 cycles of platinum-based salvage therapy to assess chemotherapy sensitivity; responding pts proceeded to PBSC mobilization and subsequent ASCT. The intensive therapy regimen consisted of high-dose VP16 60 mg/kg day -4 and melphalan 180 mg/m2 day -3 with PBSC infusion day 0. Pts with bulky disease at relapse (> 5cm) received involved field radiation post-ASCT. RESULTS: The median age at the time of transplant was 62 (range 61–66) in the OG vs. 50 (range 19–60) in the YG. Histology was similar in both groups: DLBCL and variants (OG: 63%; YG: 48%), transformed FL (OG: 10%; YG: 16%), MCL (OG: 7%; YG: 13%) (chi square 0.525). Prior chemotherapy was R-CHOP (OG: 23%; YG: 9%), CHOP or CHOP-like (OG: 69%; YG: 72%), chi-square p=0.10. There was no difference in prior radiotherapy (OG:40%;YG:38%, chi square 0.859). Advanced stage disease at relapse was seen in 56% (OG) vs. 44% (YG) (p=0.52 chi-square). Disease response [complete response (OG; 17%; YG:32%, p=0.09) and partial response rate (OG:67%, YG:68%, p=0.92)] pre-ASCT was not statistically different between groups. With a median follow-up of 41 months for OG and 81 months YG pts, the OS post-ASCT was 53% (OG) vs. 65% (YG), (p-value 0.06). Progression-free survival post-ASCT was 40% (OG) vs. 52% (YG), p-value 0.04. TRM was 7% (OG) vs. 3% (YG) (chi-square P=0.310) and NRM was 1% (OG) vs. 3% (YG) (chi square P=0.942). CONCLUSIONS: While the OS between the OG and YG was not significantly different, PFS was inferior in the older pts. This difference was not expected based on available prognostic factors pre-ASCT although full IPI data is not available in all cases. This may suggest other factors related to tumour biology in patients age > 60 may be responsible for inferior PFS. TRM, NRM and OS were not statistically different and this may in part be due to small numbers in the OG. Well-designed prospective trials should address the role of salvage chemotherapy and ASCT in patients with aggressive NHL above the age of 60.

Multiple myeloma (MM) rarely occurs in patients 40 years of age and younger. This young age has been reported to correlate with improved survival in patients with MM. The objective of this study is to describe presenting features and outcomes of patientsor =40 years of age with MM who undergo autologous stem cell transplantation (ASCT) as first-line treatment, and compare overall survival (OS) and progression free survival (PFS) to patients aged 41-65 years. We performed a retrospective institutional review of all patientsor =40 years of age and 41-65 years of age at the time of diagnosis of MM who had undergone upfront ASCT from January 1, 1990, to July 31, 2007. Thirty-eight patientsor =40 years of age and 608 patients aged 41-65 were identified. There was a high rate of plasma cell leukemia (PCL) in young patients at 11% compared to the reported rate of 2%-4%. At diagnosis, there was an increased rate of renal failure in the young cohort compared to patients aged 41-65 years at 25% versus 16% and Bence Jones proteinuria at 81% versus 51%. The rate of complete or partial response was similar between the groups at 79% and 83% in the young and older cohorts, respectively. Median PFS post-ASCT was 22.0 months (95% confidence interval [CI]: 16.1, 28.0), versus 26.9 months (95% CI: 24.0, 29.8) for patients aged 41-65 years (P = .66). Median OS from date of ASCT was also similar to those over 40 years: 68.1 months (95% CI: 39.0, 97.2) versus 80.7 months (95% CI: 68.1, 93.4); P = .90. Treatment-related mortality (TRM) was low at 2.6% and 2.3% in the young and older cohorts, respectively. Despite previous reports that young age is a positive prognostic marker, our study found OS post-ASCT is equivalent to those aged 41-65 years. This study emphasizes the importance of developing strategies to better the outcomes of young patients with MM.