Prior auto-HCT Research Articles

Daratumumab-Based Maintenance in Patients with Relapsed Multiple Myeloma after Salvage Autologous Hematopoietic Stem Cell Transplantation

Introduction: Maintenance therapy is considered standard of care after upfront autologous hematopoietic stem cell transplantation (auto-HCT) for patients with newly diagnosed multiple myeloma (MM). However, there is paucity of data on the use of maintenance after a salvage auto-HCT, whether first or second. Aim: We designed a clinical trial for relapsed MM patients who underwent salvage auto-HCT after disease relapse to receive post-transplant maintenance with daratumumab (dara), with the addition of pomalidomide (pom) in a later amendment. Methods: We hypothesized that maintenance therapy with dara +/- pom will improve the progression-free survival (PFS) after a salvage auto-HCT. Patients with prior exposure to dara or pom were included, but patients refractory to either drug were excluded. The trial was planned to enroll a total of 56 patients. Patients received dara SQ weekly for weeks 1-8, every 2 weeks for weeks 9-24, and monthly from week 25 until progression. Pom was given at 2 mg PO from day 1-21 every 28 days. Patients received herpes zoster prophylaxis for the duration of the trial. The primary endpoint of this phase II trial was PFS. Disease response was assessed according to the International Myeloma Working Group (IMWG) uniform response criteria. Minimal residual disease (MRD) was measured by multiparametric flow cytometry (10 -5) in the bone marrow at day 90-180 after transplant. Results: The trial was terminated due to poor accrual after 13/56 patients were enrolled between May 2019 and August 2022. Median age at salvage auto-HCT was 64 (range: 43-76) years, and 7 patients (54%) were male. Median prior lines of treatment was 2 (range: 2-4). Six patients (46%) had a prior auto-HCT, and 7 (54%) had a hematopoietic stem cell comorbidity index (HCT-CI) of >3. Median time from diagnosis to salvage auto-HCT was 58.3 (range 7.6-132) months. Five patients (38%) had high-risk cytogenetic abnormalities (1q+ in all 5). Eight (61%) patients received melphalan alone, 4 (31%) received busulfan/melphalan, and 1 (8%) received gemcitabine/busulfan/melphalan/panobinostat as their conditioning regimen (Table 1). Three patients (23%) started maintenance with dara alone, while the remaining 10 (77%) patients received dara + pom. At study entry, 6 patients (46%) had a complete response (CR), 4 (31%) in very good partial response (VGPR), 2 (15%) in partial response (PR), and 1 (8%) had stable disease (SD). At day 100 post maintenance, 9 (69%) were in CR, while 1 (8%) each had VGPR, PR, SD and progressive disease (PD), respectively. For the 12 patients that did not progress at day 100, best response to dara +/- pom maintenance was CR in 10 (83%), and VGPR and SD in 1 (8%) each. With a median follow up of 26.1 months (range: 14.2-37.7) from the start of maintenance, 3 patients had progressed but there are no deaths so far. Median PFS from the date of auto-HCT was not reached, and from start of maintenance 28.5 (95% CI 26.3-NA) months. 2-year PFS was 92% (Figure 1). Most common adverse events were neutropenia (n=11, 84%; none grade>3), grade 1-2 fatigue (n=6, 46%), and grade ≤3 bacterial infection, grade ≤3 viral infection, grade 1-2 diarrhea and grade 1 thrombocytopenia (n=5, 38% each). Conclusion: Maintenance therapy with dara, with or without pom, is safe and feasible after a salvage auto-HCT for MM, with 83% achieving a CR. After a median follow up exceeding 2 years, the median PFS was 28.5 months. The trial was terminated due to poor accrual.

Outcome of Second Primary Malignancies Developing in Multiple Myeloma Patients.

There is an increased risk of second primary malignancies (SMPs) in patients with multiple myeloma (MM). This multinational 'real-world' retrospective study analyzed the characteristics and outcomes of MM patients that developed SPMs. 165 patients were analyzed: 62.4% males; 8.5% with a prior cancer; 113 with solid SPMs, mainly ≥stage 2; and 52 with hematological SPM (hemato-SPM), mainly MDS/AML. Patients with hemato-SPM were younger (p = 0.05) and more frequently had a prior AutoHCT (p = 0.012). The time to SPM was shorter in the older (>65 years) and more heavily pretreated patients. One hundred patients were actively treated at the time of SPM detection. Treatment was discontinued in 52, substituted with another anti-MM therapy in 15, and continued in 33 patients. Treatment discontinuation was predominant in the patients diagnosed with hemato-SPM (76%). The median OS following SPM detection was 8.5 months, and the main cause of death was SPM. A poor ECOG status predicted a shorter OS (PS 3 vs. 0, HR = 5.74, 2.32-14.21, p < 0.001), whereas a normal hemoglobin level (HR = 0.43, 0.19-0.95, p = 0.037) predicted longer OS. With the continuing improvement in OS, a higher proportion of MM patients might develop SPM. The OS following SPM diagnosis is poor; hence, frequent surveillance and early detection are imperative to improve outcomes.

Allogeneic Hematopoietic Cell Transplant Yields Long Term Disease Free Survival in a Significant Number of Patients with Classic Hodgkin Lymphoma

Background: Classic Hodgkin's lymphoma (cHL) is a highly curable disease. A minority of patients, however, will have relapse/refractory (RR) disease and these patients are challenging to manage especially those who relapse after autologous hematopoietic cell transplant (auto-HCT). Even though a number of salvage options are available for these patients none of them is considered curative except allogeneic hematopoietic cell transplant (allo-HCT). Design and Methods: Retrospective analysis of 33 patients who had allo-HCT using matched family donors for cHL between January 2007 and December 2021. Continuous variables were summarized using medians and ranges. Categorical variables were summarized using frequencies and percentages. Probabilities of overall survival (OS) and disease free survival (DFS) were calculated using Kaplan-Meier estimate. Statistical analysis was conducted sing R studio (version 1.3.959 © 2009-2020 RStudio, PBC). Results: The median patient age at allo-HCT was 27 years. Seventeen patients were males and 16 were females. Five patients had early stage disease (Ann Arbor stage I, II) and 28 had advanced stage disease (Ann Arbor III, IV). Regarding the histologic type of cHL, eighteen had nodular sclerosis (NS), eight had mixed cellularity (MC), one had lymphocyte rich (LR), one had lymphocyte depleted (LD) and five cases were labeled as classic HL without further classification. Seventeen patients received brentuximab vedotin and fourteen patients received check point inhibitors prior to allo-HCT. The median number of chemotherapy lines prior to allo-HCT was 4 (range: 2-8). Twenty seven patients had chemosensitive disease (complete or partial remission) while 6 patients had chemoresistant disease (stable or progressive) prior to allo-HCT. Twenty seven patients had undergone auto-HCT prior to allo-HCT. Eighteen patients had elevated (>50) erythrocyte sedimentation rate (ESR) while 15 had normal ESR prior to allo-HCT. The majority of patients were conditioned with a reduced intensity regimen (29 patients versus 4 patients conditioned with myeloablative regimen). Twenty five patients received non-TBI (total body irradiation) based conditioning while 8 patients had TBI based regimen. The most frequently used conditioning regimen was fludarabine + melphalan. Nine patients received ATG (anti thymoglobulin) as a part of the conditioning while 24 patients did not. Thirty one patients received peripheral blood graft while 2 patients received bone marrow graft. The five years DFS was 37.5%. Twenty seven % of patients had acute GVHD (graft versus host disease) and 48% had chronic GVHD. The effect of a number of variables (number of chemotherapy lines, pre-allo-HCT ESR, conditioning intensity, ATG vs no ATG, receipt of pre-allo-HCT brentuximab or check point inhibitors, prior auto-HCT, chemosensitivity pre-allo-HCT and histologic subtype) was tested on the DFS. The only two variable that were statistically associated with a better DFS were pre-allo-HCT chemosensitivity (P=0.006) and non-NS histologic subtype (P=0.027). (Figure 1 and 2). Conclusions: Allogeneic stem cell transplantation can result in long-term progression-free survival in heavily pre-treated patients with Hodgkin's lymphoma. Patients with no response to salvage chemotherapy pre-allo-HCT and patients with NS subtype had detrimental outcomes. Better selection of patients before allo-HCT can result in a higher cure rates. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Allogeneic transplant and CAR-T therapy after autologous transplant failure in DLBCL: a noncomparative cohort analysis

AbstractAllogeneic transplant (alloHCT) and chimeric antigen receptor modified (CAR)-T cell therapy are potentially cuarative options of diffuse large B-cell lymphoma (DLBCL) relapsing after an autologous (auto)HCT. Although the Center for International Blood and Marrow Transplant Research (CIBMTR) prognostic model can predict outcomes of alloHCT in DLBCL after autoHCT failure, corresponding models of CAR-T treatment in similar patient populations are not available. In this noncomparative registry analysis, we report outcomes of patients with DLBCL (≥18 years) undergoing a reduced intensity alloHCT or CAR-T therapy with axicabtagene ciloleucel during 2012 to 2019 after a prior auto-HCT failure and apply the CIBMTR prognostic model to CAR-T recipients. A total of 584 patients were included. The 1-year relapse, nonrelapse mortality, overall survival (OS), and progression-free survival for CAR-T treatment after autoHCT failure were 39.5%, 4.8%, 73.4%, and 55.7%, respectively. The corresponding rates in the alloHCT cohort were 26.2%, 20.0%, 65.6%, and 53.8%, respectively. The 1-year OS of alloHCT recipients classified as low-, intermediate- and high/very high-risk groups according to the CIBMTR prognostic score was 73.3%, 59.9%, and 46.3%, respectively (P = .002). The corresponding rates for low-, intermediate-, and high/very high-risk CAR-T patients were 88.4%, 76.4%, and 52.8%, respectively (P < .001). This registry analysis shows that both CAR-T and alloHCT can provide durable remissions in a subset of patients with DLBCL relapsing after a prior autoHCT. The simple CIBMTR prognostic score can be used to identify patients at high risk of treatment failure after either procedure. Evaluation of novel relapse mitigations strategies after cellular immunotherapies are warranted in these high-risk patients.

ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION FOR PERIPHERAL T‐CELL LYMPHOMA: COMPARABLE OUTCOMES OF HAPLO‐IDENTICAL VS. MATCHED DONORS. A CIBMTR &amp; EBMT ANALYSIS

Introduction: The advent of immunosuppression with post-transplant cyclophosphamide (ptCY) has facilitated allogeneic hematopoietic cell transplantation (alloHCT) from haplo-identical donors in patients lacking a matched donor. The aim of this study was to compare the outcomes of ptCY haplo-identical transplantation (haploHCT) with that of alloHCT from matched sibling donors (msdHCT), matched unrelated donors with in-vivo T-cell depletion (mudHCT-TCD), and matched unrelated donors without T-cell depletion (mudHCT-TRD) in patients with peripheral T-cell lymphoma (PTCL). Methods: Eligible for this retrospective registry study were patients aged 18 or older who had undergone alloHCT for anaplastic large cell lymphoma(ALCL), angioimmunoblastic T-cell lymphoma (AITL), or PTCL-not other specified (PTCL-NOS) from the 4 donor types described between 2008 and 2018 and were registered with the CIBMTR or the EBMT. Co-primary endpoints were overall survival (OS) and progression-free survival (PFS); secondary endpoints included engraftment, acute and chronic GVHD, non-relapse mortality (NRM), and relapse/progression incidence (RI). Results: Altogether 1942 patients were eligible (haploHCT 237; msdHCT 911; mudHCT-TCD 468; mudHCT-TRD 326). HaploHCT and matched aloHCT recipients were comparable for histology, age, gender, comorbidity score, pretreatment lines, prior autoHCT, and disease status at HCT. However, haploHCT patients were more likely to have a Karnofsky score of 90-100, and had more often received reduced intensity conditioning as well as bone marrow grafts (31% vs 6%). On univariate and multivariate comparisons, OS and PFS, RI, and NRM were not significantly different between haploHCT, msdHCT, mudHCT-TCD, and mudHCT-TRD with 3-year estimates for OS and PFS of 60%, 63%, 59%, and 64; and 50%, 50%, 48%, and 52%, respectively. Engraftment was significantly delayed after haploHCT (neutrophils >0.5/nl at d +28 86% vs 95%, 94%, 97%, respectively, p < 0.001; platelets >20/nl at d +100 80% vs 96%, 93%, 96%, respectively, p < 0.001). Whilst risk of acute GVHD was comparable between haploHCT, msdHCT, and mudHCT-TCD, there was a lower 1-year cumulative incidence of chronic GVHD after haploHCT (28% vs 41%, 35%, and54%; p < 0.001); retaining significance after multivariate adjustment for confounders. Factors significantly impairing both OS and PFS on multivariate analysis were advanced disease status at alloHCT, age >50, and poor Karnofsky score. Patients undergoing alloHCT in 1st line had significantly better OS than patients allografted later. Conclusions: These data, the largest study to date, confirm that alloHCT can result in durable PFS in a sizable proportion of patients with ALCL, AITL, and PTCL-NOS. The outcome of haploHCT in PTCL is comparable to that of matched donor alloHCT, suggesting that haploHCT might be a valid alternative in this setting. Keywords: Stem Cell Transplant Conflicts of interests pertinent to the abstract P. Dreger Consultant or advisory role: Gilead, Novartis, BMS, Bluebird Bio, Takeda

Nivolumab Combined with Brentuximab Vedotin for Relapsed/Refractory Mediastinal Gray Zone Lymphoma: Primary Efficacy and Safety Analysis of the Phase 2 CheckMate 436 Study

Nivolumab Combined with Brentuximab Vedotin for Relapsed/Refractory Mediastinal Gray Zone Lymphoma: Primary Efficacy and Safety Analysis of the Phase 2 CheckMate 436 Study

A Matching-Adjusted Indirect Comparison of Nivolumab Versus Brentuximab Vedotin for Relapsed/Refractory Classical Hodgkin Lymphoma after Failure of Autologous Hematopoietic Cell Transplantation

A Matching-Adjusted Indirect Comparison of Nivolumab Versus Brentuximab Vedotin for Relapsed/Refractory Classical Hodgkin Lymphoma after Failure of Autologous Hematopoietic Cell Transplantation

Outcomes of Patients with T-Lymphoblastic Lymphoma Undergoing Allogeneic Stem Cell Transplantation: Retrospective Results from a Single Center

Background: T-lymphoblastic lymphoma (T-LBL) is a highly aggressive non-Hodgkin lymphoma seen in young adults that usually presents with a mediastinal mass and less than 20% bone marrow involvement with neoplastic cells. T-LBL and T-cell ALL are morphologically and immmunophenoytpically similar and are thus frequently grouped together. However there are differences in clinical presentation, cytogenetic features and molecular pathogenesis indicating biologic differences. Patients with relapsed refractory T-LBL have poor prognosis and there is a paucity of data on allogeneic HCT (allo-HCT) outcomes in this setting. Methods: We retrospectively reviewed medical records of 25 consecutive patients with T lymphoblastic lymphoma without prior auto-HCT who underwent allo-HCT at City of Hope from January 2000 to June 2018 after IRB approval was obtained. Descriptive statistics were used to summarize baseline patient demographic, treatment, and disease characteristics. Kaplan-Meier curves and the log-rank test were used to evaluate the overall survival (OS) and progression-free survival (PFS). Cumulative incidences of time to relapse and time to non-relapse mortality (NRM) were calculated with relapse and NRM as competing risks. Cumulative incidences of acute and chronic GVHD were calculated as time to onset of GVHD with relapse and death as competing events for GVHD. Results: 25 patients were included for the analysis. Median age at the time of allo-HCT was 25 years (range 7-70 years). 21 patients (80%) received myeloablative conditioning: FTBI containing regimens (n=20) with FTBI/VP-16 being most commonly used(n=16) and one patient received Bu/Cy based conditioning; 4 patients received reduced intensity conditioning with Flu/Mel. Sibling HCT was performed in 12 patients (48%), while MUD HCT was performed in 13 patients (52%) with fully matched HLA unrelated donor in 9 (36%) and HLA mismatched in 4 (16%) patients. GVHD prophylaxis consisted of tacrolimus/sirolimus (n=10), tacrolimus or cyclosporine/MTX (n=7), tacrolimus/sirolimus/MTX (n=4) and others (n=4) Source of stem cells was PBSC in 19 (76%), bone marrow in 5 (20%), and cord blood in 1 (4%) patients. At the time of allo-HCT, there were a total of 11 (44%) patients in complete remission (CR1 n=4, CR2+ n=7), 9 (36%) patients in partial remission and unknown remission status (n=5). The median follow-up among survivors was 8.9 years (range 2.3-12.1). The 5- and 10-year PFS was 31% (95% CI: 14%-50%). The 5- and 10-year OS was 31% (95% CI: 14%-49%) (Fig.1). Cumulative incidence of relapses at 5 and 10 years were both 36% (95% CI: 18%-55%) while NRM at 5 and 10 years was 33% (95% CI: 15%-52%). At day 100 after allo-HCT, the rates of acute GVHD grade II-IV were 63% (95% CI: 39%-79%) and grade III-IV of 25% (95%CI: 10%-44%). Chronic GVHD rates at 3 years were 60% (95% CI: 37%-77%). In univariate analysis, preHCT remission status did not improve PFS on long term follow up. Conclusions: Our results in patients with T-LBL shows 5-year PFS and OS of 31%, respectively, indicating that a subset of patients can be cured with allo-HCT in the high-risk setting. Disclosures Salhotra: Celgene: Other: Research Support; Kadmon Corporation: Other: Non paid consultant. Popplewell:City of Hope: Employment. Herrera:Kite Pharma: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Pharmacyclics: Research Funding; AstraZeneca: Research Funding; Immune Design: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Mei:Seattle Genetics, Inc.: Research Funding. Aldoss:AUTO1: Consultancy; Helocyte: Consultancy, Honoraria, Other: travel/accommodation/expenses; Jazz Pharmaceuticals: Honoraria, Other: travel/accommodation/expenses, Speakers Bureau; Agios: Consultancy, Honoraria. Zain:Seattle Genetics: Honoraria, Speakers Bureau; spectrum: Honoraria.

Comparison of Reduced-Intensity Conditioning (RIC) Regimens for Allogeneic Hematopoietic Cell Transplantation (alloHCT) in Non-Hodgkin Lymphomas (NHL)-a Center for International Blood & Marrow Transplant Research (CIBMTR) Analysis

Introduction: Reduced-intensity and non-myeloablative (RIC/NMA) conditioning regimens are frequently used in alloHCT for NHL, because they are associated with decreased non-relapse mortality (NRM) risk in comparison with myeloablative conditioning regimens and allow older patients and patients with comorbidities to receive alloHCT. However, the optimal RIC/NMA regimen in allo-HCT for NHL is not known. Using the CIBMTR database we compared the transplant outcomes between the commonly used RIC/NMA regimens in NHL. Methods: 1823 adult (≥18 years) NHL patients in CIBMTR registry undergoing alloHCT using matched related or unrelated donors, between 2008-2016 were included. Analysis was limited to patients receiving four commonly used RIC/NMA regimens: fludarabine/ i.v. busulfan (6.4mg/kg) (Flu/Bu), fludarabine/melphalan (140mg/m^2) (Flu/Mel 140), fludarabine/cyclophosphamide (Fly/Cy) and Flu/Cy with 2Gy Total Body Irradiation (Flu/Cy/TBI). Graft-versus-host disease (GVHD) prophylaxis was limited to calcineurin inhibitor-based regimens. Patients who received post transplantation cyclophosphamide for GVHD prophylaxis were excluded. The primary outcome was overall survival (OS). Secondary outcomes included cumulative incidence of NRM, relapse, progression-free survival (PFS) and cumulative incidence of acute and chronic GVHD. Probabilities of OS and PFS were calculated using the Kaplan-Meier estimator. Multivariable regression analysis was performed for GVHD, relapse/progression, NRM, PFS, and OS. Covariates with a p&amp;lt;0.01 were considered significant. Results: The study cohort was divided into 4 groups; Flu/Bu (n=458), Flu/Cy/TBI (n=89), Flu/Mel 140 (n=885) and Flu/Cy (n=391). The baseline characteristics are shown in Table 1. The 4 cohorts were comparable with respect to median patient age, gender, donor type, remission status at alloHCT, and use of prior auto HCT. There was no interaction between NHL histological subtype and type of conditioning regimen. Results of multivariate analysis are shown in Table 2. The Flu/Mel 140 regimen was associated with a higher NRM (HR 1.78, 95% CI 1.37-2.31; p&amp;lt;0.001) when compared to Flu/Bu. Although the risk of relapse with Flu/Mel 140 was lower when compared to Flu/Bu (HR 0.79, 95% CI 0.66-0.94); p=0.007), this did not result in an improvement in PFS. Moreover, the Flu/Mel 140 cohort had an inferior OS (HR 1.34, 95% CI 1.13-1.59; p&amp;lt;0.001) when compared to Flu/Bu. There was no significant difference in terms of OS, PFS, relapse and NRM between Flu/Bu, Flu/Cy and Flu/Cy/TBI. There was no difference in risk of grade 3-4 acute GVHD across the four cohorts and compared to Flu/Cy/TBI, Flu/Mel 140 had a higher risk of chronic GVHD (HR 1.38, 95% CI 1.15-1.65; p&amp;lt;0.001). Four year adjusted PFS was 38% for Flu/Bu, 51% for Flu/Cy/TBI, 39% for Flu/Mel 140 and 35% for Flu/Cy (p=0.07). Four year adjusted OS was 58% for Flu/Bu, 67% for Flu/Cy/TBI, 49% for Flu/Mel 140 and 63% for Flu/Cy (p&amp;lt;0.001). Disease relapse was the most common cause of death across all 4 cohorts. Conclusion: This is the largest analysis comparing the impact of various RIC/NMA conditioning regimens on the outcomes of NHL patients undergoing alloHCT. We report that the choice of RIC/NMA conditioning regimen significantly impacted OS. The most commonly used conditioning regimen, Flu/Mel 140 was associated with a higher NRM and an inferior OS. The Flu/Bu, Flu/Cy, and Flu/CY/TBI conditioning regimens appear to provide comparable OS. Disclosures Ghosh: Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; SGN: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Research Funding; Forty Seven Inc: Research Funding; AstraZeneca: Honoraria, Speakers Bureau. Kharfan-Dabaja:Pharmacyclics: Consultancy; Daiichi Sankyo: Consultancy. Sureda:Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Sanofi: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Novartis: Honoraria; Roche: Honoraria. Hamadani:Merck: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Otsuka: Research Funding; Medimmune: Consultancy, Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Sanofi Genzyme: Research Funding, Speakers Bureau.

Transplant outcomes for patients with therapy-related acute myeloid leukemia with prior lymphoid malignancy: an ALWP of EBMT study.

Allogeneic hematopoietic cell transplant (HCT) is a curative therapy for patients with secondary acute myeloid leukemia (sAML), though the impact of conditioning regimens on HCT outcomes for patients with antecedent lymphoid malignancy is largely unknown. This multicenter, retrospective registry study of the ALWP of the EBMT assessed HCT outcomes in this population. In all, 549 patients ≥18 years with sAML following an antecedent lymphoid malignancy treated with first allograft between 2000-2016 were included. Myeloablative (MAC) and reduced intensity conditioning (RIC) was given in 258 (47%) and 291 (53%), respectively. At 2 years, leukemia-free survival (LFS) was 31.7% (95% CI, 27.5-35.9), overall survival (OS) was 37.4% (95% CI, 33-41.8), nonrelapse mortality (NRM) was 28.9% (95% CI, 25-33), and GVHD-free, relapse-free survival (GRFS) was 22.8% (95% CI, 19-26.6). In multivariate analysis, patients receiving RIC regimens had lower risk of NRM (HR: 0.58, CI: 0.40-0.83, p = 0.003), and improved LFS (HR: 0.67, CI: 0.52-0.85, p = 0.001). Patients with prior autologous HCT had inferior LFS (HR: 1.30, CI: 1.01-1.67, p = 0.01). This study demonstrates that sAML patients following prior lymphoid malignancy treated with RIC regimens have a lower risk of NRM and improved LFS, OS, and GFRS. Other variables associated with inferior outcomes include older age, active disease, adverse cytogenetics, and prior auto-HCT.

Allogeneic hematopoietic cell transplantation provides effective salvage despite refractory disease or failed prior autologous transplant in angioimmunoblastic T-cell lymphoma: a CIBMTR analysis

BackgroundThere is a paucity of data on the role of allogeneic hematopoietic cell transplantation (allo-HCT) in patients with angioimmunoblastic T-cell lymphoma (AITL). Using the CIBMTR registry, we report here the outcomes of AITL patients undergoing an allo-HCT.MethodsWe evaluated 249 adult AITL patients who received their first allo-HCT during 2000–2016.ResultsThe median patient age was 56 years (range = 21–77). Majority of the patients were Caucasians (86%), with a male predominance (60%). Graft-versus-host disease (GVHD) prophylaxis was predominantly calcineurin inhibitor-based approaches while the most common graft source was peripheral blood (97%). Median follow-up of survivors was 49 months (range = 4–170 months). The cumulative incidence of grade 2–4 and grade 3–4 acute GVHD at day 180 were 36% (95% CI = 30–42) and 12 (95% CI = 8–17), respectively. The cumulative incidence of chronic GVHD at 1 year was 49% (95%CI 43–56). The 1-year non-relapse mortality (NRM) was 19% (95% CI = 14–24), while the 4-year relapse/progression, progression-free survival (PFS), and overall survival (OS) were 21% (95% CI = 16–27), 49% (95% CI = 42–56), and 56% (95% CI = 49–63), respectively. On multivariate analysis, chemoresistant status at the time of allo-HCT was associated with a significantly higher risk for therapy failure (inverse of PFS) (RR = 1.73 95% CI = 1.08–2.77), while KPS < 90% was associated with a significantly higher risk of mortality (inverse of OS) (RR = 3.46 95% CI = 1.75–6.87).ConclusionOur analysis shows that allo-HCT provides durable disease control even in AITL patients who failed a prior auto-HCT and in those subjects with refractory disease at the time of allografting.

Impact of Allogeneic Hematopoietic Cell Transplantation (allo-HCT) on the Outcomes of Angioimmunoblastic T-Cell Lymphoma (AITL): A Center for International Blood and Marrow Transplant Research (CIBMTR) Analysis

Introduction: AITL is a distinct clinicopathologic entity among the mature T-cell and NK-cell lymphomas, accounting for approximately 1-2% of all non-Hodgkin lymphomas. Although autologous HCT (auto-HCT) provides high response rates, there is a high relapse risk associated with this procedure. Allo-HCT may result in a lower risk of relapse in part due to a graft-versus-lymphoma effect mediated by alloreactive donor cells. The role of allo-HCT in AITL with advanced disease (prior auto-HCT failure, or chemorefractory state) is not well described. Using the CIBMTR registry, we report here the outcomes of AITL patients undergoing an allo-HCT.Methods: We evaluated 249 adult (≥18years) patients with AITL who received a first allo-HCT during 2000-2016. Patients receiving mismatched unrelated donor, cord blood or haploidentical donor transplantation were excluded due to small numbers. The primary end-point was overall survival (OS). Secondary endpoints included cumulative incidence of acute graft-versus-host disease (GVHD), chronic GVHD, non-relapse mortality (NRM), relapse/progression (R/P) and progression-free survival (PFS).Results: Baseline patient characteristics are summarized in Table. The median patient age was 56 years (range=21-77 years). The graft source was mainly peripheral blood. Median follow-up of survivors was 49 months (range=4-170 months).The cumulative incidence of grade 2-4 and grade 3-4 acute GVHD at day 180 were 36% (95% CI=30-42)% and 12 (95% CI=8-17)%, respectively. The cumulative incidence of chronic GVHD at 2 years was 58% (95% CI=51-64)%. The 1-year NRM was 19% (95% CI=14-24)%, while the 4-year R/P, PFS, and OS were 21% (95% CI=16-27)%, 49% (95% CI=42-56)% and 56% (95% CI=49-63)%, respectively [Figure]. On multivariate analysis, chemoresistant status at allo-HCT was associated with a significantly higher risk for progression (RR=1.73 95% CI=1.08-2.77), while KPS <90% was associated with a significantly higher risk of mortality (RR=3.46 95% CI=1.75 - 6.87). Subgroup analysis looking at the effect of prior auto-HCT (no prior auto-HCT vs prior auto-HCT), the 4-year PFS (50% vs 47%, p=0.60) and OS (57% vs 54%, p=0.70) were not significantly different. Similarly, on comparing the disease status at allo-HCT (CR1 vs CR>1 vs PR vs refractory), there was no significant difference in the 4-year PFS (58% vs 45% vs 47% vs 38%, p=0.41) or OS (70% vs 54% vs 50% vs 52%, p=0.27). The 1-year NRM was 24%, while the 4-year R/P, PFS, and OS in patients with refractory AITL were 32%, 38%, and 52%, respectively. The most common cause of death was organ failure.Conclusion: In this largest series of mostly advanced AITL patients, allo-HCT was shown to provide durable disease control (4-year PFS=47%) with a clear plateau in relapse at 1-year post-transplantation. Allo-HCT provided durable disease control even in patients with a failed prior auto-HCT and those subjects with refractory disease at the time of allografting. DisclosuresKharfan-Dabaja:Alexion Pharmaceuticals: Speakers Bureau; Incyte Corp: Speakers Bureau; Seattle Genetics: Speakers Bureau. Smith:BMS: Consultancy; Portola: Honoraria. Sureda:Sanofi: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria; Roche: Honoraria; BMS: Consultancy, Honoraria. Hamadani:Merck: Research Funding; Celgene Corporation: Consultancy; ADC Therapeutics: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Ostuka: Research Funding; Janssen: Consultancy; MedImmune: Consultancy, Research Funding; Takeda: Research Funding; Cellerant: Consultancy.

Carfilzomib Plus High Dose Melphalan Conditioning Prior to Autologous Hematopoietic Cell Transplantation Followed By Carfilzomib Maintenance in Patients with Relapsed Multiple Myeloma

Background: Melphalan at 200mg/m2 (Mel-200) preceding autologous hematopoietic cell transplantation (auto-HCT), is part of the upfront management of patients with multiple myeloma (MM) and has also been used in the salvage setting, often as second transplant. While lenalidomide or bortezomib are routinely employed as maintenance therapy after upfront auto-HCT, there is no established maintenance strategy for patients receiving auto-HCT for relapsed MM. Proteasome inhibitors (PI) have been shown in vitro to impair the Fanconi/BRCA pathway of DNA repair and increase DNA fragmentation and apoptosis induced by alkylating agents in MM cells. Carfilzomib (K), a second generation PI, has been combined with conventional doses of alkylator agents with encouraging efficacy. We hypothesized that K could be safely combined with Mel-200 (K-Mel) in a conditioning regimen prior to auto-HCT and employed as post-transplant maintenance.Methods: We performed a phase 1, multi-center, dose escalation trial with traditional 3+3 design to determine the maximal tolerated dose (MTD) of K in combination with Mel-200. Subsequently in phase 2, the MTD cohort was expanded for additional safety and efficacy information on the conditioning regimen and to test the safety, efficacy, pharmacodynamics and patient-preference of two distinct schedules of K maintenance. Eligible patients had symptomatic MM, relapsed after at least one line of therapy, with evaluable disease and having obtained at least a minimal response (MR) after the most recent salvage regimen. Patients were required to have ≥2 x 106 CD34+ cells/kg available for transplant. Conditioning consisted of two doses of K administered IV over 30 min. on days -3 and -2. The day -2 dose was administered 1 h prior to administration of Mel-200. K dose consisted of 20(day-3)/27 (day -2) mg/m2 (cohort 0), 27/27 (cohort 1), 27/36 (cohort 2), 27/45 (cohort 3) and 27/56 mg/m2 (cohort 4, phase 2 dose). Maintenance was initiated after 100 days from transplant (phase 2 only). During maintenance patients received K 36 mg/m2 on days 1,8 and 15 (schedule A) or days 1,2,15 and 16 (schedule B) of each 28-day cycle. Each patient receives 2 cycles of each schedule with starting schedule determined by randomization, and 8 subsequent cycles of the patient-preferred schedule.Results: Fifteen patients were treated during phase 1 with no dose-limiting toxicity. Therefore no MTD was reached and the maximal tested dose was employed during phase 2. Accrual is complete with 31 patients treated in phase 2. Overall 46 patients (phase 1 + phase 2) have received K-Mel conditioning. Among all the 46 patients, median age was 58.5 years (range 41-69). Median number of prior lines of therapy was 3 (range 2-6); 98% received prior bortezomib, 93% lenalidomide, 16% pomalidomide, 51% prior carfilzomib, and 58% prior auto-HCT. Pharmacodynamic studies in peripheral blood mononuclear cells revealed that K precluded melphalan-induced increase in FANCD2 and FANCI mRNA. Thirty-five patients (15 phase 1 + 20 phase 2) had 100 days of follow up and underwent disease reassessment, while 11 received K-Mel and auto-HCT but have not yet reached day 100. Median time for engraftment was 10 days (range 8-15) for neutrophils and 16 days (range 9-24) for platelets. There were no non-hematologic grade 4 toxicities after K-Mel. Response categories before and 100 days after K-Mel conditioning are displayed in Figure 1. The proportion of patients with response ≥ VGPR increased from 17.2% before to 54.2% after K-Mel (P=0.003). Twenty patients (phase 2 only) have entered maintenance. Two patients discontinued maintenance due to toxicity (congestive heart failure and acute renal failure) and 5 due to progression. There have been no deaths on study. Interim one-year PFS is 69.6% (Figure 2, 95% C.I. 46.9-92.3%). Among the 16 patients who have completed at least 4 cycles of K maintenance, 9 have choose schedule A and 7 schedule B for subsequent cycles.Conclusion: K-Mel is a well-tolerated and active conditioning regimen for patients with relapsed MM. K is a feasible and active maintenance agent for patients undergoing auto-HCT for relapsed MM. Updated safety, efficacy, pharmacodynamics and patient preference for maintenance schedule will be presented at the meeting. [Display omitted] [Display omitted] DisclosuresCosta:Sanofi: Honoraria, Research Funding. Landau:Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx/Amgen: Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hari:Merck: Research Funding; BMS: Honoraria. Saad:Astellas: Research Funding; American Porphyria foundation: Research Funding; Alexion: Honoraria; Spectrum: Honoraria. Hamadani:Takeda: Research Funding. Petrovic:Amgen: Employment.

Ibrutinib for Bridging to Allogeneic Hematopoietic Stem Cell Transplantation (alloHCT) in Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL) Is Safe and Effective: First Results of a Survey By the Chronic Malignancy and the Lymphoma Working Parties of the EBMT

BACKGROUND: The advent of the Bruton's tyrosine kinase inhibitor ibrutinib has improved the outlook of patients with CLL and MCL failing chemoimmunotherapy (CIT). However, the impact of ibrutinib on the feasibility and safety of a subsequent alloHCT is unknown. Here we present results of the ibrutinib cohort of an ongoing EBMT survey on the outcome of alloHCT following prior exposure to pathway inhibitors (PI) in patients with CLL or lymphoma (EBMT study code LWP 2013-N-03/CMWP 44204425).DESIGN: Eligible were patients aged >18 years registered with the EBMT data office for a planned alloHCT for CLL or lymphoma after pre-exposure to ibrutinib at any time before transplant. Baseline patient, disease, and transplant data were collected from MED-A forms. Centers were requested to provide additional treatment and follow-up information. Statistical analysis used Gray’s test to assess the impact of baseline characteristics on the cumulative incidence of relapse (REL) in a competing risk framework.RESULTS: As of July 4, 2016, 38 patients (84% male) were evaluable in the ibrutinib cohort. Diagnosis was CLL in 28 patients, MCL in 9 patients, and follicular lymphoma (FL) in 1 patient. The median age was 51 (33-68) years and the median number of treatment lines prior to ibrutinib 2 (1-9). Eight of the 9 patients with MCL but none of the other patients had a prior autoHCT. Patients had been on ibrutinib for a median of 190 (39-432) days. In 2 patients, ibrutinib had been stopped because of disease progression >100d before transplant, whereas the interval between ibrutinib withdrawal and alloHCT was 15-100d in 30%, 4-14d in 51%, and 0-1d in 14% of the patients. Of the CLL patients, 43% had a TP53 lesion, and 87% and 79% met at least one of the 2007 and 2014 EBMT criteria for high-risk CLL, respectively, including PI failure in 29%. Disease status at alloHCT was sensitive in 78% of the CLL patients, and in 60% of the patients with lymphoma. Conditioning was reduced-intensity in 60% of the transplants and included in-vivo T cell depletion with ATG (71%) or alemtuzumab (11%) in the majority of cases. Donors were identical siblings in 26%, matched unrelated in 66%, and partially matched unrelated in 8%, with PBSC (89%) being the predominant stem cell source (bone marrow 8%, cord blood 3%). The median time to reach neutrophils of >0.5/nl and platelets of >20/nl was 17 (10-26) and 15 (10-46) d post transplant, respectively. Acute GVHD grade 2-4 (3-4) was observed in 37% (10%) of 30 evaluable patients, and limited and extensive chronic GVHD occurred in 24% and 16% of 25 patients at risk. With a median observation time of survivors of 8 (1-24) months, there were only 2 non-relapse deaths, translating into a 1-year non-relapse mortality (NRM) of 6% (95%CI 0-15%). 1-year REL, progression-free survival, and overall survival was 36%, 61%, and 73% for CLL, and 14%, 75%, and 75% for lymphoma. In the 25 evaluable patients with CLL, PI-sensitive compared to refractory disease status at alloHCT tended to be associated with a lower 1-y REL (29% vs 60%; p 0.071), whereas prior PI failure, TP53 status, duration of ibrutinib exposure, interval between ibrutinib withdrawal and alloHCT, and conditioning intensity had no significant impact on REL.CONCLUSIONS: Ibrutinib for bridging to alloHCT for CLL and MCL does not appear to adversely affect engraftment, GVHD risk, and NRM. Patients with CLL still responding to ibrutinib at the time of alloHCT might benefit from ibrutinib bridging as our preliminary results indicate that also after PI exposure sensitive disease translates into a lower risk of relapse. Therefore, ibrutinib may improve the perspective of CIT-refractory patients scheduled for alloHCT. The optimum timing of ibrutinib administration in the interrelation to alloHCT in CLL and MCL needs to be defined by additional studies. DisclosuresDreger:Gilead: Consultancy; Janssen: Consultancy; Novartis: Speakers Bureau; Gilead: Speakers Bureau; Novartis: Consultancy; Roche: Consultancy. Michallet:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria. Berg:Celgene: Other: Travel Funding; Astellas: Other: Travel Funding; Alexion: Other: Travel Funding. Niederwieser:Novartis Oncology Europe: Research Funding, Speakers Bureau; Amgen: Speakers Bureau. Montoto:Gilead: Research Funding; Roche: Honoraria. Schetelig:Sanofi: Honoraria.

Phase I/II Trial of Lenalidomide and High-Dose Melphalan with Autologous Stem Cell Transplantation for Relapsed Myeloma: Updated Results

IntroductionWhile high dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) is an accepted part of up front therapy for patients with multiple myeloma (MM), the role of this treatment modality for relapsed patients is still evolving. In light of data suggesting safety and synergy in combining novel therapeutics with traditional cytotoxic chemotherapy, we hypothesized that lenalidomide could be safely combined with high dose melphalan in the salvage auto-HCT setting and yield a meaningful duration of disease control.MethodsWe conducted a phase I/II study of lenalidomide and high dose melphalan + auto-HCT. MM patients with relapsed or progressive disease were treated with 7 days of oral lenalidomide (doses of 25, 50, 75 or 100 mg daily for the 7 days) on days (-8) to (-2). High dose melphalan (total of 200 mg/m2) was administered as 100 mg/m2 IV on days (-3) and (-2) followed by auto-HCT on day 0. The Eff-Tox method of Thall, Cook, and Estey was used for dose escalation with cohorts of 3 to maximize the trade-off between efficacy and toxicity, defined as CR at day 90 and regimen-related death, graft failure, or select grade 3+ events within 30 days after transplant, respectively. Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) and the log-rank test was used to assess univariate differences between dose levels. Bayesian logistic regression and survival time models were used for multivariable analyses, with posterior probabilities greater than 0.95 or less than 0.05 considered significant. Initial results after 12.3 months of follow-up were published in 2015; we now present an update with 39.8 months of follow-up.Results57 patients were enrolled, of which 18 (32%) had received a prior auto-HCT. A total of 3, 5, 24 and 25 patients received 25, 50, 75 and 100 mg of lenalidomide, respectively. Median age at auto-HCT was 60 (34-72) years. Median prior lines of treatment were 3 (1-11). Twenty-two patients (39%) were lenalidomide-refractory at study entry. Patient characteristics did not differ significantly between the lenalidomide dose levels. In total, only 2 dose-limiting toxicities were seen, both at dose level 75 mg. Two patients died of nonrelapse causes (viral infection 1, cardiac failure 1) for a treatment-related mortality of 4%. Median time to both neutrophil and platelet engraftment was 11 days. One patient developed a second primary malignancy (squamous cell cancer of the skin). 63% received maintenance therapy, (54% lenalidomide-based). By day +90, 8 patients (14%) had achieved a complete response (CR), 17 (30%) a very good partial response (VGPR), and 17 (30%) a partial response (PR), with no significant differences in response rates among the 4 lenalidomide dose levels. Best responses were PR: 26%, VGPR: 18%, near CR: 18%, CR: 7%, stringent CR: 23% for a ≥VGPR rate of 66. 23% achieved bone marrow minimal residual disease negativity by flow cytometry. Median time to achieve best response was 92 days (range: 16-732). One patient (2%) had progressive disease and 3 patients (5%) achieved only stable disease. Multivariable Bayesian logistic regression revealed that high-risk cytogenetics, (deletion 13q, t(4:14) or del 17p) by conventional cytogenetics or (t(4:14), t(14:16) or del17p by fluorescent in-situ hybridization), bone marrow disease burden and number of prior lines of treatment were each significantly associated with a lower probability of reaching CR by day 90. With a median follow up of 39.8 months (range: 0.5- 66.9), median PFS was 17.1 months (95% CI: 10.8 - 23.0, Figure 1) and median OS was 48.0 months (95% CI: 22.6 months, not estimated, Figure 2). There was no significant effect of dose level on PFS or OS. Multivariable Bayesian survival time models found high-risk cytogenetics to be significantly harmful to both OS and PFS. In addition, degree of plasma cell infiltration of bone marrow before auto-HCT was significantly harmful to PFS.Conclusion: Lenalidomide up to 100 mg PO daily x 7 can be safely combined with high dose melphalan and auto-HCT. Longer follow-up demonstrates PFS and OS as comparable to other salvage treatments for MM, suggesting that this regime can be applied as a part of the sequence of therapies for these patients. [Display omitted] [Display omitted] DisclosuresOrlowski:Takeda Pharmaceuticals: Research Funding. Champlin:Intrexon: Equity Ownership, Patents & Royalties; Ziopharm Oncology: Equity Ownership, Patents & Royalties.

Allogeneic transplantation provides durable remission in a subset of DLBCL patients relapsing after autologous transplantation.

For diffuse large B-cell lymphoma (DLBCL) patients progressing after autologous haematopoietic cell transplantation (autoHCT), allogeneic HCT (alloHCT) is often considered, although limited information is available to guide patient selection. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified 503 patients who underwent alloHCT after disease progression/relapse following a prior autoHCT. The 3-year probabilities of non-relapse mortality, progression/relapse, progression-free survival (PFS) and overall survival (OS) were 30, 38, 31 and 37% respectively. Factors associated with inferior PFS on multivariate analysis included Karnofsky performance status (KPS) <80, chemoresistance, autoHCT to alloHCT interval <1-year and myeloablative conditioning. Factors associated with worse OS on multivariate analysis included KPS<80, chemoresistance and myeloablative conditioning. Three adverse prognostic factors were used to construct a prognostic model for PFS, including KPS<80 (4 points), autoHCT to alloHCT interval <1-year (2 points) and chemoresistant disease at alloHCT (5 points). This CIBMTR prognostic model classified patients into four groups: low-risk (0 points), intermediate-risk (2-5 points), high-risk (6-9 points) or very high-risk (11 points), predicting 3-year PFS of 40, 32, 11 and 6%, respectively, with 3-year OS probabilities of 43, 39, 19 and 11% respectively. In conclusion, the CIBMTR prognostic model identifies a subgroup of DLBCL patients experiencing long-term survival with alloHCT after a failed prior autoHCT.

Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation (allo-HCT) Provides Durable Progression-Free Survival (PFS) in a Subset of Diffuse Large B-Cell Lymphoma (DLBCL) Patients Relapsing after Autologous (auto-) HCT

▪Background: DLBCL relapsing after an auto-HCT has a poor prognosis. Unfortunately this is a common clinical dilemma, since ~50% of auto-HCTs for DLBCL ultimately fail. Allo-HCT is often considered following failure of an auto-HCT; however, limited information is available regarding prognostic factors identifying DLBCL patients likely to benefit from a subsequent allo-HCT.Methods: Adult (≥18 years) DLBCL patients undergoing an alloHCT between 2000-2012, after experiencing disease progression/relapse (P/R) following a prior autoHCT and reported to the CIBMTR were included. Patients undergoing tandem auto-allo HCT and those receiving allo-HCT for indications other than relapsed DLBCL were excluded. Primary outcomes were non-relapse mortality (NRM), P/R, PFS, and overall survival (OS). Cox regression method was used to develop a prognostic model of PFS and OS.Results: Characteristics of 503 patients included in this analysis are shown in Table 1. The 3-yr univariate probabilities of NRM, P/R, PFS and OS were 30%, 38%, 31% and 37% respectively. Factors associated with higher NRM on multivariate analysis (MVA) included chemoresistance disease prior to allo-HCT (RR=1.86; p=0.003), myeloablative conditioning (MAC) (RR=1.99; p=0.0006; within 1st 10months following alloHCT) and unrelated donors (URD) grafts (RR=1.44; p=0.03). Factors associated with P/R on MVA included chemoresistance (RR= 2.25, p<0.0001), Karnofsky performance status (KPS) <80 (RR 1.81, p=0.006), and interval between auto-HCT and allo-HCT of <1 yr (RR=2.28, p<0.0001). Factors associated with inferior PFS on MVA included KPS <80 (RR=1.79, p=0.0005), chemoresistance (RR=2.04, p<0.0001), auto-HCT to allo-HCT interval <1 yr (RR=1.32, p=0.01), and MAC (RR 1.29, p=0.03). Factors associated with worse OS on MVA included KPS <80 (RR1.86, p=0.0003), chemoresistance (RR=1.94, p<0.0001), MAC (RR=1.39, p=0.008). Three adverse prognostic factors were used to construct a prognostic model for PFS, including; (i) KPS <80 (2 points) (ii) Interval between auto-HCT & allo-HCT of <1yr (1 point) and (iii) chemoresistant disease at allo-HCT (2 points). This CIBMTR prognostic model classified patients into three prognostic groups: low risk (0-1 points), intermediate risk (2-3 points), or high risk (4-5 points), predicting 3-yr PFS probabilities of 38% (95% CI=32-44), 19% (95% CI=11-27) and 10% (95% CI=0-22), respectively (Fig 1). The 3-yr OS probabilities in similar order were 43%, 25% and 14% respectively.Conclusion: The CIBMTR prognostic model identifies a subgroup of DLBCL patients relapsing from an auto-HCT who can experience long-term PFS following an allo-HCT. Reduced-intensity conditioning is preferred in this setting. TableN=503 (%)Median age at alloHCT, years52 (range 19-72)Male gender305 (61)KPS ≥80393 (78)Stage III-IV at diagnosis54%Rituximab prior to HCT72%Median lines of therapy4 (range 1-7)High LDH at HCT34%Time from auto-HCT to allo-HCT, months15 (range 1-198)Disease status at transplantCR175 (35)PR197 (39)Chemorefractory106 (21)Untreated12 (2)Missing13 (3)Type of donorSibling253 (50)URD250 (50)Myeloablative conditioning127 (25)PB graft456 (91)TBI in conditioning133 (26)Median follow up, months55 (range 1-149) [Display omitted] DisclosuresSmith:Celgene: Consultancy; Pharmacyclics: Consultancy. Sureda:Seattle Genetics Inc.: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau.

Phase I/II Trial of Lenalidomide and High Dose Melphalan with Autologous Stem Cell Transplantation for Relapsed Myeloma

IntroductionWhile high dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) is an accepted part of up front therapy for patients with multiple myeloma (MM), the role of this treatment modality for relapsed patients is still evolving. In the era of modern therapeutics, it is reasonable to consider that the advantages gained for relapsed patients in the conventional setting may also extend to auto-HCT. We thus hypothesized that lenalidomide could be safely combined with high dose melphalan in the salvage auto-HCT setting and yield a meaningful duration of disease control.MethodsWe conducted a phase I/II study of lenalidomide and high dose melphalan + auto-HCT. MM patients with relapsed or progressive disease were treated with 7 days of oral lenalidomide (doses of 25, 50, 75 or 100 mg daily for the 7 days) on days (-8) to (-2). High dose melphalan (total of 200 mg/m2) was administered as 100 mg/m2 IV on days (-3) and (-2) followed by auto-HCT on day 0. The Eff-Tox method of Thall, Cook, and Estey was used for dose escalation with cohorts of 3 to maximize the trade-off between efficacy and toxicity, defined as CR at day 90 and regimen-related death, graft failure, or select grade 3+ events within 30 days after transplant, respectively. Kaplan-Meier curves were used to estimate PFS and OS and the log-rank test was used to assess univariate differences between dose levels. Bayesian logistic regression and survival time models were used for multivariable analyses, with posterior probabilities greater than 0.95 or less than 0.05 considered significant.Results57 patients were enrolled, of which 18 (32%) had received a prior auto-HCT. A total of 3, 5, 24 and 25 patients received 25, 50, 75 and 100 mg of lenalidomide, respectively. Median age at auto-HCT was 60 (34-72) years. Median prior lines of treatment were 3 (1-11). Twenty-two patients (39%) were lenalidomide-refractory at study entry. Patient characteristics did not differ significantly between the lenalidomide dose levels. In total, only 2 dose limiting toxicities were seen, both at dose level 75mg. Two patients died of nonrelapse causes (viral infection 1, cardiac failure 1) for a treatment-related mortality of 3%. Median time to both neutrophil and platelet engraftment was 11 days. One patient developed a second primary malignancy (squamous cell cancer of the skin). By day +90, 8 patients (14%) had achieved a CR, 25 (44%) a CR or very good partial response (VGPR), and 42 (74%) a CR, VGPR or partial response (PR), with no significant differences in response rates among the 4 lenalidomide dose levels. By day 180, 12 patients (21%) had achieved a CR. Multivariable Bayesian logistic regression revealed that high-risk cytogenetics, bone marrow disease burden and number of prior lines of treatment were each significantly associated with a lower probability of reaching CR by day 90. With a median follow up of 12.3 months (range 0.5-41), median PFS was 23.7 months and median OS had not yet been reached. The 1-year progression-free rate was 64% (95% CI: 49-75%). Multivariable Bayesian survival time models found both dose level and longer time between diagnosis and transplant to be significantly beneficial to both OS and PFS. In addition, high risk cytogenetics and LDH were significantly harmful to OS, and LDH was moderately harmful for PFS as well (Figures 1 and 2).Conclusion: Lenalidomide up to 100 mg PO daily x 7 can be safely combined with high dose melphalan and auto-HCT. Our previous data has shown a median PFS of 12.3 months in a comparable population. Thus this treatment regimen yields an encouraging PFS, offering relapsed or refractory patients another option for disease control. [Display omitted] [Display omitted] DisclosuresShah:Sanofi Aventis: Membership on an entity’s Board of Directors or advisory committees; Celgene: Research Funding. Off Label Use: This presentation discusses lenalidomide in a transplant preparative chemotherapy combination. . Shah:Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Array: Consultancy, Research Funding. Orlowski:Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Spectrum Pharmaceuticals: Research Funding; JW Pharmaceutical: Research Funding; Array BioPharma: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity’s Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees. Champlin:Celgene: Consultancy, Research Funding.

Brentuximab Vedotin Improves HCT-CI, CR Status, and Peri-Transplant Toxicity In Patients With Relapsed/Refractory Hodgkin Lymphoma Heading To RIC Allo-HCT

BackgroundThe prognosis of patients with Hodgkin lymphoma (HL) who relapse following autologous hematopoietic cell transplantation is poor. Although reduced intensity allogeneic hematopoietic cell transplantation (RIC allo-HCT) can induce durable remissions in some patients with relapsed/refractory HL, its use is limited by patient co-morbidities, lack of disease control prior to HCT, and transplant related morbidities/mortalities. Brentuximab vedotin (BV), a novel antibody-drug conjugate, has a 75% objective response rate in patients with relapsed/refractory HL (Younes 2012). We performed a retrospective analysis comparing patient characteristics prior to HCT and outcomes after HCT in relapsed/refractory HL patients who received BV and underwent RIC allo-HCT versus those who did not receive BV but underwent RIC allo-HCT. MethodsBetween Jan 2003 and July 2009 (Pre-BV era), we identified a consecutive case-series of 23 HL patients who underwent RIC allo-HCT with no prior BV exposure (no-BV group). From July 2009 to Dec 2012, we identified a consecutive case-series of 21 additional HL patients who received BV prior to RIC allo-HCT (BV group). Co-morbidities at the time of HCT were measured by the HCT-CI. The Bearman scale was used to capture toxicities associated with RIC allo-HCT. PFS and OS were calculated using Kaplan-Meier method. ResultsBaseline characteristics are listed in Table 1. All patients received fludarabine and melphalan conditioning regimens. Groups were similar in terms of age, stage, response to induction, number of prior therapies, donor type, cell source, and prior auto-HCT. Groups differed in terms of GVHD prophylaxis (institutional shift to tacro/siro from 2005), remission status, and co-morbidity index (HCT-CI) at the time of HCT. Patients in the BV group were more likely to be in complete remission (CR) at the time of transplant (p=0.04). The median HCT-CI was better in the BV group (0 vs. 2, p=0.003). Also the Bearman toxicity score during transplant showed fewer grade III-IV events in the BV patients (0 vs. 7, p=0.015).Table 1RIC allo-HCT following BV: BV group (n=21)RIC allo-HCT: no-BV group (n=23)Median age (range)31 (22, 55)37 (16, 63)Median number of prior regimens (range)4 (3, 6)4 (3, 6)Prior Auto-HCT19/21 (90.5%)19/23 (82.6%)Stages at diagnosisI-II: 9 (42.9%)III-IV: 11 (52.4%)Unknown: 1I-II: 11 (47.8%)III-IV: 11 (47.8%)Unknown: 1Median number of cycles of b-vedotin (range)7 (2, 16)Response to inductionRefractory: 5 (23.8%)Relapsed: 16 (76.2%)Refractory: 7 (30.4%)Relapsed: 16 (69.6%)ChemosensitivitySensitive: 19(90.5%)Resistant: 2 (9.5%)Sensitive: 16 (69.6%)Resistant: 7 (30.4%)Disease status at transplantationCR 6 (28.9%)PR: 9 (42.9%)SD/PD: 6 (28.6%)CR 1 (4.3%)PR: 9 (39.1%)SD/PD: 13 (56.5%)Co-morbidity score at transplant (HCT-CI)0 (0, 3)2 (1, 4)Type of transplantMUD: 11 (52.4%)MRD: 10 (47.6%)MUD: 11(47.8%)MRD: 12 (52.2%)Conditioning regimenFludarabine/melphalan 100%Fludarabine/melphalan 100%GVHD prophylaxisTacro/Siro: 16 (76.2%)Tacro/Siro/MTX: 3CsA/MTX: 2Tacro/Siro: 12 (52.2%)Tacro/Siro/MTX: 4Tacro/MTX: 1CsA/Cellcept: 3CsA/Cellcept/ATG: 1CsA/Cellcept/MTX: 2WBC engraftment (range)14 (11, 21)15 (10, 20)Plt engraftment (range)13 (11, 26)13 (8, 35)Chimerism100%100%aGVHD I-IV, III-IV28.6% , 4.8%47.8%, 8.7%cGVHD76.2%78.3%Bearman ToxicityGrade III-IV07The median follow-up for living patients in the no-BV group was 70.2 month and 23.3 months for the BV group (5 year lag for BV group). The 2-yr PFS for the no-BV group was 26.1% (95% CI: 21.5, 30.9) compared to 51.8% (95% CI: 38.5, 63.6) for the BV group, p=0.099. The 2-yr cumulative incidence of relapse/progression for no-BV was 56.5% (95% CI: 33.2, 74.4) compared to 28.9% (95% CI: 9.9, 51.4) for BV, p= 0.066. The 2-yr OS was 56.5% (95% CI: 44.3, 67) for no-BV compared to 66.6% (95% CI: 47.8, 80.0) for BV. Non-relapse mortality (NRM) at day 100 was 4.3% and 17.4% at 1 yr for the no-BV group. For the BV group NRM at day 100 was 0% and 11.8% at 1 yr. The rate of aGVHD and cGVHD were 56.5% and 78.3% for no-BV, and 33.3% and 76.2% for BV groups, respectively. ConclusionBV prior to RIC allo-HCT in relapsed HL leads to improvements in 1) HCT-CI 2) CR status at time of transplant, and 3) reduced peri-transplant toxicity. Disclosures:Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau, Trave expenses Other. Siddiqi:Seattle Genetics: Speakers Bureau.

Allogeneic hematopoietic cell transplantation for neuroblastoma: the CIBMTR experience

While the role of auto-HCT is well established in neuroblastoma, the role of allo-HCT is controversial. The CIBMTR conducted a retrospective review of 143 allo-HCT for NBL reported in 1990-2007. Patients were categorized into two different groups: those who had not (Group 1) and had (Group 2) undergone a prior auto HCT (n=46 and 97, respectively). One-year and five-year overall survival (OS) were 59% and 29% for Group 1 and 50% and 7% for Group 2. Amongst donor types, disease free survival (DFS) and OS were significantly lower for unrelated transplants at 1 and 3 years but not 5 years post-HCT. Patients in complete response (CR) or very good partial response (VGPR) at transplant had lower relapse rates and better DFS and OS, compared to those not in CR or VGPR. Our analysis indicates that allo-HCT can cure some neuroblastoma patients, with lower relapse rates and improved survival in patients without a history of prior auto-HCT as compared to those patients who had previously undergone auto-HCT. Although the data do not address why either strategy was chosen for patients, allo-HCT after a prior auto-HCT appears to offer minimal benefit. Disease recurrence remains the most common cause of treatment failure.