Choice Of Induction Therapy Research Articles

Positive Long-Term Outcome of Kidney Allocation via Acceptable Mismatch Program in Highly Sensitized Patients

Introduction: Eurotransplant established the acceptable mismatch (AM) program to facilitate timely kidney transplantations of highly sensitized patients, but long-term granular clinical and immunological outcomes regarding overall graft survival and de novo DSA (dnDSA) formation are still intensively researched. The right choice of induction therapy in patients with differing immunological risk is not conclusively determined, as well as the impact of human leukocyte antigen (HLA) epitope matching on dnDSA formation. Methods: This monocentric, retrospective study analyzed 94 patients transplanted within the AM program between 2000 and 2019 compared to case-control matched cohorts of non- (PRA 0–5%; PRA-0) and intermediately sensitized (PRA 6–84%; PRA-6/84) patients transplanted through Eurotransplant Kidney Allocation System. Results: Estimated 10-year overall graft survival between the PRA-0 and AM cohorts was similar, whereas PRA-6/84 was significantly disadvantageous compared to PRA-0. Estimated 10-year incidence of antibody-mediated rejection rates was significantly lower in the PRA-0 group compared to AM and PRA-6/84 groups. Compared to the AM group, estimated incidence of de novo donor-specific antibody (dnDSA) was significantly lower in PRA-0 patients, with no differences between the AM and PRA-6/84 cohorts. The PRA-6/84 cohort was the only subgroup in which interleukin-2 receptor antagonist (IL2RA) induction was associated with longer overall graft survival, patient survival, and graft survival compared to depleting induction (ATG or OKT3). Broad HLA-A, -B, -DR mismatches (mmABDR) and HLA epitope mismatches determined by Eplets and PIRCHE-II were predictive for dnDSA formation in the total cohort, and the AM subgroup. Discussion: The high efforts expended on AM patients are justified to allow timely organ transplantation with acceptable risk profile and non-inferior outcomes. IL2RA induction in intermediately sensitized patients is associated with superior overall graft survival, patient survival, and graft survival compared to ATG/OKT3 induction, without negative effects on rejection episodes or dnDSA formation. In silico epitope matching might further help reduce dnDSA formation, particularly in high-risk AM patients.

Development of a case fatality prognostic score for HIV-associated histoplasmosis

ObjectivesThe burden of histoplasmosis is as great as that of tuberculosis in Latin America and the attributable mortality is even higher. A better assessment of severity could help reduce mortality. MethodsFrom the French Guiana HIV-histoplasmosis database, we attempted to identify factors associated with 30-day death after antifungal drug initiation and constructed a prognostic score. We evaluated its discrimination performance using several resampling methods. ResultsOf the 415 patients included, 56 (13.5%) died within 30 days of treatment. The fatality-associated factors were performance status ≥3, altered mental status, dyspnea, C-reactive protein ≥75 mg/l, hemoglobin <9 g/dl and/or a platelet <100000/ml, and an interstitial lung pattern on chest X-ray. We constructed a 12-point prognostic score. A threshold ≥5 classified patients as alive or dead at 30 days with a sensitivity of 84%, a specificity of 81%, a positive predicted value of 40%, and a negative predicted value of 97%. The area under the curve of the receiver operating characteristic curves from the different resamples were stable between 0.88 and 0.93. ConclusionThe histoplasmosis case fatality score, which is easy and inexpensive to perform, is a good tool for assessing severity and helping in the choice of induction therapy. An external validation remains necessary to generalize these results.

Delayed diagnosis resulting in increased disease burden in multiple myeloma: the legacy of the COVID-19 pandemic

The COVID-19 pandemic has had global healthcare impacts, including high mortality from SARS-CoV-2 infection in cancer patients; individuals with multiple myeloma (MM) are especially susceptible to poor outcomes. However, even for MM patients who avoided severe infection, the ramifications of the pandemic have been considerable. The consequences of necessary socio-geographical behavior adaptation, including prolonged shielding and interruptions in delivery of non-pandemic medical services are yet to be fully understood. Using a real-world dataset of 323 consecutive newly diagnosed MM patients in England, we investigated the impact of the COVID-19 pandemic on routes to myeloma diagnosis, disease stage at presentation and relevant clinical outcomes. We demonstrate increasing MM presentations via emergency services and increased rates of bony and extra-medullary disease. Differences were seen in choice of induction therapy and the proportion of eligible patients undertaking autologous stem cell transplantation. Whilst survival was statistically inferior for emergency presentations, significant survival differences have yet to be demonstrated for the entire cohort diagnosed during the pandemic, making extended follow-up critical in this group. This dataset highlights wide-ranging issues facing MM patients consequent of the COVID-19 pandemic, with full impacts for clinicians and policy-makers yet to be elucidated.

Analysis of induction and maintenance immunosuppression choices in the US during the first year post kidney transplant for patients over 70

Rates of kidney transplantation in patients over 70 years of age have steadily increased over the last 20 years, however age-appropriate immunosuppression regimens in the elderly remain unclear. Investigators utilized the SRTR database to evaluate elderly kidney transplant recipients’ outcomes against a younger population. Post-transplant outcomes measured at an approximately 1-year time interval included graft survival, patient survival, rejection, malignancy, and serum creatinine. Elderly patient survival was improved for those patients that were on dialysis for less than 1 year (95.4% vs. 91.4% p &lt; .01). Patients able to be maintained on CNI immunosuppression regimens also had improved graft survival compared to those managed with other immunosuppression (95.5% vs. 91.1%, p &lt; .01). Patients maintained on mTOR inhibitors had the lowest patient survival (85.5% vs. 92.6%, p &lt; .01). The choice of induction therapy did not affect long term patient or graft survival. These results translated to investigators’ own centers in patients over 60. Results for the SRTR database showed that minimizing time on dialysis prior to transplant improved graft and patient survival, while the type of induction agent had minimal effect on all outcomes at the time of follow-up. The results also support the use of CNI’s and belatacept for maintenance immunosuppression but did not encourage the use of mTOR inhibitors.

Evolving Treatment Patterns of Healthcare Providers (HCPs) and Multiple Myeloma (MM) Experts from 2013-2017: Analysis of an Annually Updated Online Treatment Decision Tool

BackgroundExpanding availability of novel agents for treating MM has transformed management strategies, particularly for relapsed/refractory (R/R) disease. Since 2013, experienced MM physicians from leading academic institutions and cancer centers (experts) have annually updated an online tool designed to provide HCPs with treatment recommendations for specific patient cases. Previous reports from our tool analyses have shown yearly changes in treatment patterns among experts but a multiyear delay by HCPs in the adoption of many expert-recommended treatment strategies into their practice.MethodsTo develop the tool, 5 MM experts provided treatment recommendations for hundreds of case scenarios across induction, maintenance, and R/R disease settings. To use the tool, HCPs seeking treatment consultation entered patient and disease factors with a planned treatment for that specific patient using dropdown menus and received 5 expert recommendations for their case. HCPs were asked to indicate the impact of expert recommendations on their planned treatment. This report includes analysis and comparison of intended treatment of HCPs for 790 cases entered into the 2017 iteration of tool with expert recommendations for those patient cases. Treatment trends observed in 2017 will also be compared with those from previous years.ResultsConsensus (≥ 3 of 5 experts choosing the same treatment) among experts has been increasing for induction therapy since 2013. In ASCT-eligible patients, regardless of any other factors, experts recommended bortezomib/lenalidomide/dexamethasone (VRd) in 75% of tool cases in 2017, up from 58% in 2016 and 45% in 2013 and 2014. By comparison, HCPs used VRd for 44% of ASCT-eligible patient cases in 2017 and only 19% in 2016. Expert recommendation of VRd for 66% (vs 48% of HCPs) of ASCT-ineligible cases in 2017 also increased from 38% (vs 18% of HCPs) in 2016. Expert recommendations for induction therapy changed most for cases with varying comorbidities, and data from the 2017 tool are shown in the figure below. In patients without specific comorbidities or with cardiac dysfunction only, experts recommended VRd for 87% to 90% of these cases (vs 41% to 44% of HCPs). In cases involving peripheral neuropathy, experts recommended carfilzomib/lenalidomide/dexamethasone (KRd) for 60% and VRd for 30% compared with HCPs selecting KRd for 10% and VRd for 71% of those cases.In the R/R setting, the novelty and broad range of available regimens are reflected in the lack of consensus in treatment recommendations by both the experts as well as the planned treatment of HCPs. In 304 R/R case scenarios, only 36 cases (12%) had an exact expert treatment consensus and 63 cases (21%) had 2 pairs of experts agreeing on the same treatment recommendations. However, overall treatment strategies were similar among experts, with use of triplet regimens including novel agents increasing in 2017. Experts recommended Kd or daratumumab monotherapy for 40% of cases refractory to lenalidomide in 2016. In 2017, experts no longer recommended monotherapy or doublet therapy for R/R cases in this setting. In 2017, the experts recommended triplet regimen therapy for 87% to 97% of cases involving bortezomib-refractory or lenalidomide/bortezomib-refractory patients, and each of the recommendations included either carfilzomib, ixazomib, daratumumab, or elotuzumab compared with only 55% to 60% of their recommendations including triplet therapy with one of these agents in 2016. Again, variation was observed in the intended treatment of HCPs compared with the expert recommendations for R/R cases. In 2017, the intended treatment of HCPs did not match any of the experts' recommendations for 45% of the R/R cases entered into the tool.ConclusionsAnalysis of cases entered into our expert-developed treatment decision tool shows that a wide gap remains between expert treatment recommendations and the intended treatment plans of HCPs for many of the same MM case scenarios. Experts had nearly full consensus on choice of induction therapy; however, differences between expert recommendations in R/R MM are due to availability of multiple triplet-based treatment options in this setting. In addition, newly approved therapies continue to have a strong impact on experts' recommendations as they quickly integrate new agents into their treatment approaches. A detailed analysis of expert and HCP MM practice trends will be presented. [Display omitted] DisclosuresKumar:Celgene, Millennium, BMS, Onyx, Janssen, Noxxon, AbbVie, Amgen, Merck, Oncopeptides, Skyline Diagnostics, Takeda: Consultancy; Skyline: Honoraria; Celgene, Millennium/Takeda, Onyx, AbbVie, Janssen, Sanofi, Novartis, Amgen, Genentech, Merck, Oncopeptides, Roche, Skyline Diagnostics: Research Funding. Lentzsch:Caelum Biosciences: Other: leadership position and stock; BMS: Consultancy; Amgen: Consultancy. Anderson:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees; Oncopep: Other: scientific founder; C4 Therapeutics: Other: scientific founder; Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; MedImmune: Membership on an entity's Board of Directors or advisory committees.

Evaluation of Residual Disease Positivity Rates in Adult Acute Lymphoblastic Leukemia Patients Treated with Asparaginase Versus Non-Asparaginase Containing Regimens

Introduction: Treatment of acute lymphoblastic leukemia (ALL) generally includes multi-agent chemotherapy. The regimens used at our institution include: HyperCVAD with or without rituximab (R), CALGB 10403, CALGB 19802 and CALGB 8811. All of these regimens include an induction backbone of vincristine, anthracycline, and corticosteroid. Additionally, all regimens, with the exception of HyperCVAD/R-HyperCVAD, include an asparaginase product. At the current time, treatment choice for adult ALL patients has been provider specific and there is no data to suggest one regimen is better than another, as rates of complete remission and 5 year overall survival are similar.Purpose: The purpose of this study was to determine whether choice of induction therapy between asparaginase and non-asparaginase containing regimens had an impact on the rate of residual disease positivity in adult ALL patients treated at a large academic medical center.Patients and Methods: We conducted a single-center, retrospective cohort study of 66 consecutive adult patients with a diagnosis of ALL between January 2002 and October 2016 treated at our center. Data collected on study subjects included: demographics, ALL subtype, chemotherapy regimen, toxicities, treatment delays, treatment dose reductions, cytogenetic disease risk category, and residual disease positivity by flow cytometry after first induction therapy. First induction was defined as the first cycle or course of the chemotherapy framework. Descriptive statistics were used to summarize the sample. Association of post-induction residual disease positivity and adverse effects were examined using Chi-squared tests.Results: The median follow up of survivors for the study was 38 months. Induction treatment with an asparaginase-containing regimen was associated with a lower rate of residual disease post-induction when compared to treatment with non-asparaginase containing regimens (36.8% vs 12.8%; p=0.0260). There was no statistically significant difference found in one-year mortality, two-year mortality, treatment for neuropathy, and rate of relapse between asparaginase and non-asparaginase containing regimens.Conclusion: Adult ALL patients treated with asparaginase-containing regimens have lower rates of residual disease analyzed by flow cytometry after induction; however, this is not translated into a difference in overall survival. [Display omitted] DisclosuresRizzieri:Erytech: Research Funding; Shire: Research Funding.

Rabbit antithymocyte globulin induces human lymphocyte activation, proliferation, and apoptosis in the absence of complement: an experimental study.

Rabbit antithymocyte globulin (rATG) has become the first choice for induction therapy in HLA-presensitized patients undergoing organ transplantation. Meanwhile, complement inhibitors have been approved for preventing or treating antibody-mediated rejection in these patients. The biological effects of rATG on lymphocytes in cases of complement deficiency or significant inhibition are not yet clear. We measured lymphocyte activation, proliferation, and apoptosis in response to rATG treatment in the absence of complement. T-cell subsets were analyzed transcriptomically features to rATG stimulation. Activation-related phenotypes on T cells were determined in patients after rATG administration. We found that rATG treatment led to lymphocyte activation and proliferation in vitro without the addition of complement. A dose-dependent apoptosis in rATG-treated lymphocytes was detected, which was partially caspase-3-dependent but Fas/FasL-independent. T cells were more sensitive to rATG stimulation than were non-T cells. Both CD4+ T cells and CD8+ T cells upregulated a series of genes related to cell activation, cytokine production and apoptosis to rATG stimulation. CD69 and CD25 levels in surviving T cells were increased in patients after rATG administration. These findings indicate that rATG can stimulate lymphocyte activation, proliferation, and apoptosis in the absence of complement. Biologic effects of rATG other than complement-dependent cytotoxicity need to be concerned.

Clinicopathologic features and outcomes of de novo transformed indolent lymphoma.

8061 Background: Untreated transformed indolent lymphoma (unTIL) can present as a composite lymphoma (COM), 2 or more separate sites of disease with one site transformed (discordant; DIS) or following indolent lymphoma sequentially (SEQ). Current practices are guided by small retrospective studies or extrapolated from trials involving non-transformed lymphomas. Methods: 353 patients (pts) with biopsy-proven unTIL treated with curative chemoimmunotherapy between 01/2000 to 01/2019 were included (intention to treat). All indolent B-cell lymphomas (iNHL) were included except CLL/SLL. Patients with MCL and non-DLBCL transformation were excluded. Prior therapy for iNHL was not allowed except one line of non-chemotherapy-based therapy. Kaplan-Meier method was used for time-to-event analysis including progression-free (PFS) and overall survival (OS). Results: 252 (71%) pts presented with COM, 50 (14%) DIS and 51 (14%) SEQ lymphoma. The underlying iNHL was: 308 (87%) follicular lymphoma, 37 (10%) nodal MZL, 7 (2%) MALT lymphoma, and 1 (0.3%) WM. Frontline therapy (FLT) included: RCHOP for 271 (77%), DAEPOCHR for 60 (17%), clinical trial for 7 (2%), BR for 4 (1%), RHCVAD for 2 (1%), RCEOP for 2 (1%), radiation therapy for 2 (1%), RFND for (1%) 2, RCVP for 2 (1%), and rituximab only for 1 (0.3%). 9 (3%) pts had ASCT in first remission. 50 (15%) pts received maintenance rituximab (MR) with fewer cases of HGBL-DH compared to the non-MR cohort (0% v 10%). With a median follow-up of 3.4 years (range 0.1-19.1), 4-year PFS and OS rates were 59% and 88%. By univariate analysis (UVA) the underlying type of iNHL, cell-of-origin and choice of induction therapy (DAEPOCHR v RCHOP) were not associated with inferior outcomes. SEQ transformations were associated with inferior OS on UVA (P = 0.02) which was not significant on multivariable analysis (MVA) (P = 0.3). MVA identified ECOG PS &gt; 1, B symptoms and HGBL-DH as independent prognostic factors for inferior PFS and OS. In patients who achieved PR or greater following FLT, MR was associated with improved PFS on MVA (HR 0.6, 95% CI 0.3-0.9, P = 0.04) without an OS benefit (P = 0.2). 39 (31%) pts relapsed with iNHL only (mPFS 2.4 yrs, 4-yr OS 94%) and 88 (69%) relapsed with transformed lymphoma (mPFS 1.1 yrs, 4-yr OS 69%) with no significant difference in pattern of relapse with MR (P = 0.2). Conclusions: The clinicopathologic features of unTIL are similar to those of de novo DLBCL. Escalation of therapy beyond R-CHOP may not be required in the absence of HGBL-DH. unTIL should be included in future clinical trials involving de novo DLBCL given the similar clinicopathologic features.

PB2125 THE IMPACT OF RVD OR VCD INDUCTION ON RESPONSE 3 MONTH AFTER FIRST LINE AUTOLOGOUS STEM CELL TRANSPLANT IN MULTIPLE MYELOMA. A SINGLE_CENTER RETROSPECTIVE ANALYSIS

Background:The use of triple agent induction therapy before first line high‐dose therapy (HDT) and autologous stem cell transplant (ASCT) in multiple myeloma is now considered standard of care. Cross‐study comparisons show that the combinations of proteasome inhibitors (PIs) and immunomodulatory drugs (IMIDs) have the highest response rates (Malankody Nat Rev Clin Onc 2015).Aims:In recent years there has been a shift in choice of induction therapy from the VCD to the RVD regimen in our region. We have evaluated how this shift has affected depth of response 3 months after ASCT in all patients receiving first line HDT with ASCT in our region from January 1st, 2015, and how frequently our patients needed to change induction regimen, based on choice of first line therapy.MethodsAll patients receiving first line HDT with ASCT for multiple myeloma in our institution in the period from January 1st, 2015 to October 26th, 2019 were evaluated for the final analysis of response 3 months post‐ASCT. The patients received 3‐5 cycles of induction therapy before leukapheresis, HDT (melphalan 200 mg/m2) and ASCT. All patients received a follow‐up consultation in our institution 3 months post‐ASCT, where response was evaluated and recorded according to the IMWG 2016 response criteria.Age, sex, date of ASCT, the presence of high‐risk cytogenetics, ISS stage at diagnosis, choice of induction regimen and response 3 months post‐ASCT was recorded by the primary investigator (Table 1).Results:48.3% (125 patients) received VCD as first‐line induction therapy, while 37.5% (97 patients) received RVD. 12.0% (15 patients) in the VCD group changed induction therapy vs 5.2% (5 patients) in the RVD group. In the RVD group 87.5% (77 patients) achieved ≥VGPR vs 84.5% (93 patients) in the VCD group. In addition, 11.3% in the RVD group (8 patients) achieved PR, while 3.4% (3 patients) had disease progression (PD) 3 months after ASCT. In the VCD group, 13.6% (15 patients) achieved PR, while 1.8% (2 patients) had PD 3 months after ASCT (Table 2, Figure 1). 26% (32 patients) starting VCD induction therapy and 16% (16 patients) starting RVD achieved a response rate &lt;VGPR, or needed to switch induction regimen. We define this as a poor outcome (figure 2).Summary/Conclusion:RVD induction therapy before HDT with ASCT trended toward higher rates of at least VGPR compared to VCD induction (87.5% s 84.5%). The choice of RVD as first line induction therapy necessitated fewer changes of induction regimen due to insufficient response or unacceptable toxicities compared to VCD induction (5.2% vs 12.0%). Fewer patients receiving RVD induction achieved a “poor outcome”: Response &lt;VGPR or need to change induction regimen. These results should be confirmed in larger patient materials, and in prospective studies. Updated data with approximately 30 additional patients, mainly receiving RVD induction, will be presented at the EHA annual meeting if our abstract is selected for presentation.

The Impact of RVD or VCD Induction on Response 3 Months after First Line Autologous Transplant in Multiple Myeloma. a Single-Center Retrospective Analysis

Introduction: The use of triple agent induction therapy before first line high-dose therapy (HDT) and autologous stem cell transplant (ASCT) in multiple myeloma is now considered standard of care. While thalidomide/bortezomib/dexamethasone (VTD) is the only induction regimen approved by EMA, both cyclophosphamide/bortezomib/dexamethasone (VCD) and lenalidomide/bortezomib/dexamethasone (RVD) are recommended in the most recent ESMO guidelines (Moreau et al., Annals of Oncology, 2017).Prospective comparisons of VCD and RVD are lacking. Cross-study comparisons show that the combinations of proteasome inhibitors (PIs) and immunomodulatory drugs (IMIDs) have the highest response rates (Malankody Nat Rev Clin Onc 2015).In recent years there has been a shift in choice of induction therapy from the VCD to the RVD regimen in our region. We have evaluated how this shift has affected depth of response 3 months after ASCT in all patients receiving first line HDT with ASCT in our region from January 1st, 2015, and how frequently our patients needed to change induction regimen, based on choice of first line therapy.Methods: All patients receiving first line HDT with ASCT for multiple myeloma in our institution in the period from January 1st, 2015 to March 16th, 2018 were evaluated for the final analysis of response 3 months post-ASCT. The induction regimen was chosen at their local physician´s discretion. The patients received 3-5 cycles of induction therapy before leukapheresis, HDT (melphalan 200mg/m2) and ASCT. All patients received a follow-up consultation in our institution 3 months post-ASCT, where response was evaluated and recorded according to the IMWG 2016 response criteria. No patients had started maintenance therapy at the time of evaluation. Age, sex, date of ASCT, the presence of high-risk cytogenetics, ISS stage at diagnosis, choice of induction regimen and response 3 months post-ASCT was recorded by the primary investigator (Table 1). In case of change of regimen during induction treatment, the reason was recorded. Patients receiving either VCD or RVD as induction therapy, who did not change regimen during induction, were included in the final response analysis.Results: 212 patients received HDT with ASCT in the period. 209 patients were evaluated 3 months after ASCT as of June 21st, 2018. 57.5% (122 patients) received VCD as first-line induction therapy, while 25.9% (55 patients) received RVD. 11.5% (14 patients) in the VCD group changed induction therapy vs 3.6% (2 patients) in the RVD group. Reasons for changing regimen were: not achieving at least a partial response (PR) (n=10), unacceptable toxicity (n=4), lack of documented reason (n=2). In the RVD group, 1 patient died from sepsis 2 weeks post-ASCT, and 1 patient refused to attend the post-ASCT evaluation. Therefore, 108 patients in the VCD group and 51 patients in the RVD group were included in the final response analysis.29 patients could not confirm a complete response (CR) due to lack of bone marrow and/or serum immunofixation at response evaluation. For that reason, patients achieving CR, unconfirmed CR and very good partial response (VGPR) were compounded to a ≥VGPR response grade.In the RVD group 94,1% (48 patients) achieved ≥VGPR vs 85,2% (92 patients) in the VCD group. Similar differences were also present for confirmed CR (25% vs 18%) and unconfirmed CR (44% vs 35%). In addition, 2% in the RVD group (1 patient) achieved PR, while 3.9% (2 patients) had disease progression (PD) 3 months after ASCT. In the VCD group, 13.0% (14 patients) achieved PR, while 1.8% (2 patients) had PD 3 months after ASCT (Table 2, Figure 1).Discussion: RVD induction therapy before HDT with ASCT yielded higher rates of at least VGPR compared to VCD induction (85,2% s 94,1%). The choice of RVD as first line induction therapy necessitated fewer changes of induction regimen due to insufficient response or unacceptable toxicities compared to VCD induction (3,6% vs 11,5%). The differences were not statistically significant, possibly because of too few patients. Still, our results support the trend in our region of choosing RVD as first-line induction for transplant-eligible patients. These results should be confirmed in larger patient materials, and in prospective studies.Updated data with approximately 35 additional patients, mainly receiving RVD induction, will be presented at the ASH annual meeting if our abstract is selected for presentation. [Display omitted] DisclosuresMoksnes:Shire: Consultancy. Schjesvold:Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy; Bayer: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy; Abbvie: Honoraria; Adaptive: Consultancy; Novartis: Honoraria.

Follicular lymphoma: results of multicenter study of first-line therapy with bendamustine and rituximab, risk factors for adverse events (fl-rus-2013 protocol)

Follicular lymphoma: results of multicenter study of first-line therapy with bendamustine and rituximab, risk factors for adverse events (fl-rus-2013 protocol)

Does Rabbit Antithymocyte Globulin (Thymoglobuline®) Have a Role in Avoiding Delayed Graft Function in the Modern Era of Kidney Transplantation?

Delayed graft function (DGF) increases the risk of graft loss by up to 40%, and recent developments in kidney donation have increased the risk of its occurrence. Lowering the risk of DGF, however, is challenging due to a complicated etiology in which ischemia-reperfusion injury (IRI) leads to acute tubular necrosis. Among various strategies explored, the choice of induction therapy is one consideration. Rabbit antithymocyte globulin (rATG [Thymoglobuline]) has complex immunomodulatory effects that are relevant to DGF. In addition to a rapid and profound T-cell depletion, rATG inhibits leukocyte migration and adhesion. Experimental studies of rATG have demonstrated attenuated IRI-related tissue damage in reperfused tissues, consistent with histological evidence from transplant recipients. Starting rATG intraoperatively instead of postoperatively can improve kidney graft function and reduce the incidence of DGF. rATG is effective in preventing acute rejection in kidney transplant recipients at high immunological risk, supporting delayed calcineurin inhibitor (CNI) introduction which protects the graft from early insults. A reduced rate of DGF has been reported with rATG (started intraoperatively) and delayed CNI therapy compared to IL-2RA induction with immediate CNI in patients at high immunological risk, but not in lower-risk patients. Overall, induction with rATG induction is the preferred choice for supporting delayed introduction of CNI therapy to avoid DGF in high-risk patients but shows no benefit versus IL-2RA in lower-risk individuals. Evidence is growing that intraoperative rATG ameliorates IRI, and it seems reasonable to routinely start rATG before reperfusion.

Induction Therapy in Renal Transplant Recipients: A Review

Transplant science has improved significantly over the last decade. Influenced by novel advancements, rejection rates and short-term graft losses diminished substantially. Induction therapy was shown to reduce rejection rates and improve short-term graft survival. In this article, we discuss the most commonly used induction agents and the choice of induction therapy in different renal transplant recipient subgroups. The medical literature as well as our own experience was used to prepare this review. At this time, induction therapy is commonly used in upwards of 80%, of renal transplant recipients. Depleting agents are the most frequently used agents and they account for more than 75% of all induction therapies in the United States. Currently, there is no consensus regarding the choice of induction therapy. The type of induction therapy is generally selected based on a comprehensive evaluation of the recipient and the donor’s immunological risks, the risk of developing opportunistic infection and malignancy, recipient comorbidities, financial burden and the choice of maintenance immunosuppressive regimen.

Results of a Large Randomized Controlled Trial of Alemtuzumab-Versus Basiliximab-Based Induction Therapy in Kidney Transplantation.

Background Calcineurin inhibitors reduce short-term kidney transplant failure, but may contribute to late transplant loss. The role of alemtuzumab (a potent lymphocyte-depleting antibody) as induction therapy followed by an early reduction in CNI exposure after kidney transplantation is uncertain. The 3C Study aims to assess the efficacy and safety of alemtuzumab (followed by low-dose CNI) compared to basiliximab (with standard dose CNI) among patients receiving kidney transplants. Methods This randomized trial included 852 patients scheduled to receive a kidney transplant who were randomly assigned alemtuzumab-based induction therapy (followed by low-dose tacrolimus and mycophenolate) or basiliximab-based induction therapy (followed by standard-dose tacrolimus, mycophenolate and steroids). The primary outcome is biopsy-proven acute rejection at 6 months. Key secondary outcomes include delayed graft function, steroid resistant rejection, transplant survival, serious infections (defined as opportunistic infections or infection requiring hospitalisation) and cause-specific mortality. Tertiary outcomes include the incidence of the primary outcome in different types of transplant recipient. Results 426 participants were assigned alemtuzumab and 426 to basiliximab. Average age was 51 years and 65% were male. Approximately one-third of transplants followed each of donation after brain death, donation after cardiac death and living donation. During the first 6 months of follow-up, about 100 participants had biopsy-proven acute rejection, about 30 transplants failed and over 250 participants had a serious infection. Conclusion The 3C Study is the largest randomized trial to assess the clinical efficacy and safety of alemtuzumab-based induction in kidney transplantation and the unblinded clinical efficacy results would be presented for the first time during the WTC meeting. With about 100 rejection episodes and 250 serious infections, the study has excellent statistical power to detect clinically important treatment effects. These results should have an important impact on the choice of induction therapy at the time of kidney transplantation. DISCLOSURE:Haynes, R.: Grant/Research Support, Novartis. Harden, P.: Grant/Research Support, Novartis. Landray, M.: Grant/Research Support, Novartis. Baigent, C.: Grant/Research Support, Novartis. Friend, P.: Grant/Research Support, Novartis.

The value of repeat kidney biopsy in quiescent Argentinian lupus nephritis patients

The duration of maintenance therapy after induction therapy for lupus nephritis has not been rigorously established. A common practice is to maintain immunosuppression for 1-2 years after complete remission, and longer for partial remission. The present work addresses whether a repeat kidney biopsy might be informative in deciding who should continue immunosuppression after complete or partial remission. The practice in a large Buenos Aires nephrology unit is to repeat a kidney biopsy before finalizing the decision to withdraw or continue immunosuppression. This work reports on a cohort of 25 Hispanic patients that had two or more kidney biopsies, the last occurring after at least 24 months of clinically quiescent disease. Despite normalization of serum creatinine and reduction of proteinuria to <500 mg/d, 30% of patients still had significant activity at the last biopsy. Conversely, 60% of patients with ongoing proteinuria (500-1000 mg/d), or stable but abnormal serum creatinine, had no activity by biopsy. Univariate association analyses demonstrated that improvement in the activity index (AI) of the last biopsy was associated with choice of induction therapy (cyclophosphamide or mycophenolate), improvement in serum creatinine over the first six months of treatment, and improvement in complement component C4. By multivariate regression analyses, two AI prediction models emerged. Cyclophosphamide plus change in serum creatinine or cyclophosphamide plus change in C4 accounted for 50% of the improvement in AI. These data suggest that a repeat biopsy may be useful in making the decision to withdraw or continue maintenance immunosuppression.

Rabbit anti-thymocyte globulin induction in renal transplantation: review of the literature

Rabbit anti-thymocyte globulin induction in renal transplantation: review of the literature Leah Andress,1 Anjali Gupta,2 Nida Siddiqi,3 Kwaku Marfo2,3 1University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Department of Pharmacy Practice, Buffalo, 2Montefiore Medical Center, The University Hospital for Albert Einstein College of Medicine Department of Abdominal Organ Transplant Program, Bronx, 3Montefiore Medical Center, Department of Pharmacy, Bronx, NY, USA Abstract: Rabbit anti-thymocyte globulin (rATG) has proven benefit as induction therapy in renal transplant recipients, achieving reduced acute rejection rates and better short-term allograft function, with slightly higher rates of complications such as infections and malignancy. Compared with other agents, the most benefit from rATG induction has been observed in renal transplant recipients at high immunologic risk for rejection. However, in special populations, such as pediatrics, the elderly, and hepatitis C-positive and human immunodeficiency virus-positive renal transplant recipients, additional information is needed to delineate the absolute benefit of rATG induction compared with other induction agents. Selection of rATG as the choice of induction therapy in renal transplant recipients should be guided by a cost-effective approach in balancing efficacy, safety, and cost. This review summarizes the published literature on efficacy, safety, and cost of rATG induction in renal transplantation. Keywords: anti-thymocyte globulin, renal transplantation, induction therapy

Comparison Of Epigenetic Versus Intensive Chemotherapy For Newly Diagnosed Acute Myeloid Leukemia Patients ≥60 Years Old: The Roswell Park Experience

Abstract Background Epigenetic therapy (Epi) with the hypomethylating agents, azacitidine (Aza) and decitabine (Dec), is increasingly being utilized for induction treatment of older AML patients (pts) based on studies demonstrating both tolerability and prolonged survival. By contrast, standard “7+3” intensive chemotherapy (IC) effectively induces remission in many individuals but is associated with significant toxicity and higher mortality. We compared our institute's experience with Epi vs. IC for the upfront treatment of newly diagnosed AML pts ≥60 years old. Methods We performed a retrospective chart review of 164 pts ≥ 60 yrs old with newly diagnosed AML who underwent initial therapy at our center between 3/2008-2/2013. Half (n=84; 51%) received IC with regimens containing cytarabine 100 mg/m2 IV for 7 days and daunorubicin 60 mg/m2 IV for 3 days. Half were treated with Epi (n=82; 49%) regimens containing either Dec (20 mg/m2 IV daily for 5 or 10 days) or Aza (75 mg/m2 sq daily for 7 days). Kaplan Meier method, log rank test, and univariate cox proportional hazard models were used to assess overall survival (OS) and correlation with covariates of interest. Results Baseline pt characteristics demonstrated a difference in the median age of pts in each group (IC 67 vs. Epi 75 yrs; p &lt;0.01). All other factors were comparable: ECOG status 0-2 (96% vs. 96%, p=1.0), WBC (12.0 x 109/dL vs. 4.5 x 109/dL; p=0.08), hemoglobin (9.2g/dL vs. 9.4g/dL; p=0.39), platelets (69 x 109/dL vs. 54 x109/dL; p=0.99), marrow blasts (53% vs. 45%; p=0.10), peripheral blasts (21% vs. 9%; p=0.14), poor-risk cytogenetics (56% vs. 66%; p=0.21). At our center, older AML pts receiving IC had superior complete response at any time point (CRatp)(43% vs. 21%; p&lt; 0.01) and higher overall response rates (ORR=CR+CRp) (50% vs. 28%; p&lt;0.01) versus Epi-treated pts. IC also resulted in a longer median OS as compared to Epi (10.6 vs. 7.9 mos; p=0.01). Thirty-day mortality and leukemia-free survival (LFS) were similar across the two groups (IC 10% vs. Epi 11%; p=0.8; 11.2 vs. 9.3 mos; p=0.47 respectively). Interestingly, in pts with AML characterized by poor-risk cytogenetics (n=77; 46%), the choice of induction (IC vs. Epi) did not impact outcome and yielded similar CRatp (39% vs. 27%; p= 0.4) and OS (10.3 vs. 7.8 months; p=0.4). Choice of Epi drug (Aza vs. Dec) did not impact results. Thirty-three percent of pts (n=55; IC 38% vs. Epi 28%) had refractory or relapsed disease (RR-AML) after induction, requiring ≥1 salvage treatment. We found that selection of either IC or Epi as prior treatment had no effect on CR or ORR in RR-AML pts receiving salvage. In multivariate Cox regression analysis, older age, higher ECOG score, increased peripheral blasts, and poor-risk cytogenetics were independently associated with inferior survival. By comparison, marrow blast percentage, hemoglobin, and choice of induction therapy did not impact OS (IC vs. Epi: HR 0.79; CI 0.508-1.237, p= 0.31). Conclusions Our results suggest that IC and Epi represent clinically equivalent approaches for the upfront treatment of older AML pts. In spite of significantly higher CR and ORR in the IC group, our finding of improved OS following IC vs. Epi was not substantiated in multivariate analysis, suggesting that this difference may be explained by the comparatively younger age of pts in the IC group. Leukemia-free survival and 30-day mortality were the same for IC vs. Epi-treated pts, as were all response and survival outcomes in the poor-risk cytogenetics subgroup. These data highlight the growing need for prospective clinical trials to conclusively determine the respective roles of IC vs. Epi therapy in older AML pts. Disclosures: No relevant conflicts of interest to declare.

Diagnosis and Management of Cryptococcal Relapse

Despite improvements in the antifungal regimens and the roll out of antiretroviral therapy (ART) in sub-Saharan Africa, mortality due to cryptococcal meningitis remains high. Relapse of an initially successfully treated infection contributes to this mortality and is often a clinical dilemma in differentiating between paradoxical immune reconstitution inflammatory syndrome (IRIS) and culture-positive relapse or treatment failure. Herein, we present a clinical case scenario and review the case definitions, differential diagnosis, and management of relapse with an emphasis on the current diagnostic and management strategies. We also highlight the challenges of resistance testing and management of refractory relapse cases. The risk of relapse is influenced by: 1) the choice of induction therapy, with higher mortality risk with fluconazole monotherapy which can select for resistance; 2) non-adherence to or lack of secondary prophylaxis; 3) failure of linkage-to-care or retention-in-care of HIV ART programs.

The Influence of Single Dose Induction Therapy on Graft Function in a Developing Country

Introduction: Induction with single dose therapy is rarely practiced in renal transplantation. Hence, we did this prospective study to see the influence of single dose induction therapy on graft function. Methods: Our study cohort comprised 358 patients (253 Males, 105 females) with a mean age of 43.42±13.22. Patients were divided into 4 groups based on the choice of induction therapy used (Basiliximab, Daclizumab, Thymoglobulin or no induction). Details such as age, sex, modality of dialysis and related details prior to transplantation, induction and immunosuppressive regimen, rate of rejection, diabetic status, previous transfusions, previous pregnancies, biopsy results and mortality were collected. Analysis was done using PASW Statistics 18 with chisquare test and one way Anova with post-hoc Tukey. The PRA values in thymoglobin was 26.17% ± 8.63% (Range:12.5% to 45.5%). The cost of the drugs is as follows - Basiliximab USD 1122, Thymoglobulin USD 551 and Daclizumab USD 800. Results: Of the 358 patients, single dose-induction was initiated on 310 patients; 125 with Basiliximab, 143 with Daclizumab (2 doses) and 42 patients with Thymoglobulin. Overall, 29.9% of patients were diabetic, however this was not significantly different across the groups (p=0.25). The transfusion rate was 53.8% in patients on thymoglobulin induction while the overall rate of transfusion was only 21.1% (p < 0.001). A positive biopsy report was seen in 24.5% of all patients (20.8% no induction; 27.2% Basiliximab, 23.8% Daclizumab, 23.1% Thymoglobulin) (p=0.82). Death-censored graft survival showed a lower incidence of graft survival with no induction (87.1%) (p=0.54).[Table 1 - Demographic and renal parameters]Figure: [Death-censored graft survival]Conclusion: Our study shows that single dose induction with thymoglobulin is the most cost effective modality in preventing rejection in patients with high PRA.

Induction Therapy by Anti-Thymocyte Globulin (Rabbit) Versus Basiliximab in Deceased Donor Renal Transplants and the Effect on Delayed Graft Function and Outcomes

The use of induction therapy significantly reduces the incidence of acute rejection (AR) episodes posttransplantation and prevents delayed graft function (DGF). In our program, all adult deceased donor kidney transplant (DDKT) recipients receive immunosuppression induction therapy with either Basiliximab (anti-CD25 Ab) or rabbit anti-thymocyte globulin (RATG). Our protocol is risk adjusted such that patients who are at a higher risk for DGF or AR received RATG and all other patients receive anti-CD25 Ab. We hypothesized that treating our higher-risk patients with RATG induction at the time of transplantation would lead to a lower rate of DGF and better outcomes. From August 1, 2005 through August 31, 2010, 116 consecutive adult patients received a DDKT in a single academic transplantation center. All DDKT patients received induction with RATG or anti-CD25 Ab. The induction decision was made prior to transplantation based on donor and recipient risk factors for AR and DGF. Transplants that were deemed at higher risk for DGF or AR based on donor factors or recipient factors received RATG. Medical records and patient databases were reviewed retrospectively. The use of RATG in higher-risk recipients for DGF and AR did not significantly reduce the DGF rate. At 6 months the function of the allograft function measured as creatinine clearance or serum creatinine was lower in the RATG group than the patients who received anti-CD25 Ab induction. The choice of induction therapy did not improve outcomes in high-risk patients in this short-term study.