Post Autologous Hematopoietic Stem Cell Transplantation Research Articles

Inefficacy of Rituximab Post-Autologous Hematopoietic Stem Cell Transplant to Prevent Relapses in Persons with Multiple Sclerosis

Background In an effort to reset the immune system, individuals with multiple sclerosis (MS) have undergone autologous hematopoietic stem cell transplant; this approach has produced promising results in terms of feasibility, efficacy and safety, however, the role of post-transplant adjuvant therapeutic agents needs to be further clarified. Methods Consecutive patients autografted using the Mexican method (ClinicalTrials.gov NCT02674217) to graft persons with MS were prospectively accrued in the study. All autografts were carried out on an outpatient basis, using cyclophosphamide (Cy) and filgrastim as mobilization regimen, the cumulative dose of Cy being 200 mg/kg, delivered on two separate blocks, nine days apart. After granulocyte recovery, all individuals received a rituximab infusion (375 mg/m2) and at discharge, patients were recommended to continue a follow-up period with additional rituximab infusions (100 mg) every two months for 1 year. Results Eighty two subjects were prospectively enrolled between June 2015 and November 2016. Twenty nine were male (35%). Median age was 45 y (range, 28-66 y). Nineteensubjects (23%) had primary progressive MS, 37 (45%) relapsing remitting MS and 26 (32%) secondary progressive MS. Median EDSS score was 5.5 (range, 0 - 7). After recovering hematopoiesis and receiving the initial dose of rituximab, 41 patients were administered rituximab in their residence countries every two months during one year, whilst 41 did not. There were not significant differences in clinical and demographic data among both groups. In order to analyze data comparatively, the EDSS values prior to and 12 mo. after the HSCT were compared in the groupswith and without additional rituximab; the median change in the EDSS score in the rituximab group was 0 (CI -3.5 to 4), and in the no rituximab group was also 0 (CI -1.5 to 3); accordingly, the change in the EDSS score between patients receiving or not rituximab was not statistically significant (P = 0.93, 95% CI -0.5 to 0.5). We found no short-term difference in MS-relapse free survival (RFS). Conclusion The 12-month period therapy with rituximab in patients with MS who underwent autologous transplant was not effective to prevent relapses nor to cause reduction in the EDSS score.

Abstract A43: Comparative analysis of germline mutations of immune biomarkers pre- and post-HSCT in pediatric cancer patients

Abstract Background/Objectives: Hematopoietic stem cell transplantation (HSCT) is a high risk but curative treatment for many patients with malignant and non-malignant disorders; however, comes with significant and varying chemotherapy-induced toxicities. Here we probe variability in response of DNA collected pre-versus-post autologous-HSCT from pediatric patients. Germline DNA mutations in this population have not been assessed. The overall hypothesis is that new germline mutations are generated by exposure to high-dose chemotherapy in pediatric patients receiving autologous-HSCT and that these genetic changes may also be potential biomarkers of therapeutic response. It has been reported that activation of complement protein, C3, can decrease the risk of infections following HSCT by enabling stem cells to home to the bone marrow and stimulate their differentiation to various immune cells. This process then helps mediate the reconstitution of the immune system via regulatory mechanisms. In this study, chemotherapy-induced germline mutations among pre- and post-autologous HSCT pediatric patients, and the complement component, C3 were evaluated. Developing strategies to identify predictive biomarkers such as variability in chemotherapy-induced mutational burden of C3 among pediatric HSCT patients, could result in innovative approaches to treating these high-risk patients. Design/Methods: Whole exome sequencing from an HSCT biorepository was exploited to assess genetic mutations and search for molecular signatures induced by anti-cancer therapy and autologous HSCT. Peripheral blood mononuclear cells (PBMCs) were isolated pre- and post-HSCT in six pediatric subjects undergoing autologous HSCT following myeloablative conditioning regimen involving carboplatin in combination with other standard of care agents. Whole exome sequencing was performed on germline DNA followed by canonical ingenuity pathway analysis® (IPA). Miliplex MAP Human Complement Panel 2 Multiplex Assay was performed on plasma from each patient pre- and post-HSCT to gain insight into status of the C3 complement protein levels following HSCT. Results: Whole exome DNA sequencing indicated that approximately 10% of genes analyzed (959 genes) were commonly mutated in the germline DNA isolated from the post-HSCT versus the pre-HSCT, which included C3 complement component. Canonical IPA analysis using hypergeometric test indicated that the 10% commonly mutated genes are relevant in at least thirty-six statistically significant biological. Specifically, C3 was found to be associated with the PI3K signaling pathway in immune cells such as B lymphocytes (p=0.04). Preliminary multiplex complement panel data revealed a trend for increased complement protein concentrations for C3 in plasma at day 7 post-HSCT versus plasma collected pre-HSCT. Conclusion: These preliminary experimental findings demonstrate that among the 959 commonly mutated genes, C3 consists of germline DNA mutations, as well as, having differences in expression at the protein level in patients pre- and post-HSCT. While investigation of the other commonly mutated genes and the thirty-five other relevant pathways elucidated in these studies is still ongoing, these studies highlight the importance for further investigation of the complement component C3 and its role in PI3K signaling in immune cells following chemotherapy-induced genetic mutations which may impact patient prognosis and care. Future studies using high-throughput exome sequencing may help elucidate predictive signatures and/or immune biomarkers such as differences in C3 gene and protein for developing personalized treatments for HSCT therapy, for properly managing HSCT-induced toxicities, and ameliorating clinical outcomes. Citation Format: Pankita H. Pandya, Hongyu Gao, ChienWei Chiang, Sydney Ross, Steven Rhodes, Jenny Then, Laura Haneline, Mary Murray, Lang Li, Karen Pollok, Jamie Renbarger. Comparative analysis of germline mutations of immune biomarkers pre- and post-HSCT in pediatric cancer patients. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A43.

The Use of a Novel CME Format to Ellicit and Develop True Competence in Hematologist Ability to Risk Stratify Patients with Hodgkin Lymphoma

Introduction/Background: Novel approaches for the post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation treatment now exist for patients with classical Hodgkin lymphoma (HL) at high risk of relapse or progression. This advancement can potentially reduce the frequency of disease progression following autologous stem cell transplantation (ASCT) for certain patients at high risk. However, before such treatment can be administered, hematologists must appropriatelyrecognize and apply prognostic factors to identify patients at risk who would benefit from such treatment.Materials and Methods: We developed an online CME initiative that aimed to match each leaner with needed education as determined by his/her baseline competency and skill level. This tailored-learning approach used a single case-based screening question to segment the participants based on their knowledge regarding risk stratification of patients with HL. Hematologists who incorrectly answered the screening question were directed to Activity 1 - Interpreting Risk Factors for Post-Transplantation Relapse in Hodgkin Lymphoma (http://www.medscape.org/viewarticle/842624). Those who correctly identified a patient at risk for post-ASCT relapse were directed to Activity 2 - Post-Autologous Transplantation Therapy for Hodgkin Lymphoma (http://www.medscape.org/viewarticle/842640). . Online survey instruments using knowledge- and case-based, multiple-choice questions were administered to compare the same participants' responses to identical questions before and after each activity. McNemar's chi-squared test was used to determine statistical significance between responses. The initiative launched on June 1, 2015 and data collected through October 23, 2015.Results: 1600 hematologists answered the case-based screening question; 74% of hematologists answered incorrectly and were directed to Activity 1, indicating a deficit in understanding which patients would benefit from consolidation treatment in HL. Among hematologists who participated in Activity 1 and completed all pre- and post-assessment questions during the study duration (n=272), comparison of individually linked pre-assessment question responses to the respective post-assessment question responses demonstrates statistically significant improvements in knowledge (P <.05) on appropriate treatments for patients with HL who have received HDT/ASCT, and ways to optimize outcomes for those receiving consolidation/maintenance therapy. Correct responses on post-assessment questions were up to 48% higher after CME completion (compared with the pre-assessment question responses) with an overall medium effect size of d=0.621 [Figure 1]. Among those who were directed to Activity 2 (26% of learners) and completed all pre- and post-assessment questions (n=37), there was 26% increase in recognition that treatment with brentuximab vedotin consistently improved progression-free survival across all prespecified subgroups [Figure 2].Conclusions: This study demonstrated the success in using online branching logic to segment the participants based on a screening question to identify presence or absence of a specific knowledge gap in hematologist learners. Participation in this initiative led to the identification of large group of learners who benefited from segmented learning. Recognizing that individual hematologists are at various stages of understanding of best practices in managing HL, this approach may be used to maximize translation of evidence-based recommendations into clinical decisions. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Extending Autologous Hematopoietic Stem Cell Transplantation As First Line Treatment in Multiple Myeloma Patients with Severe Renal Impairment: A Retrospective Study of the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC)

IntroductionRenal impairment occurs in 20-30% of newly diagnosed multiple myeloma patients, requiring dialysis for up to 10% of patients.Recent results ofan IFM (Intergroupe Francophone du Myélome) study confirm the effectiveness of high dose melphalan followed by Autologous Hematopoietic Stem Cell Transplantation (ASCT) as first line therapy in multiple myeloma patients. Most centers exclude renal failure patients due to concerns of toxity, because data are limited for safety and toxicity to consider. This current retrospective study observes toxicity and outcome in 55 multiple myeloma patients with severe renal impairment, undergoing high dose melphalan and ASCT, in the age of bortezomib.MethodsUsing the PROMISE database, 55 multiple myeloma patients French SFGM-TC centers were included from January 2002 to November 2012. Characteristics of the patients presenting with creatinine clearance less than 30ml/min at time of ASCT were included.ResultsMedian age was 61 (40-75) years old. Thirty-nine (71%) presented free light chain myeloma. Twenty-three (42%) patients were on dialysis at the time of ASCT and during hospitalization. Thirty-one (56%) patients received bortezomib as induction therapy. Melphalan dose ranged from 75mg/m² to 200mg/m². Thirty (55%) patients were treated with a dose of 140mg/m². Median delay between diagnosis and ASCT was 5.3 months.Among 50 patients evaluated for toxicity, respectively febrile neutropenia and mucositis occurred in 92% and 90% of patients. Half of the mucositiscases were grade 3-4. The median number of days before neutrophil and platelet recovery was respectively 12 days (10 - 34) and 16 days (7 - 331). Two patients experienced cardiac toxicity (grade 1-2), and 4 patients neurologic toxicity (grade 3 for one patient).Among 51 patients evaluated for response, 12 patients (24%) were at least in Very Good Partial Response (VGPR) before ASCT, including 5 in Complete Response (CR). All of them were treated with bortezomib as induction therapy.After ASCT, 30 patients (58.8%) reached at least VGPR (22 CR and 8 VGPR). Among 30 patients in VGPR or more post ASCT, 22 (73%) were treated with bortezomib before ASCT.Table 1 shows the responses.Fourteen (26%) received two ASCT. One patient died from toxicity (cerebral bleeding during second ASCT). There is no argument for dramatic response improvement with this procedure in comparison to single ASCT.After a median follow-up of 55 months, median progression free survival (PFS) was 55 months, and median overall survival (OS) was 95 months. In multivariate analysis, dose of melphalan at 140mg/m² was significantly correlated with a better PFS (p=0.006), compared to 100mg/m² (or less) and to 200mg/m².During follow-up 29 patients (54%) relapsed and 25 died. The main causes of death were relapse and disease progression (72%). There were only 3 cases of treatment related mortality (TRM). At day 100, the cumulative incidence of TRM was 6%.Among 23 dialysis patients, 6 patients (26%) became dialysis independent, but not during ASCT. Thirteen (56%) were still alive at last follow-up, and 8 (34%) experienced relapse. Median PFS for this subgroup of patients was 73 months.ConclusionWith an acceptable TRM, without major toxicities, high dose melphalan (140mg/m²) following by ASCT appears to be a real benefit for multiple myeloma patients with severe renal failure. This includes patients on dialysis. Response is dramatically improved by this procedure, with median PFS similar to that of patients with normal renal function. Finally, adjunction of bortezomib as induction therapy also improves the efficacy of ASCT. [Display omitted] DisclosuresAugeul-Meunier:gilead: Consultancy; janssen: Consultancy. Karlin:amgen: Consultancy, Honoraria; janssen-cilag: Consultancy, Honoraria; celgene: Consultancy, Honoraria; Bristol: Consultancy; takeda: Consultancy. Benboubker:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Avet-Loiseau:sanofi: Consultancy; amgen: Consultancy; janssen: Consultancy; celgene: Consultancy.

Effect of Melphalan 140 Mg/m2 Versus 200 Mg/m2 on Toxicities and Outcomes in Multiple Myeloma Patients Undergoing Single Autologous Stem Cell Transplantation

Introduction: Although melphalan at a dose of 140 mg/m2 (MEL-140) is known to be an effective preparative regimen for autologous hematopoietic stem cell transplantation (ASCT) in multiple myeloma (MM) patients, there are very few studies comparing it to the most commonly used dose of 200 mg/m2 ( MEL-200).Methods: We retrospectively reviewed the records of all myeloma patients who underwent an ASCT between 2001 and 2010 at our institution. We then identified patients who received melphalan as their preparative regimen at doses of 140 mg/m2 or 200 mg/m2. Patients who received any other drug as conditioning regimen or had more than one ASCT or had documented amyloidosis were excluded. Data were collected for variables known to possibly affect prognosis of MM patients. We assessed effect of melphalan dose on toxicities and outcomes.Results: A total of 129 eligible patients were identified, with 33 receiving MEL-140 and 96 receiving MEL-200. As was expected significantly higher percentage of patients in the MEL-140 arm were older than 65 years (P=<0.001) or had cardiac ejection fraction < 50 (P=0.0001) or had Karnofsky score < 80 (P=0.01) or had creatinine > 2 either at diagnosis (P=0.004) or the time of ASCT (P=0.001). Rest of the patient and disease characteristics including Durie-Salmon stage, myeloma subtype and disease status at ASCT were not significantly different between the 2 arms. Patients in MEL-140 needed significantly longer time to ANC engraftment (P=0.037) and also had significantly higher frequency of neutropenic fever (P=0.003). There were no significant differences in mucositis (including grade), nausea, vomiting, diarrhea, bacteremia, or length of hospital stay and frequency of repeat hospitalizations among both groups. There was no treatment related mortality in either group. At a median follow up of 74 months (range, 52-140) from ASCT, there were no significant differences in relapse free survival (RFS) (P=0.4988) and overall survival (OS) (P=0.6936) between the two groups. Five year OS for MEL-140 and MEL-200 is 71.6% and 78.9%, while RFS is 23.9% and 34%, respectively. Proportion of patients whose myeloma status improved to ≥ VGPR at 3 months post ASCT was also not different (P=0.385). Importantly, similar proportions of patients received various post ASCT maintenance therapy (P=0.605). In multivariate cox proportional hazards model only disease status of ≥VGPR at the time of ASCT significantly affected RFS (P=0.024) but did not impact OS (P=0.104).Conclusion: MM patients who received MEL-140 had similar long term outcomes as those who received MEL-200 despite their older age, lower performance status and renal insufficiency. DisclosuresNo relevant conflicts of interest to declare.

Orthotopic Heart Transplant Facilitated Autologous Hematopoietic Stem Cell Transplantation in Light-chain Amyloidosis

Abstract Abstract 4489 Dominant cardiac involvement by primary systemic amyloidosis (AL) precludes effective AL treatment and is associated with short survival (median survival for stage-III AL= 3–4 months). Three patients who presented with severe cardiac dysfunction as their major AL manifestation underwent orthotopic heart transplantation (OHT) followed by autologous hematopoietic stem cell transplantation (ASCT). The clinicopathological characteristics of these patients form the basis of this report. Age at AL presentation was 63, 62 and 44 years in 2 females and 1 male. The time from initial symptoms of AL to diagnosis was 12, 24 and 12 months. Diagnosis of cardiac AL was established via endomyocardial biopsy, Congo red staining and immunohistochemistry. Standard work-up for plasma cell dyscrasia included; serum and urine electrophoresis, immunofixation, measurement of serum-free light-chain ratio and bone marrow biopsy. All patients had stage III AL based on cardiac troponin I and NT-pro-BNP. All had end stage heart failure with New York Heart Association class 4 symptoms and developed cardiogenic shock requiring intra-aortic balloon pump support as a bridge to OHT. All were considered unsuitable for ASCT. Initial treatment was with lenalidomide, dexamethasone in two patients while the third received melphalan and dexamethasone. Table -1 shows the timeline of diagnosis and dual transplants. Table-1: . Orthotropic cardiac transplantation (OHT) followed by ASCT Age/Sex Time to AL diagnosis (months) Organ involvement (months) Time * to OHT (months) Time to ASCT s/p OHT (months) Survival (months) 63/F 12 Heart, Kidney, PN 7 13 30+ 62/F 24 Heart, Kidney, PN 5 16 26+ 44/M 12 Heart, Kidney, tongue 4 13 14+ * Time to OHT from onset of heart failure symptoms, PN= peripheral nerve, F = female, M= male, s/p= status post ASCT was performed 13, 16 and 13 months after OHT. All 3 patients were on tacrolimus and prednisone at the time of stem cell mobilization and hematopoietic transplant; two patients were also receiving mycophenolate mofetil and valganciclovir. We collected 6.1 and 6.2 × 106/kg CD-34+ cells in 2 days with filgrastim (5 ug/kg, twice, daily) and plerixafor (16 mg/kg based on day- 4 CD-34+ counts) in two subjects. The third initially failed to mobilize but 4.3×106/kg CD-34+ cells were subsequently obtained when she (patient #2) was remobilized with filgrastim and plerixafor 4 weeks after stopping mycophenolate mofetil. The creatinine clearance at the time of high-dose chemotherapy was 36, 30 and 43 ml/minute. All 3 patients received renal adjusted dose of melphalan at 140mg/m2. Mycophenolate mofetil and Valganciclovir were withheld during neutropenia until engraftment. Time to engraftment for neutrophils (ANC of >500/uL x3 days) was 13, 11 and 14 days. Platelets engraftment (untransfused >20 × 109 for 3 consecutive days) occurred in 14, 13 and 16 days. No patients received post-transplant filgrastim. Patients were hospitalized for 17, 18 and 18 days. Renal function remained stable during ASCT and non-hematological toxicity was limited to grade I-II apart from one grade III oral mucositis and colitis. One patient achieved hematologic complete remission (patient#2) while 2 patients had partial response following ASCT. Post OHT and ASCT all patients are alive and well at follow-up of 14, 26 and 30 months from OHT. OHT should be considered in select patients with dominant cardiac involvement and advanced heart failure to allow subsequent ASCT and improve survival. Disclosures: No relevant conflicts of interest to declare.

Bone Marrow Mesenchymal Stromal Cells Isolated from Multiple Sclerosis Patients have Distinct Gene Expression Profile and Decreased Suppressive Function Compared with Healthy Counterparts

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system, due to an immune reaction against myelin proteins. Multipotent mesenchymal stromal cells (MSCs) present immunosuppressive effects and have been used for the treatment of autoimmune diseases. In our study, gene expression profile and in vitro immunomodulatory function tests were used to compare bone marrow-derived MSCs obtained from MS patients, at pre- and postautologous hematopoietic stem cell transplantation (AHSCT) with those from healthy donors. Patient MSCs comparatively exhibited i) senescence in culture; ii) similar osteogenic and adipogenic differentiation potential; iii) decreased expression of CD105, CD73, CD44, and HLA-A/B/C molecules; iv) distinct transcription at pre-AHSCT compared with control MSCs, yielding 618 differentially expressed genes, including the downregulation of TGFB1 and HGF genes and modulation of the FGF and HGF signaling pathways; v) reduced antiproliferative effects when pre-AHSCT MSCs were cocultured with allogeneic T-lymphocytes; vi) decreased secretion of IL-10 and TGF-β in supernatants of both cocultures (pre- and post-AHSCT MSCs); and vii) similar percentages of regulatory cells recovered after MSC cocultures. The transcriptional profile of patient MSCs isolated 6 months posttransplantation was closer to pre-AHSCT samples than from healthy MSCs. Considering that patient MSCs exhibited phenotypic changes, distinct transcriptional profile and functional defects implicated in MSC immunomodulatory and immunosuppressive activity, we suggest that further MS clinical studies should be conducted using allogeneic bone marrow MSCs derived from healthy donors. We also demonstrated that treatment of MS patients with AHSCT does not reverse the transcriptional and functional alterations observed in patient MSCs.

Utilization Trend and in-Hospital Complications of Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma in the United States: 13 Years Perspective

Background: We aimed to explore utilization, complication and in-hospital mortality related to Autologous Hematopoietic Stem Cell Transplant (ASCT) in Multiple myeloma (MM) from 1998 to 2011 in United States.Methods: We used Nationwide Inpatient Sample (NIS) database to isolate multiple myeloma cases undergoing ASCT. Study included adults age >18 years. Patient and hospital demographics were extracted from NIS. Peri-procedural complications were calculated using ICD-9-CM codes. Hierarchical multivariate regression models were formulated to assess predictors of in-hospital mortality and complication.Results: Total of 6,957 (weighted-34,837) were available for analysis. Majority of patients were male (57%), white (57%) who presented to large bed size (78%),teaching (96%) hospital. Utilization of ASCT for MM increased from 5% in 1998 to 21.6% in 2011 (p<0.001). Despite temporal increase in mean age and comorbidites, mortality reduced (2.9 vs. 0.7, p<0.01) significantly from 1998 to 2011. In-hospital complications were common after ASCT with stomatitis (44.7%) being the most common followed by anemia requiring transfusion (28.5%), febrile neutropenia (16.5%) and bacteremia (15.0%). Mechanical ventilation and acute respiratory failure are the strongest predictors of in hospital mortality post ASCT followed by acute kidney injury,total Body irradiation (TBI) and bacteremia. Higher Charlson comorbidity index, female sex and TBI were associated with higher complication rates post ASCT.Conclusions: Utilization of ASCT for MM patients has increased significantly since 1998 and even though complications are very common in patients undergoing ASCT (77.4%), in-hospital mortality is rare (<2%) and has decreased significantly over the years secondary to decreased use of pre transplant TBI and better transplant care. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Outcomes and Survival in Hepatitis C Virus Seropositive Lymphoma and Myeloma Patients After Autologous Stem Cell Transplantation

Introduction: Hepatitis C virus (HCV) seropositive patients who undergo autologous hematopoietic stem cell transplantation (HSCT) are at risk of HCV acute exacerbation (AE). Furthermore impact of high dose chemotherapy in patients who have hepatitis C is unknown. We sought to determine the risk factors for AE and the impact of HCV seropositivity on survival post-autologous HSCT. Methods: We retrospectively reviewed the medical records of all 64 HCV seropositive patients who had undergone autologous HSCT at our institution. COX regression model was used to evaluate the predictive risk factors for AE. Results: Twenty (32%) of the 64 patients had AE, defined as a 3-fold or greater increase in serum alanine aminotransferase level (ALT) from the pre-transplant value. Age above 60 years was found to be a risk factor for post-transplant AE (Figure 1). The occurrence of AE (analyzed as time-dependent variable) had no impact on the overall survival of patients who had undergone autologous HSCT. The overall and progression-free survival rates for chemosensitive lymphoma patients 2 years after autologous HSCT were 64% (range 41-80) and 47% (range 27-64), respectively. Median overall and progression-free survival durations in myeloma patients were 54 and 22 months, respectively.Figure 1: Cumulative incidence of acute exacerbation (AE) for all patients in the study and for the two age groups >60 years and ≤60 years.Conclusion: Our results suggest that the survival post autologous HSCT is not impacted by either the development of AE or the pre-transplant HCV seropositivity, as the survival of HCV seropositive patients post-transplant is similar to the survival of non-HCV seropositive historical controls. Hence, our study implies that HCV seropositivity is not a contraindication for autologous transplant.

PK-Directed Intravenous Busulfan in Combination with High-Dose Melphalan and Bortezomib As Conditioning Regimen for Patients with Multiple Myeloma

Introduction High dose therapy followed by autologous hematopoietic stem cell transplantation (ASCT) has an established role in the treatment of patients with multiple myeloma (MM). The most commonly used conditioning regimen in this setting is high-dose melphalan (200mg/m2; Mel200), which has been shown to result in improved progression free (PFS) and overall survival (OS). Achievement of a complete response (CR) following ASCT is an indicator for freedom from relapse, as well as PFS and OS. The CR rate observed after Mel200 followed by ASCT is between 10-35%. There is evidence that the combination of busulfan (Bu) and melphalan (Mel) results in longer PFS and OS compared to Mel alone. Additionally, the use of bortezomib (Btz) during conditioning with either high dose Mel alone or the combination of Mel and intravenous (i.v.) Bu has shown to be both safe and to have promising efficacy. The objective of our trial is to assess whether the combination of PK-directed Bu, Mel and Btz (BuMelBtz) during conditioning for a first ASCT in MM patients is both safe and efficacious. Methods Patients aged 18-72 with multiple myeloma, who had 1) measurable disease, 2) received less than one year of prior myeloma-directed therapy, 3) adequate organ function and performance status, and 4) an indication for ASCT were eligible. Exclusion criteria were >/= grade 2 neuropathy, prior stem cell transplant, uncontrolled intercurrent illnesses or comorbidities, unresolved >/= grade 2 toxicities from prior therapies, and prior malignancies except non-melanoma skin cancer. Treatment consisted of PK-directed i.v. Bu (4 daily 3-hour infusions from day (D) -6 to -3 to target a total AUC of 20,000 μMxmin), i.v. Mel 140mg/m2 on D-2, and i.v. Btz 1.4mg/m2 on D-6, -4, +1 and +4. The individual daily doses for Bu on D-6 and D-5 were determined by PK measures following a test dose (0.8mg/kg) 5-9 days prior to first Bu treatment dose; the last 2 doses (day -4 and -3) could be adjusted following another PK measure after the first full treatment dose on D -6. Stem cells were infused on D0. Subsequent consolidative or maintenance therapy was left to investigator choice. Primary outcome was CR rate assessed on D +100 post ASCT as per IMWG criteria. Secondary outcomes were overall response rate (ORR), toxicities, PFS and OS. The trial is registered at clinicaltrials.gov ([NCT01605032][1]). Results To date, 13 patients have been treated. The median age was 63 years (range 44-70), 62% (n=8) were male, 23% had ISS stage 3 (3/13), no patient had high risk cytogenetic features. The median number of regimens prior to ASCT was 1 (range 1-3) and included bortezomib in 92% (n=12). Prior to BuMelBtz the best treatment response had been stable disease (SD) in 3 patients, partial response (PR) in 8; only 1 patient each had achieved a very good partial response (VGPR) or CR. Following BuMelBtz/ASCT, median days to ANC >/=0.5 x 109/L and platelet count >/=30 x 109/L were 11 (range 10-13) and 17 (11-29), respectively. The most common non-hematological toxicities were alopecia (100%), oral mucositis (62% G3), dysphagia (85% G3, but no patient required TPN or enteral feeding), as well as electrolyte abnormalities (62% G3/4). Other common toxicities were nausea (92%, all G1/2), diarrhea (84% G1/2, 8% G3), while 77% of patients developed fully reversible transaminitis (15% G3). Less common G3 toxicities included delirium (8%), colitis (8%), skin infection (zoster, 8%), other infections (23%), and delirium (8%). One patient developed GI symptoms suggestive of acute GVHD on a gastric biopsy 8 weeks after ASCT. No patient developed sinusoidal obstruction syndrome of the liver. At 100 days post BuMelBtz/ASCT, response assessment was available for 8 patients: 1 achieved a stringent CR (12.5%), 4 VGPR (50%), and 3 PR (37.5%), resulting in a 100% ORR. One patient improved from a VGPR to a stringent CR during follow up. After a median follow up of 5 months (range 1-15) all patients are alive and no patient has relapsed. The trial is ongoing. Conclusion PK directed i.v. Bu in combination with Mel and Btz (BuMelBtz) is an effective and safe conditioning regimen for patients with multiple myeloma. Further evaluation is warranted. Disclosures: Barta: Otsuka: Research Funding; Onyx: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Honoraria. Off Label Use: IV Busulfan for the treatment of multiple myeloma. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01605032&atom=%2Fbloodjournal%2F122%2F21%2F5513.atom

Analysis Of Immune Cell Populations Before and After Autologous Hematopoietic Stem Cell Transplant For Multiple Myeloma: Association With Early Recovery Of Absolute Lymphocyte Count and Progression-Free Survival

The treatment of transplant-eligible, multiple myeloma (MM) patients usually consists of induction therapy followed by autologous hematopoietic stem cell transplant (ASCT). In addition to typical cytogenetic and biochemical prognostic factors, there are other risk factors that predict for relapse and progression after ASCT. This includes absolute lymphocyte count (ALC) recovery (>0.5 cells/μL) by day +15 post ASCT, which has previously been shown to correlate with prolonged progression-free (PFS) and overall survival (OS). In a cohort of 70 MM patients who received high dose melphalan with ASCT between 8/2007 and 9/2012, we performed a comprehensive immunophenotyping panel including 35 T-, B-, NK- and Dendritic Cell (DC)-cell subsets a median of 25 days before ASCT (N=70), at day +30 post-ASCT (N=40) and at day +100 (N=51) post-ASCT. Specifically, the immunophenotyping panel included total numbers of T cells (CD3+, CD4+, CD8+), B cells (CD19+, CD20+), NK cells (CD56+CD16+) and myeloid (CD11c+) and plasmacytoid (CD123+) dendritic cells. T cell subsets included the relative proportions of double positive (CD3+CD4+CD8+), double negative (CD3+CD4-CD8-), CD4+ and CD8+ Naïve (CD3+ CD45RA+ CD45RO- CD27+), CD4+ and CD8+ central memory (CD3+ CD45RA- CD45RO+ CD27+), CD4+ and CD8+ effector memory (CD3+ CD45RA- CD45RO+ CD27-), recent thymic emigrants (CD3+ CD4+ CD45RA+ CD31+), and T-regulatory cells (CD3+ CD4+ CD25(br), CD3+CD4+CD25+CD127(d), CD3+CD4+CD25+CD127-HLADr+). B cell subsets included proportions of naïve (CD19+ CD27-), and memory (CD19+ CD27+, pre-switch CD19+ IgD+ CD27+, post-switch CD19+ IgD- CD27) cells. All patients survived to day +100. We examined MM response to ASCT, recovery of ALC by day +15 post-ASCT, clinically significant infections, PFS and OS. Characteristics in 70 patients pre-ASCT were: median (range) age 60 (28-75) yrs; 54% females; 26% KPS ≥90; response to most recent therapy was 13% in CR/sCR, 40% in VGPR, 41% in PR, 6% stable disease. MM responses at day + 100 included: 51% achieved or maintained CR/sCR, 17% VGPR, 10% PR, 24% SD and 6% progressed. The frequency of different immune cell subsets at either pre-ASCT or day +100 post-ASCT were not associated with CR/sCR status at day 100 post-AHSCT. ALC recovery by day +15 post-ASCT was associated with significantly longer median PFS (651 vs 288 days, P=0.001) and OS (804 vs 391 days, P=0.02) than those who did not recover ALC by day 15. For patients showing early recovery of ALC, the absolute numbers of T-cells pre-ASCT (P=0.08), as well as the proportion of CD4+ naïve (P=0.07) and CD8+ NK (CD8+/CD16+/CD56+, P=0.06) populations tended to be higher, whereas the absolute counts of gamma-delta T cells (P=0.02), CD4+ helper (P=0.03, See Figure), CD8+ effector (P=0.02) T-cells and total B-cell count (P=0.05) were significantly higher as compared to patients who did not achieve ALC recovery by day +15. Of note, within the T-cell compartment, CD4+ central memory (P=0.02, see Figure), CD8+ central memory (P=0.05), T-regulatory (T reg) (P=0.02, CD4+25+) populations were significantly lower. The distribution of different immune cell subsets pre-ASCT was not associated with development of clinically significant infections before day +100 post-AHCT; however, the proportion of memory B cells measured at day+100 was significantly higher (p=0.02) in patients who had experienced an infection before day +100. In the present study we show that the distribution of different immune cell populations correlates with ALC recovery in MM. Moreover, we also confirmed the association of ALC recovery with prolonged PFS and OS. The increase in the relative proportions of CD4+ and CD8+ effector cell subpopulations and the decrease in CD4+ and CD8+ central memory and T-reg populations demonstrate that the pre-ASCT effector cell phenotype contributes to faster ALC recovery, and improved PFS/OS. Therapeutic strategies to alter the pre-ASCT and/or day + 100 immune phenotype may improve outcomes after ASCT. [Display omitted] [Display omitted] Disclosures:McCarthy:Janssen: Honoraria; Celgene: Consultancy.

PK-Directed Intravenous Busulfan In Combination With High-Dose Melphalan and Bortezomib As Conditioning Regimen For Patients With Multiple Myeloma

IntroductionHigh dose therapy followed by autologous hematopoietic stem cell transplantation (ASCT) has an established role in the treatment of patients with multiple myeloma (MM). The most commonly used conditioning regimen in this setting is high-dose melphalan (200mg/m2;Mel200), which has been shown to result in improved progression free (PFS) and overall survival (OS). Achievement of a complete response (CR) following ASCT is an indicator for freedom from relapse, as well as PFS and OS. The CR rate observed after Mel200 followed by ASCT is between 10-35%. There is evidence that the combination of busulfan (Bu) and melphalan (Mel) results in longer PFS and OS compared to Mel alone. Additionally, the use of bortezomib (Btz) during conditioning with either high dose Mel alone or the combination of Mel and intravenous (i.v.) Bu has shown to be both safe and to have promising efficacy. The objective of our trial is to assess whether the combination of PK-directed Bu, Mel and Btz (BuMelBtz) during conditioning for a first ASCT in MM patients is both safe and efficacious. MethodsPatients aged 18-72 with multiple myeloma, who had 1) measurable disease, 2) received less than one year of prior myeloma-directed therapy, 3) adequate organ function and performance status, and 4) an indication for ASCT were eligible. Exclusion criteria were >/= grade 2 neuropathy, prior stem cell transplant, uncontrolled intercurrent illnesses or comorbidities, unresolved >/= grade 2 toxicities from prior therapies, and prior malignancies except non-melanoma skin cancer. Treatment consisted of PK-directed i.v. Bu (4 daily 3-hour infusions from day (D) -6 to -3 to target a total AUC of 20,000 μMxmin), i.v. Mel 140mg/m2 on D-2, and i.v. Btz 1.4mg/m2 on D-6, -4, +1 and +4. The individual daily doses for Bu on D-6 and D-5 were determined by PK measures following a test dose (0.8mg/kg) 5-9 days prior to first Bu treatment dose; the last 2 doses (day -4 and -3) could be adjusted following another PK measure after the first full treatment dose on D -6. Stem cells were infused on D0. Subsequent consolidative or maintenance therapy was left to investigator choice. Primary outcome was CR rate assessed on D +100 post ASCT as per IMWG criteria. Secondary outcomes were overall response rate (ORR), toxicities, PFS and OS. The trial is registered at clinicaltrials.gov (NCT01605032). ResultsTo date, 13 patients have been treated. The median age was 63 years (range 44-70), 62% (n=8) were male, 23% had ISS stage 3 (3/13), no patient had high risk cytogenetic features. The median number of regimens prior to ASCT was 1 (range 1-3) and included bortezomib in 92% (n=12). Prior to BuMelBtz the best treatment response had been stable disease (SD) in 3 patients, partial response (PR) in 8; only 1 patient each had achieved a very good partial response (VGPR) or CR. Following BuMelBtz/ASCT, median days to ANC >/=0.5 x 109/L and platelet count >/=30 x 109/L were 11 (range 10-13) and 17 (11-29), respectively. The most common non-hematological toxicities were alopecia (100%), oral mucositis (62% G3), dysphagia (85% G3, but no patient required TPN or enteral feeding), as well as electrolyte abnormalities (62% G3/4). Other common toxicities were nausea (92%, all G1/2), diarrhea (84% G1/2, 8% G3), while 77% of patients developed fully reversible transaminitis (15% G3). Less common G3 toxicities included delirium (8%), colitis (8%), skin infection (zoster, 8%), other infections (23%), and delirium (8%). One patient developed GI symptoms suggestive of acute GVHD on a gastric biopsy 8 weeks after ASCT. No patient developed sinusoidal obstruction syndrome of the liver. At 100 days post BuMelBtz/ASCT, response assessment was available for 8 patients: 1 achieved a stringent CR (12.5%), 4 VGPR (50%), and 3 PR (37.5%), resulting in a 100% ORR. One patient improved from a VGPR to a stringent CR during follow up. After a median follow up of 5 months (range 1-15) all patients are alive and no patient has relapsed. The trial is ongoing. ConclusionPK directed i.v. Bu in combination with Mel and Btz (BuMelBtz) is an effective and safe conditioning regimen for patients with multiple myeloma. Further evaluation is warranted. Disclosures:Barta:Otsuka: Research Funding; Onyx: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Honoraria. Off Label Use: IV Busulfan for the treatment of multiple myeloma.

Absolute Lymphocyte Count As Predictor of Survival Following Hematopoietic Stem Cell Transplants

Abstract 4538Following hematopoietic stem cell transplantation (HSCT), morbidity and mortality are often related to opportunistic infection early post HSCT and it is accepted that immune reconstitution has a protective effect. Absolute lymphocyte counts (ALC) act as a surrogate for immune reconstitution. Prior studies suggest that an ALC greater than 0.5×10^9/L on day 15 post autologous HSCTs and greater than 0.3×10^9/L on day 30 post allogeneic HSCTs can prognosticate overall survival (OS) and progression-free survival (PFS). However, most of these studies have been single disease small studies. We designed this study to evaluate whether patients with a wide variety of diseases undergoing either autologous or allogeneic HSCT at Thomas Jefferson University Hospital would fit this model or if other cut-points were more appropriate.Data was abstracted from the charts of 585 HSCTs (265 autologous, 320 allogeneic (228 HLA identical and 92 haplo-identical) preformed consecutively between January 1999 and April 2009. Prior treatments, disease status at time of HSCT, conditioning regimens, and progression-free and overall survival were collected. Survival methods (Kaplan-Meier and logrank test, and Cox proportional hazards regression) were used to analyze PFS and OS as a function of ALC and other clinical variables. Separate models were fit for ALC counts on day 15, day 30, and day 90 post-transplantation, as predictors of PFS (or OS). ALC was categorized as less than or equal to 0.5 or greater than 0.5 ×10^9/L. The possibility of differential association between ALC counts and PFS (or OS) among autografts versus allografts was tested by including interaction terms between ALC counts at each time point and graft type.For these analyses, we excluded third and fourth HSCTs (n = 4), as well as the first of tandem autologous/allogeneic HSCTs (n = 26) and the first of two HSCTs that were performed during the same admission (n = 8). We also excluded HSCTs for which ALC counts on admission or on day 15 post-HSCT were not available (n = 14). Therefore, these analyses were based on data for a total of 532 HSCTs, including 443 first HSCTs and 89 second HSCTs.Relapse was seen in 52% (229/443) first HSCTs and 45% (40/89) second HSCTs. A total of 212 (48%) first HSCTs and 63 (71%) of second HSCTs were followed up until the patient's death. In all first HSCTs (figure 1), the median PFS correlated with ALC significantly on day 30 and day 90 (p=0.007, 0.027 respectively), while the OS correlated significantly at all three time points (p=0.003, 0.001, 0.001 respectively). For PFS, the hazard ratio at day 15 was not significant for any type of transplant, but was significant at day 30 for haplo-identical transplants (HR 0.48, p=0.032) and day 90 for HLA identical transplants (HR 0.42, p=0.001). For OS, the hazard ratio was significant at day 15 (HR 0.58, p=0.022) and day 30 (HR 0.51, p=0.021) for autologous HSCTs, day 30 (HR 0.62, p=0.022) and 90 (HR 0.27, p=0.001) for HLA identical transplants, and day 30 (HR 0.017, p=0.017) and day 90 (HR 0.24, p=0.002) for haplo-identical HSCTs (Figure 1). Similarly, for all second HSCTs, the median PFS correlated with ALC significantly only day 30 (p=0.004), while the OS correlated significantly at all three time points (p=0.006, 0.001, 0.002 respectively). For PFS, the hazard ratio for day 15 was significant for HLA identical allogeneic transplants (HR 0.44, p=0.013), while for OS the hazard ratio was significant at day 15, 30, and 90 for HLA identical allogeneic transplants (HR 0.47, p=0.021; HR 0.50, p=0.034; HR 0.46, p=0.039 respectively). There was not enough data to calculate HR for second autologous transplants. An analysis was conducted to determine if the historical cut point of 0.50 × 10^9/L was the most predictive of survival. For first transplants, the best cut points differ for autologous and for allogeneic/haplo-identical grafts (0.33 ×10^9/L and 0.08 ×10^9/L, respectively) at day 15. While for day 30 and day 90, the cut point most predictive of survival is the same for autologous and for allogeneic/haplo-identical grafts (0.34 × 10^9/L for day 30 and 0.50 × 10^9/L for day 90). [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Leuprolide Acetate (GnRH Agonist) to Enhance Immune Function Post-Autologous Hematopoietic Stem Cell Transplantation (HSCT)

AbstractAbstract 4292High-dose chemotherapy with autologous HSCT results in profound immunodeficiency early post transplant. Immune reconstitution is largely derived from the transplanted stem cells and occurs over a period of many months. Sex steroid hormones (testosterone and estrogen) have been shown to inhibit thymic function. Castration and sex steroid inhibition have been reported to stimulate thymic regeneration and production of T-cells and also, improved bone marrow function. We performed a study to test the hypothesis that temporarily blocking production of sex hormones using leuprolide acetate, a gonadotropin hormone-releasing hormone [GnRH] agonist, would improve thymic function and accelerate immune reconstitution following autologous stem cell transplantation. Methods:Adult patients receiving myeloablative autologous peripheral blood progenitor cell transplantation for lymphoma, Hodgkin's disease or multiple myeloma were eligible. Females and males, age 18–50 and 18–65 years, respectively, were included. Patients were required to be in remission or have chemosensitive relapse. Patients could not have received mediastinal radiation, or recent testosterone or estrogen treatment, or post transplant therapy that would affect immune function. Patients were randomized to receive 3 intramuscular injections of leuprolide acetate (Lupron 11.25 mg 3 Month Depot) or placebo approximately 3 months apart to cover the period from the date of transplantation to 8 months post HSCT. The primary endpoint was in vitro antibody and T cell response to vaccination with keyhole limpet haemocyanin (KLH) at 6 months post-HSCT. Immunoglobulins were measured by ELISA and interferon-gamma (IFNγ) by ELISpot. Results:25 subjects (19 males and 6 females) were enrolled into the study at 3 sites. 13 were randomized to placebo and 12 to leuprolide treatment. As expected, suppression of luteinizing hormone and total testosterone was observed in males in the leuprolide acetate group at all evaluation time points during treatment (P<0.1 vs. placebo). There was no significant difference in time to engraftment or in the adverse events and transplant related toxicities experienced by the leuprolide or the placebo group. One subject in the leuprolide acetate group died during the study due to pneumonia after hematopoietic recovery, which was not considered related to study drug. Early disease progression occurred in one patient in the leuprolide acetate and 3 in the placebo group. The study was closed due to slow patient accrual.9 patients in each group completed 6 months on study. 8 patients in the leuprolide group and 5 in the placebo group received KLH vaccination and were evaluable for response one month later. There were significantly improved IgM and IgG1 responses in the leuprolide group; no significant difference was detected for IgG2, IgG3, IgG4 and IFNγ responses. The following table shows the difference in the assays performed prevaccination and 1 month post vaccination.The output of naïve T-cell subsets and the production of TCR rearrangement excision circles (TRECs) were determined at screening, and post HSCT. There was an increase in naïve CD4+ TREC positive cells at the 6 month time point consistent with renewed thymus function. Conclusion:Despite the limited number of patients, there was a trend to increased antibody responses to the de novo antigen KLH, which reached statistical significance for IgM and IgG1, reflecting increased primary and secondary immune responses. Another indicator of thymus function was the appearance of circulating naïve, TREC+ CD4+ cells at 6 months in the leuprolide acetate group. Further study of sex steroid inhibition is needed to fully establish the enhanced thymic function and immune reconstitution following HSCT. Disclosures:Off Label Use: Leuprolide (Lupron) to enhance immune recovery after stem cell transplantation. Jiang:Abbott: Employment, Equity Ownership. Chwalisz:Abbott: Employment, Equity Ownership. Mattia-Goldberg:Abbott: Employment, Equity Ownership. Sajwani:Abbott: Employment, Equity Ownership. Boyd:Norwood Immunology: Employment.

Have Clinicians Adopted the International Uniform Response Criteria (IURC) for Multiple Myeloma (MM)? Adherence to the IURC for Posttransplant Evaluations In Patients with Multiple Myeloma

AbstractAbstract 84 Background:The introduction of novel agents and the frequent use of autologous hematopoietic stem cell transplantation (AHSCT) have increased the frequency and magnitude of responses in patients with MM. There is increasing evidence that the magnitude of response influences the outcome of patients with MM. Furthermore, the availability of more sophisticated tests including serum free-light chains (SFLC) allow for a more accurate characterization of the magnitude of response. Previous response criteria were not stringent enough to accurately distinguish magnitudes of response, in particular complete response. To address this need, the International Myeloma Working Group (IMWG) proposed guidelines in July 2006 defining an IURC for patients with multiple myeloma. These criteria define the tests necessary to evaluate patients depending on the magnitude of the response and also incorporate the SFLC assay. However, there is currently limited information regarding the adherence of these guidelines by the clinical community. Study Purpose:To determine adherence to the IURC during post AHSCT in patients with MM. Methods:We performed a retrospective analysis of all patients who underwent AHSCT at our institution for MM from January 2007 to December 2009. This study time interval was selected because it allowed 6 months for dissemination of the IURC among the oncologic community and also allowed us to assess response evaluations up to 180 days posttransplantation. Posttransplant evaluations were performed by the referring program. Specific instructions regarding tests necessary for the posttransplant day 100 evaluations were provided by our program. Referring physicians decided which tests to order for the posttransplant evaluations. The response evaluations performed 100 days and 180 days posttransplantation were reviewed. All tests performed during the response assessment were recorded and the adherence to the IURC was determined. In particular, the assessment of CR as defined by the IURC guidelines was scrutinized. Furthermore, any additional clinical tests performed as part of the response assessment that were not recommended by the IURC were also recorded. Adherence to the IURC was considered met if all recommended tests were performed at each evaluation. Obtaining additional tests during the evaluation did not affect IURC adherence determination. Results:A total of 103 patients underwent AHSCT during the study period. Four patients were ineligible due to death within 100 days posttransplantation. Of the 99 patients who comprised the study group, 83 (84%) did not have evaluations that adhered to the IURC. Of evaluations not adhering to the IURC, the most common test omitted was urine protein electrophoresis (69/83; 83%). Nearly half (37/83; 45%) of evaluations not adhering to the IURC had an additional test omitted other than urine protein electrophoresis, including serum protein electrophoresis (17/83; 20%), bone marrow biopsy (12/83; 14%) and SFLC (21/83; 25%). Of all evaluations, a majority (62/99; 63%) included at least one test not recommend in the IURC. The additional tests consisted of β2 microglobulin (28/99; 28%), quantitative immunoglobulins (44/99; 44%) and serial SFLC in the presence of measurable disease (28/99; 28%). Conclusion:Only 16% of patients with multiple myeloma underwent posttransplant evaluations that adhered to the IURC guidelines. This finding suggests that community physicians have not embraced these guidelines. Laboratory tests not included in the IURC are frequently obtained despite the fact that they do not provide additional clinical information and increase the cost of care of patients with MM. Additional studies should be performed to determine the barriers to the use of IURC as defined by the IMWG.IURC Adherence (n = 99)YesNo16 (16%)83 (84%)Tests Omitted in Evaluations not Adhering to IURC (n = 83) (Evaluations have 1–4 tests omitted)SPEP####UPEPBone Marrow BiopsySFLC17 (20%)69 (83%)12 (14%)21 (25%)Tests performed not part of the IURC (n = 99) (Evaluations could have 1–3 tests performed)β2 MicroglobulinQuantitative ImmunoglobulinsSFLC + measurable disease28 (28%)44 (44%)28 (28%) Disclosures:No relevant conflicts of interest to declare.

A Randomized Phase II Trial of High-Dose Melphalan, Ascorbic Acid and Arsenic Trioxide with or without Bortezomib in Multiple Myeloma

Background: There is a role of novel preparative regimens to further improve the outcome after high-dose chemotherapy and autologous hematopoietic stem cell transplantation (ASCT) in multiple myeloma. Arsenic trioxide (ATO) has synergistic activity with melphalan and ascorbic acid (AA) both in vitro and in vivo, and this 3-drug combination was found to be safe and feasible in both conventional and high-dose settings. Bortezomib, a proteasome inhibitor, is an active agent in newly diagnosed or relapsed multiple myeloma in conventional therapy setting. We conducted a randomized phase II trial to determine the safety and efficacy of a combination of ATO, AA and melphalan with or without bortezomib as preparative regimen in patients with myeloma.Methods: Sixty patients were enrolled and 58 patient received ASCT between October 2006 and September 2007. One patient developed respiratory failure and another developed extensive pulmonary embolism after enrollment and did not proceed to ASCT. All 58 evaluable patients received melphalan 100 mg/m2 IV on days -4 and -3, AA 1000 mg/day IV on days -9 to -3 and ATO 0.25 mg/kg IV on days -9 to -3. Patients were randomized to 3 arms; no bortezomib (arm 1), bortezomib 1 mg/m2 on days -9, -6 and -3 (arm 2), and bortezomib 1.5 mg/m2 on days -9, -6 and -3 (arm 3). Patients were also asked to fill out a standardized Quality of Life (QOL) questionnaire at enrollment and at 6 months post-ASCT.Results: Median age of patients in arms 1, 2 and 3 were 61, 59 and 64 years, respectively (p=0.08). Median interval between diagnosis and ASCT were 12.2, 9.6 and 8.8 months, respectively (p=0.3). Cytogenetic abnormalities were detected in 2, 5 and 8 patients in arms 1, 2 and 3, respectively (p=0.08). With a median follow up of 11.4 months (range 5 to 20) post ASCT in surviving patients, cumulative non-relapse mortality was1.7%. Grade 3–4 toxicity was seen in 6 patients in arm 1 (mucositis 3, dyspnea 1, acute renal failure 1, pleural effusion 1), 6 patients in arm 2 (mucositis 3, diarrhea 1, pneumonia 1 and hydronephrosis 1) and 6 patients in arm 3 (pulmonary edema 2, mucositis 1, intestinal obstruction 1, low back pain 1, elevated transaminases 1) (p=0.9). The most common adverse events were nausea, diarrhea and pedal edema. Grade 1–2 weight gain due to fluid retention was seen in 84, 70 and 95% of patients in arms 1, 2 and 3, respectively (p= 0.1). Median time to neutrophil engraftment (ANC >500/dl) was 10 days in each arm. Complete response rates in arms 1, 2 and 3 were 26, 10 and 16%, respectively (0=0.4). Kaplan-Meiers estimates of progression-free survival (PFS) and overall survival (OS) are shown in Figures 1 and 2. Median PFS and OS have not been reached. There was no significant difference in CR, PFS or OS between the 3 arms (p = 0.4, 0.62 and 0.4, respectively). Relapsed disease at ASCT (p=0.003), >12 months interval between diagnosis and ASCT (p=0.05), and cytogenetic abnormalities at diagnosis (p=0.005) predicted a shorter PFS. On a subset analysis, there was no significant difference in PFS or OS between the 3 arms in patients undergoing ASCT in first remission. Fifty-patients submitted their responses to the QOL questionnaire. More patients at 6-month post ASCT reported better overall health (56% vs.12%, p=0.0001). In contrast, more patients at study enrollment reported moderate to severe pain (44% vs. 27%, p=0.09) and debilitating emotional problems (42% vs. 23%, p=0.07).Conclusions: Adding bortezomib to ATO, AA and high dose melphalan is safe and well tolerated as preparative regimen for ASCT in patients with multiple myeloma. Patients with chromosomal abnormalities were predominantly treated in the bortezomib arms without an adverse impact on PFS or OS. Overall QOL indicators showed improvement at 6-month post ASCT. Longer follow up is needed to assess the efficacy of this combination. [Display omitted] [Display omitted]

A Higher Ratio of Dose to Actual Weight of Conditioning Chemotherapy Leads to More Toxicity without Improvement in Outcome in Autologous HSC Transplant for DLBCL.

Background: High-dose chemotherapy and hematopoietic stem cell (HSC) transplantation is considered standard therapy in patients with chemosensitive relapsed diffuse large B cell lymphoma (DLBCL). BCNU, etoposide, cytarabine and melphalan (BEAM) is a standard widely used DLBCL conditioning regimen. Chemotherapy doses, both standard and high dose, are traditionally based in body surface area (BSA) and are often calculated using the corrected ideal body weight. However, this practice is empirical and the best way to dose chemotherapy is unknown. Weight-based dosing has been suggested to better predict toxicity of the conditioning regimen. We correlate the BEAM dose/actual weight ratio with toxicity and overall outcome in a uniform cohort of patients receiving HSC transplant for relapsed DLBCL Methods: Retrospective analysis of 80 consecutive patients treated at Mayo Clinic, Rochester, MN between 2001 and 2006 who received a HSC transplant following BEAM conditioning was performed. All doses were based on BSA calculated using the corrected ideal body weight. Weight-based dose intensity was retrospectively calculated utilizing the melphalan dose/Kg as a surrogate for the entire regimen. Weight-based dose intensity was correlated with toxicity in the first 30 days after transplant and survival outcome. Results: Median age at the time of transplant was 62 (interquartile range 53–65; range 26–77); 65% were males; median number of prior chemotherapy regimens was 2. Median dose of melphalan was 3.2 mg/Kg (interquartile range 2.9–3.6; range 2.2–4.5). Only one patient died within 30 days of the transplant. Patients who received &gt; 3.6 mg/Kg of melphalan were more likely to have Grade 3 or 4 mucositis (44.4% v. 9.8%, P=0.001) than the remaining patients. Median numbers of days spent in the hospital in the first 30 days after transplant was 13 (3–18) for melphalan dose &gt;3.6 mg/kg vs. 7 (0.5–10.5) for the remaining patients (P=0.043). Weight based dose intensity did not correlate with survival (P=0.8) or disease-free survival (P=0.3). Conclusion: Weight based dose intensity of BEAM correlates with toxicity post autologous HSC transplant. Patients receiving doses corresponding to &gt;3.6 mg/kg of melphalan are at increased risk of high-grade mucositis and prolonged hospitalization. Figure Figure