Olalekan O. Oluwole

Superior Long-Term Outcome of Patients With Early Transformation of Non-Hodgkin Lymphoma Undergoing Stem Cell Transplantation

UNLABELLED In this study, we discuss the results of patients with transformed lymphoma (TL) undergoing stem cell transplantation (SCT). Because of the paucity of literature on the treatment of TL, deciding on the optimal evidence-based treatment is a challenge. Herein, our results indicate that patients with early transformation may benefit the most from SCT. BACKGROUND Transformed non-Hodgkins lymphoma arising from follicular lymphoma (TL) carries a poor prognosis with a median survival time after transformation reported to be approximately 1 year. PATIENTS AND METHODS Fifty-one consecutive patients with TL received SCT between January 2000 and December 2010 (autologous SCT, n = 44, allogeneic SCT, n = 7). RESULTS Thirty-six (70.5%) patients had an early transformation, defined as histologic evidence of transformation at the time of initial diagnosis or transformation within 1 year of follicular lymphoma. Fifteen patients had early stage disease (29%) and 36 (71%) had advanced stage disease on presentation. At the time of analysis, 37 patients were alive with an estimated 5-year overall survival (OS) and event free survival (EFS) of 61.8% and 45%, respectively. OS and EFS were not significantly different between types of transplant procedure. The major cause of transplant failure was disease recurrence, with estimated 2-year relapse rate of 37.4%. Importantly, early transformation was independently associated with improved OS (hazard ratio [HR] 3.29; P = .028) and EFS (HR 2.49; P = .029). CONCLUSION Our results indicate that an aggressive transplant approach should be considered first in patients with TL and emphasize the need to incorporate novel strategies (eg, immunomodulation) early post-SCT to prevent relapses as disease recurrence remains the major cause of failure in heavily pretreated patients.

Cutaneous manifestations and management of hematologic neoplasms

Many malignant hematologic neoplasms can directly and indirectly involve the skin with lesions that are disfiguring, painful, and compromise integumentary function. The majority of lymphomas that directly infiltrate the skin are of T-cell origin but B-cell lymphomas, and other hematologic neoplasms, including acute myeloid and lymphoblastic leukemias, can also have cutaneous involvement, whereas some have an indolent course, eg, mycosis fungoides and marginal zone lymphoma, and easily respond to localized therapy with overall survival (OS) measured in years to decades. Others have a more clinically aggressive course, eg, natural killer (NK)/T-cell lymphoma and diffuse large B-cell lymphoma, leg type, that require high-dose multimodality therapy, and have an OS measured in months to a few years. Lymphoma can also lead to secondary cutaneous alterations, including a variety of paraneoplastic phenomena. We present an overview of direct and indirect skin involvement by malignant lymphocytes and other hematologic neoplasms. We also describe molecular and immunophenotypic aspects of these diseases and how they are treated.

At The Bedside: Clinical review of chimeric antigen receptor (CAR) T cell therapy for B cell malignancies

T cells kill microbial‐infected and malignant cells by detection of nonself antigens with the TCR. Tumor reactivity can be encoded genetically by introducing a chimeric antigen receptor (CAR) into T cells. CARs are composed of an antigen‐binding domain and an intracellular T cell activation domain. Early human trials evaluating CD19‐targeted CAR T cells for chronic lymphocytic leukemia (CLL) showed limited responses until CARs included a costimulation domain, and conditioning chemotherapy was given before T cell infusion. Clinical trials evaluating CD19‐targeted CAR T cells for B cell acute lymphoblastic leukemia (B‐ALL) are demonstrating response rates up to 90%. However, these clinical outcomes are associated with a cytokine release syndrome (CRS), which is caused by T cell activation and manifests as high‐grade fever, hypotension, and other cardiovascular complications. It is currently managed conservatively but can be treated with cytokine‐directed therapy or with high‐dose steroids. Current efforts are dedicated to confirming the clinical efficacy and managing toxicities in multicenter Phase II trials. We present a thorough overview of the preclinical and clinical development of CAR T cell therapy that will highlight important areas for the basic researcher to investigate in the laboratory and contribute to this exciting field.

Consolidative therapy with stem cell transplantation improves survival of patients with mantle cell lymphoma after any induction regimen

Intensive induction regimen followed by high-dose chemotherapy and autologous stem cell transplantation (auto-SCT) is frequently used to improve outcomes in patients with mantle-cell lymphoma. The comparative impact of conventional vs intensive induction regimen before transplantation is unknown. Forty-eight patients with mantle-cell lymphoma receiving SCT at our institution between January 2000 and December 2010 were included in this study. At the time of initial presentation, 43 (89.5%) had stage IV disease and 18 (37.5%) received more than one chemotherapy regimen before transplantation. Forty patients underwent auto-SCT and 7 had allogeneic SCT (allo-SCT); 1 patient had an allo-SCT for relapsed disease after auto-SCT. At the time of this analysis (median follow-up of 6 years from diagnosis and 4 years from transplantation), 40 patients (88%) were alive with a 5-year disease-free survival of 74.8%. Age, disease stage, number of regimens pre-SCT, pre-SCT disease status, and type of SCT had no impact on long-term outcomes. Importantly, there were no differences among the types of induction regimen on outcomes in this cohort receiving SCT. Based on our data, we believe that future studies should focus on strategies to prevent disease relapse rather than comparing induction regimens before stem cell transplantation.

Abstract CT019: Primary results from ZUMA-1: a pivotal trial of axicabtagene ciloleucel (axicel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL)

Introduction: Outcomes for pts with refractory aggressive NHL are poor with current therapies (Crump, ASCO 2016). Results from the interim analysis of (n=62) of ZUMA-1, the 1st multicenter trial of an anti-CD19 chimeric antigen receptor (CAR) T cell, axi-cel, in refractory aggressive NHL, showed an objective response rate (ORR) of 79% (complete response [CR] 52%; Blood 2016;128:LBA-6). Here we present results from the primary analysis of ZUMA-1. Methods: Pts received a target dose of 2 × 106 anti-CD19 CAR T cells/kg after lowdose conditioning with cy/flu. Eligible pts (≥18 y) had diffuse large B cell lymphoma (DLBCL), primary mediastinal B cell lymphoma (PMBCL) or transformed follicular lymphoma (TFL); an ECOG performance status (PS) 0-1; and refractory disease (progressive or stable disease as best response to last prior therapy, or relapsed ≤12 m of autologous stem cell transplant [ASCT]). The primary endpoint for this analysis was ORR in the combined DLBCL, PMBCL, and TFL population. Key secondary endpoints were duration of response (DOR), overall survival (OS), and frequency of adverse events (AEs). The primary analysis was triggered when 92 pts had at least 6 m of follow-up. Results: As of January 27, 2017, 111 pts from 22 institutions were enrolled; 101 pts (91%) received axi-cel. Median age was 58 y (range, 23-76), 67% male, 85% stage IIIIV, 47% IPI 3-4, 77% refractory to ≥2nd line of therapy, and 21% relapsed ≤12 m of ASCT. Axi-cel was successfully manufactured in 110/111 (99%) pts with an average turnaround time from apheresis to the clinical site of 17 d. With an ORR of 82% (n = 92; P Conclusions: Axi-cel significantly improved ORR in patients with refractory aggressive NHL. The CR rate was 7-fold higher compared to historical controls (Crump, ASCO 2016) and nearly half the patients have an ongoing response. Axi-cel demonstrated significant clinical benefit with a manageable safety profile in pts lacking curative treatment options.[F.L.L. and S.S.N. contributed equally to this study.] Funding source: Kite Pharma and in part by funding from the Leukemia & Lymphoma Society (LLS) Therapy Acceleration Program treatment options. Citation Format: Frederick L. Locke, Sattva S. Neelapu, Nancy L. Bartlett, Lazaros J. Lekakis, David Miklos, Caron A. Jacobson, Ira Braunschweig, Olalekan Oluwole, Tanya Siddiqi, Yi Lin, John Timmerman, Jonathan W. Friedberg, Adrian Bot, John Rossi, Lynn Navale, Yizhou Jiang, Jeff Aycock, Meg Elias, Jeff Wiezorek, William Y. Go. Primary results from ZUMA-1: a pivotal trial of axicabtagene ciloleucel (axicel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT019. doi:10.1158/1538-7445.AM2017-CT019

Long-term outcome after autologous or allogeneic stem cell transplantation in patients with recurrent follicular lymphoma

Thirty-five consecutive patients with follicular lymphoma (FL) receiving SCT at our institution between January 2000 and December 2010 were included in this study. At the time of presentation, 30 (86%) had advanced stage disease and 25 (71%) received three or more chemotherapy regimens prior to transplantation. In all, 12 (34%) patients were in complete response pre-SCT following salvage therapy. At the time of analysis (median follow-up 6 years from diagnosis and 4 years from transplantation), 24 patients were alive with an estimated 5-year OS and PFS of 66.5 and 53%, respectively. OS and PFS in patients receiving auto-SCT (91.7%, 73.3%) were superior compared with patients receiving allo-SCT (53.9%, 43%). Our data support early use of auto-SCT in patients with FL and suggest the need to improve allo-SCT outcome. Integrating novel agents in a combined modality approach may improve long-term outcome in FL.

Outcomes of autologous or allogeneic stem cell transplantation for non-Hodgkin lymphoma

Transplant outcomes of autologous or allogeneic stem cell transplantation (SCT) have not been elucidated as a single cohort in non-Hodgkin lymphoma (NHL). We analyzed the outcomes of 270 adult recipients receiving autologous (auto) SCT (n = 198) or allogeneic (allo) SCT (n = 72) for NHL between the years 2000 and 2010. Five-year overall survival rates for B and T cell NHL were 58% and 50%, respectively (allo-SCT 51% vs. 54% for B and T-cell NHL, and auto-SCT 60% vs. 47% for B and T cell lymphoma, respectively). In multivariate analysis, the number of chemotherapy regimens and disease status pre-SCT were independently associated with long-term outcome after SCT (for both auto- and allo-SCT). We conclude that the type of transplantation offered to patients, based on patient selection and disease-related factors, can achieve long-term survival, highlighting the importance of further improvement in disease control and reducing procedure-related mortality. The role of transplantation needs to be reevaluated in the era of targeted therapy.

Myelodysplastic/Myeloproliferative disorder with severe leukocytosis: a case report.

Myelodysplastic myeloproliferative disorder (MDS/MPD) refers to clonal proliferative myeloid disorders that have both dysplastic and proliferative features at the time of initial presentation, and that are difficult to assign to either the myelodysplastic or myeloproliferative group of diseases. MDS/MPD could affect any of the myeloid precursors resulting in hyperplasia, and dysplasias and peripheral cytopenia. Affectation of the erythroid precursors could result in refractory anemia, ringed sideroblasts, and nucleated red blood cells. Leukocytosis when present in MDS/MPD is defined as a white blood cell count in excess of 10/UL, associated with cellular atypia and blasts. We present a case of MDS/MPD presenting with leukocytosis of 113.5 10/UL.

Post-traumatic stress disorder and depression in survivors of thrombotic thrombocytopenic purpura

INTRODUCTION Survivors of thrombotic thrombocytopenic purpura (TTP) have high rates of chronic morbidities including neurocognitive complications and depression. There is limited information regarding the psychological consequences of TTP. We conducted this cross sectional study to estimate the prevalence of symptoms of PTSD and depression in survivors of TTP. METHODS An online survey tool comprising demographic and clinical information and two validated self-administered questionnaires, the PTSD checklist for DSM-5 (PCL-5) and Beck Depression Inventory-II (BDI-II), was distributed to individuals with TTP. Multivariable regression was used to identify clinical and demographic associations of depression and PTSD. RESULTS A total of 236 individuals completed either the BDI II or PCL-5 and were included in the analysis. Median age was 44years and 87.3% were female. Median time from diagnosis was 80months. BDI-II scores >13 indicating at least mild depressive symptoms were present in 80.8% individuals (15.8%, 28.2%, and 36.8% with mild, moderate and severe symptoms, respectively) and 35.1% had a positive screen for PTSD (PCL-5 score≥38). A previous diagnosis of depression [OR 3.65 (95% CI 1.26-10.57); p=0.017] and unemployment attributed to TTP [OR 5.86 (95% CI 1.26-27.09); p=0.024] were associated with depression. Younger age (p=0.017), a pre-existing anxiety disorder [OR 3.57 (95% CI 1.76-7.25), p<0.001], and unemployment attributable to TTP [OR 6.42 (95% CI 2.75-415.00), p<0.001] were associated with PTSD. CONCLUSION We report a high prevalence of PTSD and depression in TTP survivors. These results are concerning and indicate a need for further investigation to better define this association and its consequences.

Abstract CT020: Immune signatures of cytokine release syndrome and neurologic events in a multicenter registrational trial (ZUMA-1) in subjects with refractory diffuse large B cell lymphoma treated with axicabtagene ciloleucel (KTE-C19)

Introduction: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy. ZUMA-1 is a multicenter registrational trial of axi-cel in patients with refractory, aggressive B-cell non-Hodgkin lymphoma. In a pre-specified interim analysis, ZUMA-1 met its primary endpoint with a 76% objective response rate and 47% complete response. The incidence of Grade 3 and higher (Gr 3+) cytokine release syndrome (CRS) and neurologic events (NE) was 13% and 29%, respectively, in 93 patients with 1 month follow-up (Neelapu ASH 2016). We present novel immune signatures of Gr 3+ CRS and NE by analyzing the axi-cel-related biomarker profile in association with clinical outcomes. Methods: In this interim analysis of 62 patients, 44 serum analytes pre- and post-axi-cel treatment were measured via ELISA at multiple timepoints during the first month. The number of CAR+ cells in blood was determined by qPCR. Kinetics and association of these markers with CRS and NE were analyzed. The treatment-related profile was defined by analytes with at least double an increase over baseline in at least 50% of patients. These analytes were selected and evaluated for association with Gr 3+ CRS or NE. Immune signatures were determined based on p-values applied to peak or cumulative levels of analytes and adjusted for multiplicity (stepdown method). Results: Out of 44 analytes measured, 12 demonstrated an increase by double over baseline in at least 50% of patients. This axi-cel-related biomarker profile includes immune proliferative/modulating cytokines, pro-inflammatory cytokines, markers of myeloid activation, and chemokines. Markers with the highest median-fold increase were IFNγ (44x), IL-10 (31x), IL-6 (26x), IL-15 (20x), and GRZB (17x). These peaked within 7-14 days and generally returned to baseline within 1 month post-treatment. Within this panel of 12 analytes elevated post-axi-cel treatment, markers associated with Gr 3+ CRS (p Citation Format: Frederick L. Locke, John Rossi, Xiaodong Xue, Sattva S. Neelapu, Daniel H. Ryan, Armin Ghobadi, Lazaros J. Lekakis, David Miklos, Caron A. Jacobson, Ira Braunschweig, Olalekan Oluwole, Tanya Siddiqi, Yi Lin, John Timmerman, Patrick M. Reagan, Marika Sherman, Janice Nagatani, Xiao Zhang, Lynn Navale, William Y. Go, Jeff Wiezorek, Adrian Bot. Immune signatures of cytokine release syndrome and neurologic events in a multicenter registrational trial (ZUMA-1) in subjects with refractory diffuse large B cell lymphoma treated with axicabtagene ciloleucel (KTE-C19) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT020. doi:10.1158/1538-7445.AM2017-CT020