ALBERT

Description: ASCT has been reported as a feasible, safe and effective treatment in HIV associated lymphoma patients (pts) receiving Highly Active Antiretroviral Therapy (HAART). Nevertheless comparative studies with HIV− lymphoma population have not yet been performed. We present a retrospective matched analysis comparing clinical outcomes in both HIV+ and HIV− auto-transplanted HL pts. Patients and Methods: 6 HIV+ HL pts who underwent ASCT since June 2000 were included. Twelve transplanted HIV− HL auto-transplanted pts were selected as controls. Both groups (HIV+ vs HIV−) were comparable for the most relevant clinical features (Mann-Whitney or chi-square tests p value 〉 0.05): median age (40 vs 36), Ann Arbor advanced stage (50% vs 25%), status at ASCT (CR〉1 or PR, 83% vs 75%), all 18 pts received 2 lines of chemotherapy before ASCT. BEAM was used as conditioning regimen in all 18 pts. In the HIV+ group HAART was maintained during mobilization and ASCT, except during the conditioning in 1 Pt, in which it was needed to be resumed due to an increase in viral load. The median number of infused CD34+ cells/kg was 3,65×106 in HIV+ pts and 4,75×106 CD34+ in HIV− pts (p: NS). G-CSF was used in all HIV+ pt until engraftment starting at a median of 5 days (d) after ASCT. Results: All 18 pts engrafted, at a median of 13,5 (9–29) d after ASCT in HIV+ pts and 14 (11–18) d in HIV- pts. The incidence of acute infectious and toxic events was not different in both groups. All pts developed neutropenic fever. Documented infections were (HIV+ vs HIV−): Gram+ bacteraemia (2 vs 3), Gram− bacteraemia (1 vs 0), CMV antigenemia (2 vs 1). Pneumonia was documented in one pt from each group. One HIV+ pt showed grade II liver toxicity and grade II renal toxicity occurred in 1 HIV− pt. All events were succesfully resolved. In 4 out of 6 HIV+ pts, HAART was withdrawn due to gastrointestinal toxicity. The median follow-up time was 36,5 mo in HIV+ pts and 37,5 mo in HIV− pts. Two pts relapsed in each group. Within the HIV+ group 1 pt died, due to disease progression. Within the HIV− group 3 pts died, 2 of disease progression and 1 due to post-ASCT secondary acute leukaemia. The OS at 36 mo was 83% for HIV+ pts and 80% for HIV− pts (p=NS). EFS at 36 mo was 55% in HIV+ pts and 70% in HIV− pt (p=NS). Conclusions: Our results show that clinical outcomes are comparable in HIV+ and HIV− HL pts undergoing ASCT. Engraftment, complication events and survival were not different. ASCT may be applied with guarantees in HIV associated HL on HAART pts in a similar way that in the HIV− setting.

Description: Introduction: Lymphomas continue to be a leading cause of death in HIV-positive patients (HIV+ pts) in the cART era. The aim of this study was to review our 15-year single institution experience in performing Autologous Stem Cell Transplantation (ASCT) for HIV-infected and non-HIV patients with high-risk or relapsed lymphomas, focusing on infectious complications. Patients and Methods: We retrospectively evaluated our cohort of 28 HIV+ pts who underwent an ASCT between 2000-2015, and compared it with a well-matched control group of 39 HIV-negative pts. Patient and ASCT characteristics are described in Table 1. All HIV+ pts were on cART. Chemomobilization was used in 60% of the HIV cohort and 84% of the controls. BEAM conditioning regimen was the most common. All transplants were performed in the same tertiary hospital JACIE-accredited SCT unit. The primary end points were first-year cumulative incidence (CI) of infection, total infectious episodes and infection-related mortality. For the analysis, we defined 3 different time frames: 1st Pre-engraftment; 2nd from engraftment to day +100 and 3rd from day +100 until 1 year after SCT. Events occurring during the first 2 periods were considered early infections as compared to late. Results: All patients received antiviral and anti-PJP prophylaxis, but a significantly higher proportion of HIV+ pts were given antibacterial and antifungal prophylaxis (2/3 vs 1/3 approximately, Table 1). G-CSF support was initiated in all HIV recipients and 66% of controls, and the median days of use was longer for the HIV group (7 vs 4 days, p= 0.04). Median time to neutrophil engraftment was similar in both groups (13 vs 11 days, p=0.55); 93% of HIV pts and all control pts reached ANC 〉 500c/uL by day +30. Infectious episodes (IE) are described in Table 2, divided by pathogen subtype and time frame. Globally, all infection subtypes were more common in the HIV-infected cohort at some point. The most significant findings from the analysis are as follows. CI of early global infections: HIV 75% vs non-HIV 25% (p= 0.04), Figure 1. Median number of global infectious events: HIV 65 vs non-HIV 39 (p= 0.002; OR 1.8 [1.2-2.8]). Bacteria: CI of pre-engraftment and early bacterial infections were not different among groups (42% vs 28%, p= 0.47), but the median number of bacterial episodes was clearly different: HIV 17 vs non-HIV 12 (p= 0.08; OR 2.16 [0.96-4.8]). Fungi: CI of early fungal infections: HIV 10.7% vs non-HIV 0% (p= 0.03); minor infections were not considered. Viruses: CI of early viral infections: HIV 46% vs non-HIV 15% (p= 0.004). Median nº of early viral IE: HIV 19 vs non-HIV 6 (p= 0.007; OR 4.16 [1.43-12]). CI of late viral infections: HIV 30% vs non-HIV 11.7% (p= 0.04). CMV reactivations were by far more common in the HIV cohort (p=0,01). HIV viral load bleeps were documented in 35% of the HIV patients (most commonly in the day +30 control) and one post-transplant virological failure was diagnosed, forcing HAART substitution. Of note, 1st year CI of infection-related mortality was 14% in the HIV group vs 0% in the non-HIV group (p= 0.01), Figure 2. Three HIV+ pts suffered early fulminant septic episodes (1 E. coli + Enterococcus, 1 Rothiamucilaginosa, 1 non-clarified - possible Stenotrophomonasmaltophilia) and a 29-year old woman in CR after a 1st line for a stage IVsB Burkitt-like lymphoma died due to a severe influenza A pneumonia. Length of admission was also significantly longer for the HIV+ pts (median days 34 vs 28, p=0.041). Regarding long-term outcome, median follow up as of July 2016 is 82 months for the HIV+ group and 70 months for the control group: 57% and 61% of the pts in each cohort are still alive, respectively. One HIV-infected pt and 3 controls have been lost to follow-up. EFS: 1 year 71.4% vs 81.9% (ns); 5 years: 63.9% vs 66.5% (ns). Overall Survival: 1 year 75% vs 84% (ns); 5 years 66.3% vs 74.6% (ns). Conclusion: Autologous stem cell transplantation has been proven to be feasible and effective in HIV-related lymphomas, but in our experience and despite great advances in cART and virological control, HIV+ patients are at high risk of infection and this might influence post-ASCT short-term survival. It is mandatory to focus on prophylactic and supportive measures and to choose carefully the optimal timing for transplantation. Table 2 Table 2. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 4355 Little is known about the additional benefit of Autologous Stem Cell Transplantation (ASCT) as consolidation treatment of NHL in 1st CR in HIV+ patients. We herein report a comparative analysis of HIV+ patients with a LBCL treated with chemotherapy (chemo) followed by ASCT and a matched cohort of HIV+ patients treated with chemo alone. Methodology Retrospective, registry-based, matched cohort study. ASCT cohort: patients with diffuse large B-cell (DLBC) or plasmablastic NHL treated with ASCT in 1st CR after standard chemo and reported to the EBMT Registry. Chemo cohort: For each patient within the ASCT cohort we selected two controls from the HIV+ patients with NHL GESIDA/PETHEMA registry. Patients in both cohorts were in 1st CR following front-line or rescue (for partially responding patients) chemo and were matched according to histology, IPI and the use of Rituximab. We compared overall survival (OS), disease free survival (DFS) and cumulative incidence (CI) of relapse between both cohorts. These primary outcomes were defined according to the EBMT. OS was computed from diagnosis while DFS and CI of relapse were computed from 3 weeks after the last standard chemo cycle administered (end of chemo). Results The ASCT cohort included 10 patients diagnosed between 1999 and 2005. The Chemo cohort included 20 patients, 16 diagnosed between 1999 and 2005. Both cohorts were comparable for the main clinical and patient features (Table 1). The median (range) follow-up (FU) time since the end of chemo for surviving patients was 56 months (mo) (24-106) in the ASCT cohort vs 37 mo (8-107.5) in the Chemo cohort; P=.28. Five years (yr) OS for the ASCT cohort and the Chemo cohort were 68.5% [CI95%: 39-98] and 46.5% [CI95%: 18-75], respectively; P=.6. Three yr DFS for the ASCT cohort and the Chemo cohort were 70% [CI95%: 41.5-98.5] and 59.5% [CI95%: 29-86]; respectively; P=.4. The CI of relapse in the ASCT cohort and the Chemo cohort were 21% [CI95%: 0-47] and 27% [CI95%: 2-51], respectively; P=.8 Conclusions In this retrospective registry-based, matched cohort study of HIV+ patients with large B-cell NHL we found a non-significant effect of ASCT as consolidation treatment in 1st CR patients, in terms of survival and relapse incidence. Nevertheless, due to the observed favorable tendency, future analysis including a higher number of patients and, eventually, randomized clinical studies, should be performed to further clarify these observations. Disclosures: No relevant conflicts of interest to declare.

Description: Recent studies have shown that Autologous Stem cell Transplantation (ASCT) in HIV+ patients (pts) with associated lymphoma along with highly active antiretroviral therapy (HAART) have similar results to those observed in immunocompetent pts. However there have been few reports describing Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT) in HIV+ pts with high risk hematologic malignancies. The main difficulties associated to this procedure are infections and pharmacological interactions. We present the results of three HIV+ pts with hematologic malignancies treated with HAART and AlloHSCT. Pt # 1: 37 years old male diagnosed with HIV infection (AIDS-C3) in 1988, on HAART since 1996. In 1998 a diffuse large B cell lymphoma (DLBCL) IV-B was diagnosed. He achieved complete remission (CR) after CHOPx6, but relapsed one month later. After ESHAP he underwent AlloHSCT from an HLA-identical sibling in chemo-sensitive relapse. TBI+Cy was administered as conditioning treatment (CT) and Cyclosporine (CsA) as Graft versus Host Disease (GvHD) prophylaxis. HAART (3TC, NFV, EFV, d4T) was maintained during transplantation. The patient died on day (d) +6 due to respiratory distress without engraftment. Autopsy showed pulmonary aspergillosis with no evidence of toxicity or lymphoma. Pt # 2: 45 years old female. AIDS-C3 in 1994, on HAART since 1996. Diagnosed with high risk common acute lymphoblastic leukemia in 2005. She reached CR after Hyper-CVAD+Rituximab (R) x2 and received an AlloHSCT from an HLA-identical sibling using TBI+Cy as CT and CsA + Methotrexate (MTX) as GvHD prophylaxis. HAART (T20, d4T, ABC, 3TC) was maintained throughout the procedure. Engraftment occurred on +17d and full donor chimerism (FCh) on +26d. During transplantation Herpes Zoster infection, febrile neutropenia and CMV infection were observed and suitably treated. Acute GvHD grade III occurred on +30d, successfully treated with steroids, CsA and mycophenolate mofetil. Four months (m) after transplantation the patient showed extensive chronic GvHD (cGvHD) also treated with steroids and CsA. Despite adequate immunologic recovery since +6m (CD4+: 450 cells/mm3 and serum IgG: 683mg/dl) she developed Streptococcal pneumonia (+9m) encephalitis of unknown etiology (+12m) and streptococcal sepsis together with pneumonia (+20m). The patient remains in CR with negative HIV-viral load and no cGvHD 30m after transplant. Pt # 3: 44 years old male. AIDS-C3 on HAART since 2000. He developed DLBCL-IVA in 2004 and reached CR after CHOP+R x6. Relapsed in 2006, showing refractoriness to ESHAP+R x5 and reaching 2nd CR after ASCT with BEAM as CT. He relapsed again in 2007, and received MINE-R x3 and GIFOX-R x1 obtaining partial remission. An AlloHSCT from an HLA-identical sibling was designed using reduced CT (90Y-Ibritumomab-tiuxetan, Rituximab, Fludarabine and Melphalan) and CsA + MTX as GvHD prophylaxis. HAART (DDI, T20, 3TC) was maintained during treatment, but stopped for 7 days due to mucositis. Engraftment was observed on +13d, with FCh on +32d. During transplantation the patient developed febrile neutropenia and CMV infection, successfully resolved. After CsA withdrawal on +70d, the patient showed two acute grade II GvHD episodes responsive to steroids and CsA. The patient remains in CR with cGVHD, on immunosupression, 9 months after transplant. He shows negative HIV-Viral load, CD4+ 65 cells/mm3 and serum IgG 559mg/dl. These pts show that AlloHSCT is a feasible treatment in HIV+ pts with high risk hematologic malignancies. Moreover we have not found significant interactions between immunosuppressive agents and HAART. Nevertheless early diagnosis of infection is critical in this setting.

Description: HAART has improved the outcome of AIDS patients (pts). Thus high-dose chemotherapy followed by ASCT has been used for the treatment of HIV+Ly pts, similarly to HIV-neg-Ly pts. In a recent report we found delayed engraftment after ASCT in HIV+Ly compared with HIV-neg Ly pts (Exp.Hem33;487–494,2005). To test the role played by HAART on engrafment we conducted this study, comparing engraftment results on HIV+Ly pts that received HAART with those in wich HAART was withdrawn after ASCT. Patients and Methods: From June 2000 a total of 19 HIV+Ly pts (17 male) received an ASCT in a multicenter cooperative study; 5 were Hodgkin disease (HD) and 14 non-Hodgkin high-grade malignant lymphoma (NHL). Median age was 43 years (range, 31–61); adjusted IPI (aIPI) was: 0–1 in ten pts and 2–3 in nine more pts; advanced Ann Arbor stage (III–IV) was present in 14 pts.Ten pts were treated with HAART during ASCT (HAART+) and in nine pts HAART was withdrawn due to gastrointestinal toxicity (HAART neg). Both groups were similar for the most relevant clinical characteristics (p value Mann-Whitney test or chi-square test 〉 0.05): HD/NHL, Ann Arbor stage, aIPI, status at ASCT (CR-1/more than CR-1), age, number of lines of chemotherapy before ASCT, number of cycles of mobilization to obtain an adequate amount of CD34+ cells, number of CD34+ cells infused, day of start of GCSF and duration of GCSF-treatment. Results: Median time to reach PMN〉0.5 x 109/L was 12 days (9–17) for HAART neg group and 18 days (9–33) for HAART+ pts (p=0.069). Platelet engraftment (〉20x109/L) was achieved after a median of 20 days (11–28) and 26 days (11–455) respectively (p=0.25). Nevertheless, a multivariate regression analysis using as covariates HAART, GCSF (starting day) and amount of CD34+ cells infused, was performed. Accordingly no statisticaly significant results were found to relate with myeloid engraftment. Conclusions: Despite the HAART+ group shows longer interval to reach PMN and platelets engraftment following ASCT, we can not definitively conclude that HAART plays a negative influence on engraftment in this clinical setting. In order to clarify these results further recruitment of patients is needed.

Description: ASCT has been reported as a feasible, safe and effective treatment in HIV associated lymphoma patients (pts) receiving Highly Active Antiretroviral Therapy (HAART). For a better knowledge regarding the outcomes within this setting we have compared the clinical results of a multicentre cooperative cohort of auto-transplanted HIV+ NHL pts, with a matched cohort of HIV− NHL pts who underwent ASCT in our hospital. Patients and Methods: 17 HIV+ NHL pt auto-transplanted since 2001 have been included, as well as a similar number of matched HIV− NHL pts. Both cohorts were comparable for the most relevant clinical features (p value Mann-Whitney test or chi-square test 〉 0.05) (see table). HAART was maintained during mobilization and ASCT. The median number of CD34+ cells infused was 3,73x106 CD34+ cells/kg in HIV+ pts and 4,75x106 CD34+ cells/kg in HIV− pts (p: NS). G-CSF was used in 16/17 HIV+ pts until engraftment starting at a median of 7 days (d) after ASCT. Results: All but 1 HIV+ pt who died in relapse due to multiorgan failure on day +15 engrafted. The median time to engraftment was 12,5 (9–33) d in HIV+ pts, and 13 (9–18) d in HIV− pts. The incidence of acute infectious and toxic events was similar in both groups. All pts developed neutropenic fever. The documented infections were (HIV+ vs HIV−): Gram+ bacteriemia (5 vs 4), Gram- bacteriemia (1 vs 2), CMV antigenemia (1 vs 1). Aspergillus pneumonia was documented in one HIV+ pt and Candida parapsilosis was cultured in another HIV+ pt. One case of pneumonia ocurred in the HIV− group. Two toxic events were documented in the HIV+ group: 1 VOD and 1 multiorgan failure. All but one events (multiorgan failure) were succesfully resolved. The median time of follow up was 36,5 mo in HIV+ and 32,3 mo in HIV−. Within the HIV+ group 5 pt relapsed, 3 of them died and 2 remain in CR after rescue chemotherapy. Other 3 pts died (multiorgan failure, late HIV opportunistic infection and post-ASCT myelodysplasia). In the HIV− group 8 pts relapsed and all of them died. The median time to relapse/progression was 3,5 mo (HIV+) vs 3 mo (HIV−). The OS at 36 mo was (HIV+ vs HIV−) 67% vs 49% (p=NS) and EFS at 36 mo was 55% vs 52,3% (p=NS). Conclusions: Our results show that the clinical outcomes in NHL HIV+ and NHL HIV− pt undergoing ASCT are comparable. Engraftment, infectious and toxic events as well as survival were not different. ASCT may be applied in HIV+ NHL on HAART pts with similar guarantees as in the HIV-negative setting. Table: Clinical features of both series HIV+ NHL pt HIV− NHL pts Age 43 46 Adjusted IPI: 〉2 10 12 Status at ASCT: CR1 or PR 8 12 Pre-ASCT treatment lines: 〉1 12 13 HISTOLOGY Burkitt-Burkitt like 3 1 Peripheral T-cell 1 1 Anaplastic 2 1 DLBC 9 12 Plasmablastic 2 0 B or T Lymphoblastic 0 2 CONDITIONING BEAM/BEAC 16 11 TBI-based regimens 1 1 BuCy 0 4 CBV 0 1

Description: Background: Advanced cirrhosis is related to alterations in immunity. We aimed to evaluate the levels of peripheral CD4+ T cells (Tregs) and plasma cytokine in patients coinfected with human immunodeficiency virus and hepatitis C virus (HIV/HCV) according to liver fibrosis stages [evaluated as liver stiffness measure (LSM)] and their linear relationship. Methods: We performed a cross-sectional study on 238 HIV/HCV-coinfected patients (119 had 25 kPa). Peripheral T-cell subsets were phenotyped by flow cytometry, plasma biomarkers were assessed by multiplex immunoassays, and LSM was assessed by transient elastography. Results: We found HIV/HCV-coinfected patients had higher values of CD4+ Tregs (p 〈 0.001), memory Tregs (p ≤ 0.001), and plasma cytokine levels [IFN-γ (p ≤ 0.05) and IL-10 (p ≤ 0.01)] compared with healthy donors and HIV-monoinfected patients. In the multivariate analysis, higher LSM values were associated with reduced levels of IL-10 (adjusted arithmetic mean ratio (aAMR) = 0.83; p = 0.019), IL-2 (aAMR = 0.78; p = 0.017), TNF-α (aAMR = 0.67; p 〈 0.001), and IL-17A (aAMR = 0.75; p = 0.006). When we focus on HIV/HCV-coinfected patients analyzed by LSM strata, patients with ≥25 kPa had lower values of IL-2 (aAMR = 0.66; p = 0.021), TNF-α (aAMR = 0.565; p = 0.003), and IL-17A (aAMR = 0.58; p = 0.003) than patients with

Description: Background: The use of a stem cell source homozygous for the CCR5 delta32 mutation is of particular interest in HIV+ patients in need of an allogeneic hematopoietic stem cell transplantation (SCT) given the high natural resistance against HIV-1 acquisition. In the absence of such cell source, the impact of allogeneic SCT on human immunodeficiency virus type 1 (HIV-1) reservoirs in patients receiving combination antiretroviral therapy (cART) is unknown. Methods: Size of HIV-1 reservoirs was investigated in 3 patients with hematological malignancies receiving cART, who underwent allogeneic SCT (Table 1). Patient 1 received a myeloablative single cord blood (wild type (WT) CCR5), supported with third party HLA-mismatched CD34+ cells (haplo-cord SCT). Patients 2 and 3 underwent reduced intensity conditioning SCT of an HLA-matched sibling (heterozygous CCR5 delta32 donor and WT CCR5 donor, respectively). In-depth analysis of the HIV-1 reservoir was performed in the post-transplant period using droplet digital PCR and hemi-nested qPCR (proviral DNA copies/million PBMC). Chimerism analysis was performed by short tandem repeat PCR (STR-PCR). Results: Proviral DNA showed a decreasing dynamics after allogeneic SCT and became undetectable in all 3 patients at 9, 18 and 1 months, respectively (Table 1). In patient 1, negativity of proviral HIV-1 DNA coincided with achievement of complete chimerism while being free of immunosuppression. Patient 2 showed undetectable proviral DNA together with the development of skin chronic GvHD. Finally, undetectable proviral DNA and complete chimerism was achieved in patient 3 early after transplantation. All patients remained in complete hematological remission. Conclusion: All our patients showed a small HIV-1 reservoir after allogeneic SCT. The coincidence of achievement of negative proviral HIV-1 DNA and complete chimerism and/or development of GvHD suggests a role of Ògraft versus HIV-1 reservoir effectÓ in the control of HIV infection. Disclosures No relevant conflicts of interest to declare.