Received Conditioning Chemotherapy Research Articles

ET190L1-ArtemisTM T Cell Therapy Results in Durable Disease Remissions with No Cytokine Release Syndrome or Neurotoxicity in Patients with Relapsed and Refractory B-Cell Lymphoma

Background:Chimeric antigen receptor (CAR) T-cell is rapidly emerging as a promising new therapy for cancer. Although it can induce rapid clinical responses, it is also associated with cytokine release syndrome (CRS), the most commonly observed toxicity, which in some cases can lead to life-threatening multi-organ failure. To ameliorate these problems we developed a novel chimeric T-cell therapy platform, the ARTEMIS™ platform, which functionally matches the potency of CAR T-cells, but dramatically reduces the release of cytokines upon killing of target-positive tumor cells. Herein, we describe the first-in-human clinical study of anti-CD19-ARTEMIS, ET190L1-ARTEMISTM, in relapsed and refractory (r/r) B-cell lymphoma.Methods:This dose escalating study is a single-center clinical study to evaluate the safety and efficacy of ET190L1-ARTEMIS T cells in patients with r/r CD19+ non-Hodgkin lymphoma, including diffused large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma/chronic lymphocytic lymphoma, and splenic marginal zone lymphoma. All patients received conditioning chemotherapy of cyclophosphamide and fludarabine followed by a single infusion of ET190L1-ARTEMISTM T cells at the dose of 1x106, 3x106, and 6x106 ARTEMIS+ T cells per kilogram respectively. The primary endpoint is safety and estimation of the maximum tolerated dose of ET190L1-ARTEMISTM T cells. Secondary objectives include ARTEMIS T-cell engraftment and response assessment by Lugano criteria.Results:Manufacturing was successful for all patients. As of July 18, 2018, 21 patients received autologous ET190L1-ARTEMIS T cells, 3 were infused with 1 × 106 (low dose), 13 received 3 × 106 (medium dose) and 5 received 6 × 106 (high dose) ARTEMIS+ T cells/kg. Expansion of ARTEMIS T cells after infusion was observed in all patients by qPCR and flow cytometry using anti-idiotype antibody. No dose-limiting toxicities and no greater than Grade 2 drug-related adverse events (AEs) were observed. Inflammatory-related cytokines in blood including IL-2, IL-4, IL-6, IL-8, IL-10, IFNgamma, TNFalpha, and GM-CSF were below detection level in most time points post infusion. AEs consisted of transient fever (38 ~ 39.2°C) from 1 to 4 days post infusion in 9 patients, transient grade 1 skin rash (1 × 106/kgcohort) in one patient. All of these AEs were limited and spontaneously resolved, except in 3 patients where symptomatic treatment for fever was given. No hypotension or any other clinical signs of CRS or neurotoxicity were observed. No anti-IL6 drug was given nor any hospitalization for AEs were needed. One patient with a large lymphoma mass on the right side of the neck experienced transient hand-tremor and unilateral tongue numbness on the right side, possibly due to the rapid shrinkage of tumor nodules around the neck (Table 1). Efficacy assessment was planned at 1, 2, 3, 6, 9, 12 18 and 24 months post infusion.All subjects (n=21) completed 1st month efficacy assessment: 11/21 (52%) responders, with 6/11 (55%) complete remission (CR) and 5/11 (45%) partial remission (PR). Of the 11 responders at 1 month, 8 completed 3rd month efficacy assessment, with 6/6 CRs maintained CR and 2/2 PRs had disease progression. Of the 11 responders at 1 month, 6 completed 6th month efficacy assessment, with 5/6 CRs maintained CR and 1/6 CRs releapsed. Of the 2 SDs at 1 month, 1 progressed at 4.5 month (Table 2). The median follow up time is 3 months and the range of follow up time is 1-8 months.Conclusions:The interim results show that ET190L1-ARTEMISTM T cell therapy is safe and demonstrated promising efficacy in r/r B-cell lymphoma patients at the current dose and schedule, including 11/21 responders and excellent safety profile, with no CRS and neurotoxicity observed. The durability of these efficacy and safety results will be assessed in longer follow up. Clinical trial information: NCT02658929 [Display omitted] DisclosuresLong:Eureka Therapeutics, Inc.: Employment. Liu:Eureka Therapeutics, Inc.: Employment, Equity Ownership. Song:Peking University Cancer Hospital (Beijing Cancer Hospital): Employment. Rizzieri:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nejadnik:Eureka Therapeutics, Inc.: Employment. Zhu:Beijing Cancer Hospital: Employment. Liu:Eureka Therapeutics, Inc.: Employment, Equity Ownership.

Clinical Responses and Pharmacokinetics of MCARH171, a Human-Derived Bcma Targeted CAR T Cell Therapy in Relapsed/Refractory Multiple Myeloma: Final Results of a Phase I Clinical Trial

Clinical Responses and Pharmacokinetics of MCARH171, a Human-Derived Bcma Targeted CAR T Cell Therapy in Relapsed/Refractory Multiple Myeloma: Final Results of a Phase I Clinical Trial

Effect of Obesity on the Efficacy and Toxicities in Patients Undergoing Autologous Hematopoietic Stem Cell Transplant (AHCT) for Lymphoma

Background - Increased patient obesity rates have brought into question the need for dose adjustments in chemotherapy. Strategies for dose adjustments include using adjusted body weight (adjBW) versus total body weight (TBW) (Fair, 2017). Incorrect dosing of chemotherapy can result in significant complications. Underdosing has the potential to lead to treatment failure, whereas overdosing can result in increased toxicity. Currently, there is a lack of data regarding appropriate dose adjustments for conditioning chemotherapy regimens in patients with lymphoma who undergo autologous hematopoietic stem cell transplantation (AHCT) (Fair, 2017; Bubalo, 2014).Objective - The primary objective of this study is to evaluate the effect of obesity on overall survival (OS) in lymphoma patients who have undergone AHCT. The secondary objectives are to evaluate progression-free survival (PFS), as well as safety and toxicity (particularly gastrointestinal, renal and liver toxicities, and infections).Methods - Patients with lymphoma who received an AHCT were identified from our institutional database. Baseline patient characteristics and dose adjustments to conditioning chemotherapy regimens made in the setting of obesity were collected. Obesity was defined as actual body weight that is ≥ 125% Ideal Body Weight (IBW) as per Memorial Sloan Kettering Cancer Center allogeneic/autologous hematopoietic cell transplantation chemotherapy guidelines. Transplant outcomes (OS and PFS) and toxicities were compared between non-obese and obese patients. Sub-group analysis of the obese patient population compared those who received conditioning regimens based on adjBW versus TBW. Survival outcomes were estimated using the Kaplan-Meier method with differences assessed using a log-rank test. Differences in toxicity rates were assessed using a chi-square or fisher's exact test as appropriate.Results - The 239 patients transplanted between January 2014 and August 2016 had a median age of 55.3 (range 19.1 - 77.1) and 44.8% were female. Their median Body Mass Index was 27.3 kg/m2 (range 16.8 - 53.2). Baseline characteristics of patients are summarized in Table 1, and the subset of obese patient characteristics are summarized in Table 2. Of the obese patients (N=110, 46.0%), 29.1% received chemotherapy based on adjBW. PFS and OS did not differ significantly between the non-obese group and the obese group (3-year PFS - 69.8% vs. 74.3%, P=0.25; 3-year OS - 85.7% vs. 89.7%, P=0.42). The median follow-up of surviving patients was 36.1 months. Within the obese group, PFS and OS were significantly longer in the group that received conditioning chemotherapy dosed on TBW than adjBW (3-year PFS - 84.3% vs. 49.9%, P<0.001; 3-year OS - 97.0% vs. 71.9%, P<0.001). Toxicities were graded according to the NCI Common Technology Criteria for Adverse Effects v4.0 (CTCAE). Most toxicity outcomes were similar between the non-obese and obese groups. The rate of grade 3 or 4 liver toxicity was significantly higher in the non-obese group than the obese group (5.4% vs. 0%, P=0.02). In the obese group, there were no reported grade 3 or 4 renal toxicities. No significant differences were observed between the TBW and adjBW groups for grade 3 or 4 infections (89.7% vs. 78.1%, P=0.13) or gastrointestinal toxicities (56.4% vs. 34.4%, P=0.06), potentially related to sample size. Multivariate analyses controlling for significant between-group differences in baseline characteristics are pending.Conclusion - Among obese adults with lymphoma undergoing an AHCT, conditioning chemotherapy dosed on TBW was associated with longer overall survival and progression-free survival than chemotherapy dosed on adjBW, without increased rates of toxicities. DisclosuresNo relevant conflicts of interest to declare.

A phase I trial of CD19-targeted EGFRt/19-28z/4-1BBL armored chimeric antigen receptor (CAR) modified T cells in patients with relapsed or refractory chronic lymphocytic leukemia.

TPS7568 Background: Despite the recent progress in the therapy of CLL with BTK, PI3Kδ, and BCL2 inhibitors, CLL remains incurable and patients with high-risk disease features (i.e. del17p, complex karyotype) and patients whose disease progress after treatment with the above targeted agents continue to have extremely poor prognosis. CD19-specific chimeric antigen receptor (CAR) T cell therapy with various 2nd generation CARs (19-28z or 19-41BBz) have demonstrated anti-tumor efficacy in CLL but the complete response (CR) rates in CLL have been suboptimal (20-45%) compared to CR rates in ALL (80-90%). The suboptimal activity of the current 2nd generation CAR T cells can be due to the inhibitory tumor microenvironment (TM) of CLL. We believe one approach to over the hostile TM is through the use of CD19-CAR T cells further modified to express a second costimulatory ligand, 4-1BBL. A binding of 4-1BBL to its cognate receptor enhances T cell proliferation, IL-2 secretion, and survival and cytolytic activity of the T cells compared to 19-28z. 19-41BBz and 1928BBz (Zhao Z et al. Cancer Cell 2015;28:415-428). Methods: This phase I dose escalating trial is a single-center clinical trial (MSKCC) to study the safety and efficacy of autologous EGFRt/19-28z/4-1BBL+ CAR T cells in patients with relapsed CLL. Given the concern for potential systemic toxicity the vector includes a "safety switch" in the form of a gene for the expression of truncated form of human epidermal growth factor receptor (EGFRt). Patients with relapsed CLL are eligible for the trial. Patients will receive conditioning chemotherapy of cyclophosphamide followed by escalating doses of CAR T cells (1x105 – 3x106 CAR T cells/kg). The primary endpoint is safety and maximum tolerated doses of the CAR T ells. Secondary objectives include response assessment by iwCLL criteria. The comprehensive treatment algorithms for CRS and neurotoxicity are based on our CAR T cell experience in other studies. The study will begin enrollment in February 2017 and enroll up to 30 patients. Clinical trial information: Pending.

Abstract IA07: Chimeric antigen receptor T cells for cancer immunotherapy

Abstract Background: T cells can be genetically modified to target tumor antigens through the expression of a chimeric antigen receptor (CAR). CAR structure consists of two fundamental domains – the antigen binding portion (most commonly single chain variable fragment (scFv) derived from a monoclonal antibody) joined to one or more intracellular T cell signaling domains. To be effective CAR T cells must expand, persist, exhibit enduring anti-tumor cytotoxicity, withstand and/or counteract an immunosuppressive tumor microenvironment, and overcome targeted tumor antigen escape following infusion. T cells targeting the CD19 antigen is a novel therapeutic approach for patients with hematologic malignancies. To this end, we have previously demonstrated that CAR T cells have a significant clinical benefit in adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We now extend this novel treatment approach by testing of our CD19-specific CAR in a multicenter trial for children and young adults with relapsed CD19+ B-ALL. Patients and Methods: Pediatric and young-adult patients with very high risk (VHR) or R/R CD19+ B-ALL were eligible for enrollment and leukapheresis. Patients with R/R B-ALL were eligible for infusion if they demonstrated residual disease following salvage chemotherapy. Once eligibility was determined isolation and transduction of T cells was performed using a retroviral vector encoding a CD19-specific CAR comprised of a CD19-specific scFv and the CD28 and CD3ζ signaling domains (termed 19-28z). All patients received conditioning chemotherapy followed 2 days later by 1x106 3x106 19-28z CAR T cells/kg. The primary objective of the study was to evaluate the safety and anti-tumor activity of 19-28z CAR T cells. Post-treatment response was assessed at day 14-28 bone marrow aspirate including multiparameter flow cytometry for minimal residual disease (MRD). Results: To date, 28 patients with have been enrolled on protocol with a median age of 11.5 years (range 9 months to 20 years) at time of T cell collection. We have treated 11 patients with 19-28z CAR T cells with a median age 14.9 years (range 3-22 years). Patients received a dose of 1-3 x 10^6 CAR T cells/kg and complete response (complete remission or complete remission with incomplete count recovery) occurred in 7/11 (64%) patients. Significantly, correlations with response included lower disease burden (as assessed by bone marrow cellularity; p&amp;lt;0.004) and fold expansion following CD3/28 bead activation during the generation of CAR T cells (p&amp;lt;0.03). Specifically, BM cellularity ≤50% and fold expansion (average &amp;gt;135 vs &amp;lt;40 fold expansion) was seen in responders compared to non-responders. Pre-collection peripheral blood absolute lymphocyte count, lymphocyte proliferative response (phytohemagglutinin proliferation assay), and CD3 absolute count did not correlate with response in this small sample size. Development of fever and cytokine release syndrome (CRS) occurred in responders including grade I-II (n=3) and grade III-IV (n=4). Systemic immunosuppressants (corticosteroids or anti-IL6 receptor antibody tocilizumab) abrogated clinical symptoms of CRS. Elevated serum cytokines (notably IFN-γ and IL-6) was noted in patients with CRS. Monitoring of bone marrow demonstrated peak 19-28z CAR T cell detection within 1-2 weeks following infusion with gradual contracture over 1-2 months. Conclusions: These early results demonstrate the feasibility and significant clinical impact of CAR T cells in patients with R/R B-ALL. In an effort to more rapidly generate statistically relevant data, demonstrate the exportability of this technology between academic institutions, and offer this therapeutic option to a broader number of pediatric patients with chemo-refractory B-ALL we have expanded this trial to include a collaborating institution. The objective of our trial is not to provide an intent-to-treat cohort, but rather demonstrate the tolerability of this technology in patients with relapsed B-ALL. Furthermore, patients meeting disease eligibility were not pre-screened for lymphocyte function prior to collection and/or treatment. Subsequent cohorts of patients will receive 19-28z CAR T cells and will be evaluated for toxicity, persistence of CAR T cells, and for anti-leukemic efficacy. Citation Format: Kevin J. Curran, Lewis B. Silverman, Rachel Kobos, Nancy A. Kernan, Steven P. Margossian, Jae H. Park, Craig S. Sauter, Victoria Szenes, Xiuyan Wang, Richard J. O'Reilly, Michel Sadelain, Isabelle Riviere, Reiner J. Brentjens. Chimeric antigen receptor T cells for cancer immunotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA07.

Tolerance and efficacy of autologous or donor-derived T cells expressing CD19 chimeric antigen receptors in adult B-ALL with extramedullary leukemia

The engineering of T lymphocytes to express chimeric antigen receptors (CARs) aims to establish T cell-mediated tumor immunity rapidly. In this study, we conducted a pilot clinical trial of autologous or donor- derived T cells genetically modified to express a CAR targeting the B-cell antigen CD19 harboring 4-1BB and the CD3ζ moiety. All enrolled patients had relapsed or chemotherapy-refractory B-cell lineage acute lymphocytic leukemia (B-ALL). Of the nine patients, six had definite extramedullary involvement, and the rate of overall survival at 18 weeks was 56%. One of the two patients who received conditioning chemotherapy achieved a three-month durable complete response with partial regression of extramedullary lesions. Four of seven patients who did not receive conditioning chemotherapy achieved dramatic regression or a mixed response in the haematopoietic system and extramedullary tissues for two to nine months. Grade 2–3 graft-versus-host disease (GVHD) was observed in two patients who received substantial donor-derived anti-CD19 CART (chimeric antigen receptor-modified T) cells 3–4 weeks after cell infusions. These results show for the first time that donor-derived anti-CD19 CART cells can cause GVHD and regression of extramedullary B-ALL. This study is registered at www.clinicaltrials.gov as NCT01864889.

Partial engraftment following plerixafor rescue after failed sibling donor peripheral blood stem cell harvest

Rarely, healthy donors fail adequate peripheral blood stem cell (PBSC) mobilization. If the recipient has already received conditioning chemotherapy, this can result in the donor undergoing urgent marrow harvest under general anesthesia. Plerixafor is a novel CXCR4 antagonist, licensed for autologous PBSC harvest (PBSCH) in patients who failed mobilization with granulocyte-colony-stimulating factor (G-CSF) alone. Experience using plerixafor in healthy allogeneic donors failing G-CSF mobilization is scarce. A 65-year-old patient was referred for a reduced-intensity conditioning sibling allograft for relapsed follicular lymphoma. She received fludarabine, melphalan, and alemtuzumab conditioning. Her 68-year-old brother was fully HLA matched. PBSCH was planned on Day -1 after 4 days of 10 μg/kg G-CSF. Day 1 PBSCH collected an inadequate number of CD34+ 0.35 × 10(6) /kg cells. Despite increasing G-CSF (16 μg/kg), Day 2 yielded 0.33 × 10(6) /kg CD34+ cells, giving a suboptimal total dose. He proceeded to a third PBSCH day after plerixafor (0.24 mg/kg) and G-CSF (16 μg/kg) were given the evening before. A total of 1.79 × 10(6) /kg CD34+ cells were harvested, giving a total dose of 2.46 × 10(6) /kg CD34+ cells. After initial neutrophil engraftment on Day +13, the patient's neutrophils gradually decreased to 0.02 × 10(9) /L by Day +74. A marrow aspirate on Day +81 was markedly hypocellular. Total white blood cell chimerism was near 100% donor on Days +32, +74, and +102. Despite chimeric-only engraftment, the patient remains platelet and red blood cell transfusion dependent. Rescue plerixafor to assist PBSCH in healthy allogeneic donors has been effective in terms of CD34+ cell number mobilized. It is unclear whether the partial engraftment seen was coincidental or related to a difference in PBSC quality.

Radiation- and Chemotherapy-Induced Permanent Alopecia: Case Series

Radiation- and chemotherapy-induced alopecia is mostly temporary. However, permanent scalp alopecia is reported, albeit infrequently. The objective of this observational case series was to determine the kind and doses of chemotherapeutic agents and radiation in inducing permanent alopecia of the scalp. Eleven patients referred to our department over a period of 3 years for permanent alopecia after chemotherapy/radiotherapy or combination therapy were included. A detailed medical and therapeutic history was obtained from each patient and from medical records. Photography was done, and the scalp biopsies were taken. Patients were divided into three groups according to the type of therapy. The first group received conditioning chemotherapy prior to bone marrow transplantation. The second group had radiation for brain tumors, and the third group received both. A comprehensive multicenter and multidisciplinary study is required to determine the definite causative agents, doses, and other cofactors that induce permanent alopecia following chemotherapy/radiotherapy, as well as the means to avoid this distressing outcome in surviving patients.

CD19 Targeted Allogeneic EBV-Specific T Cells for the Treatment of Relapsed ALL in Pediatric Patients Post HSCT

AbstractAbstract 353T cells can be genetically modified to target tumor antigens through the expression of a chimeric antigen receptor (CAR). CAR modified T cells targeting the CD19 antigen is a novel therapeutic approach for patients with relapse B-ALL following allo-HSCT. We have previously demonstrated donor derived Epstein-Barr virus specific cytotoxic T cells (EBV-CTLs) can be safely infused in patients following allo-HSCT. Following retroviral gene transfer with our CD19-specific CAR (19–28z), EBV-CTLs demonstrate in vitro cytotoxicity against CD19+ targets, retain EBV-specificity without allogeneic reactivity, and in vivo, eradicate systemic Burkitt lymphoma in a SCID/Beige murine model. Based on our preclinical studies we have initiated a phase I dose escalation clinical trial (NCT01430390) in pediatric patients with relapsed CD19+ B-ALL following allo-HSCT utilizing donor 19–28z+ EBV-CTLs. Three patients have received conditioning chemotherapy (fludarabine 25mg/m2 × 5 days) followed by infusion of CAR modified EBV-CTLs without infusion related toxicity. Subsequently, patient 1 and 3 safely received additional T cell infusions without (patient 1) and with (patient 3; cyclophosphamide) conditioning chemotherapy. Total CAR+ T cell dose for each infusion ranged from 1.4 – 4.1×105 cells/kg (1×106 total EBV-CTLs/kg per infusion). Patient 1 developed fever and biopsy proven skin GVHD (grade II) three days following his first infusion which resolved 2 weeks after starting topical steroids. Modified T cells were detected by Q-PCR in the bone marrow and peripheral blood up to 3 and 18 weeks respectively in patient 1 following first infusion, up to 2 weeks in the peripheral blood in patient 2, and have been below the limit of detection in patient 3. Patient 1 died from progressive disease 29 weeks following first infusion and patient 2 died from progressive disease 19 weeks post infusion. Patient 3, initially treated in remission following salvage chemotherapy, has no evidence of disease (NED) 15 months after last extramedullary relapse and 5 months post first infusion of 19–28z+ EBV-CTLs. These early results demonstrate the feasibility of allogeneic 1928z+ EBV-CTL infusions without the development of significant GVHD post allo-HSCT. Subsequent cohorts of patients will receive dose escalation of modified T cells and will be evaluated for safety, persistence of 19–28z+ EBV-CTLs, and for anti-tumor efficacy. Disclosures:No relevant conflicts of interest to declare.

Gonadotropin-releasing hormone agonist may minimize premature ovarian failure in young women undergoing autologous stem cell transplantation

To compare the rate of premature ovarian failure (POF) after stem cell transplantation (SCT) in young women receiving GnRH-agonist (GnRH-a) in conjunction with gonadotoxic chemotherapy. Prospective, nonrandomized study. Tertiary university hospital. Ninety-five women received conditioning chemotherapy, with or without GnRH-a before SCT. Complete information was available for only 83 patients. Conditioning chemotherapy, with or without GnRH-a before SCT. Cyclic ovarian function (COF) or POF after SCT. There were no significant differences in age, chemotherapy treatment, or diagnoses between the study and control groups. In the GnRH-a group, 38.3% (18/47) patients resumed COF, compared with 11.1% (4/36) for patients who did not receive GnRH-a. Patients who resumed COF were on average 3.7 years (median, 3 years) younger at the time of transplantation than those who experienced POF. GnRH-a had a significant effect on long-term COF in patients with lymphomas (66.7% [14/21] for GnRH-a group vs. 18.2% [2/11] for control) but not for leukemia patients. GnRH-a cotreatment in conjunction with conditioning chemotherapy before SCT may significantly decrease the gonadotoxicity and POF from 82% to 33% in lymphoma but not in leukemia patients.

Race, Access to Care, and Outcome After Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma.

AbstractAbstract 1509 Background:Autologous hematopoietic stem cell transplantation (AHSCT) is an essential modality in the management of younger, newly diagnosed multiple myeloma (MM) patients. Some reports have indicated inferior survival for African-American (AA) patients following diagnosis of MM, when compared to Caucasian (Ca) patients. We hypothesized that previously claimed racial differences in outcome may reflect disparity in access to care and might be negated by timely, standard, and uniform treatment. Methods:We reviewed a mature database of MM patients undergoing AHSCT at a single institution to describe and compare overall survival from diagnosis and from transplantation in AA and Ca patients. Additionally, we described time from diagnosis to transplantation in both cohorts as an additional surrogate of access to care. Results:Between August 1996 and July 2010, 128 patients underwent a first AHSCT for MM at the institution. Fifty-three patients (41%) were AA and 75 (59%) were Ca. Median age at the time of diagnosis was 54.7 years for AA and 58.3 for Ca. Sixty-six (52%) of patients were female. One hundred twenty-six (98%) patients received conditioning chemotherapy with Melphalan 200 mg/m2. Median interval from diagnosis to transplant was 10 months (IQR 7.1–15.9) for AA and 9.2 months (IQR 6.7–15.6) for Ca (p=0.23). Median overall survival for the entire group was 63 months (95% C.I. 51–76) from time of diagnosis and 51.8 months (95% C.I. 39–63) from AHSCT. There was no difference in overall survival from time of AHSCT between AA and Ca, respectively 62.6 (95% C.I. 30.9–94.4) and 51.8 months (95% C.I. 33.5–70.3, Log-rank test P=0.76). Similarly, no significant difference was seen in overall survival from time of diagnosis between AA and Ca, respectively 70.4 (95% C.I. 29.6–111.3) and 59.3 months (95% C.I. 46.8–71.8), as displayed in the Figure (Log-rank test P=0.36). Conclusion:These findings suggest that previously reported differences in outcome between AA and CA patients with MM are related to disparities in access to healthcare and not intrinsic biological differences. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Disappointing outcome of autologous stem cell transplantation for enteropathy-associated T-cell lymphoma

Background Despite treatment, enteropathy-associated T-cell lymphoma has a very poor outcome. Chemotherapy can be complicated by small bowel perforation, gastrointestinal bleeding and development of enterocolic fistulae. Here we report on the feasibility, safety and efficacy of high-dose chemotherapy followed by autologous stem cell transplantation in patients with enteropathy-associated T-cell lymphoma (three upfront and one at relapse), with or without prior partial small bowel resection. Methods Four patients [two males, two females, mean age 65 years (range 60–69 years)] received high-dose chemotherapy followed by autologous stem cell transplantation. Partial small bowel resection has been performed in three patients. Results All four patients completed the mobilization and leucopheresis procedures successfully and subsequently received conditioning chemotherapy and transplantation. Engraftment occurred in all patients. No major non-haematological toxicity or transplantation-related mortality was observed. One patient has ongoing complete remission 32 months after transplantation. Three patients died from relapse within few months after autologous stem cell transplantation. Conclusions Autologous stem cell transplantation seems unsatisfactory for patients with enteropathy-associated T-cell lymphoma. More intensive conditioning and aggressive chemotherapy with/or without targeted immunotherapy as well as allogenous stem cell transplantation needs to be explored.

Unrelated Donor Bone Marrow Transplantation for Correction of Lethal Congenital Immunodeficiencies

Unrelated donor marrow transplantation was undertaken in eight infants with severe combined immunodeficiency (SCID) and two children each with Wiskott-Aldrich syndrome (WAS) and Chediak-Higashi syndrome (CHS) who did not have histocompatible siblings. Donors for three patients were phenotypically matched at all HLA-A, B, Dr, and Dw loci, whereas nine donors were mismatched from the recipients at one of the HLA-A or B loci but phenotypically identical at evaluable D loci. All but one patient received conditioning chemotherapy and/or radiotherapy before infusion of donor marrow, which was not T-cell depleted. Prophylaxis for graft-versus-host disease (GVHD) consisted of methotrexate and prednisone combined with either cyclosporine A (six patients), antithymocyte globulin (five patients), or anti-CD5 ricin A chain immunotoxin (one patient). All patients engrafted with donor cells, and only 4 of 12 experienced any GVHD (1 of 8 SCID, 1 of 2 WAS, 2 of 2 CHS). Two children who developed grade II and two who developed grade III GVHD were successfully treated and all are now alive, off immuno-suppressive therapy, with no evidence of chronic GVHD greater than 18 months after transplant. Ten patients are alive with excellent immunoreconstitution greater than or equal to 1 year to greater than or equal to 3 years after transplant; actuarial survival is predicted to be 83% with a median follow-up of 2 years. Two children with SCID succumbed to pre-existing opportunistic infection early posttransplant. We conclude that closely matched unrelated donor bone marrow transplantation can correct congenital immunodeficiencies including variants of SCID, WAS, and CHS, with an acceptably low incidence of transplant-related complications, principally GVHD.

Unrelated donor bone marrow transplantation for correction of lethal congenital immunodeficiencies

Unrelated donor marrow transplantation was undertaken in eight infants with severe combined immunodeficiency (SCID) and two children each with Wiskott-Aldrich syndrome (WAS) and Chediak-Higashi syndrome (CHS) who did not have histocompatible siblings. Donors for three patients were phenotypically matched at all HLA-A, B, Dr, and Dw loci, whereas nine donors were mismatched from the recipients at one of the HLA-A or B loci but phenotypically identical at evaluable D loci. All but one patient received conditioning chemotherapy and/or radiotherapy before infusion of donor marrow, which was not T-cell depleted. Prophylaxis for graft-versus-host disease (GVHD) consisted of methotrexate and prednisone combined with either cyclosporine A (six patients), antithymocyte globulin (five patients), or anti-CD5 ricin A chain immunotoxin (one patient). All patients engrafted with donor cells, and only 4 of 12 experienced any GVHD (1 of 8 SCID, 1 of 2 WAS, 2 of 2 CHS). Two children who developed grade II and two who developed grade III GVHD were successfully treated and all are now alive, off immuno- suppressive therapy, with no evidence of chronic GVHD greater than 18 months after transplant. Ten patients are alive with excellent immunoreconstitution greater than or equal to 1 year to greater than or equal to 3 years after transplant; actuarial survival is predicted to be 83% with a median follow-up of 2 years. Two children with SCID succumbed to pre-existing opportunistic infection early posttransplant. We conclude that closely matched unrelated donor bone marrow transplantation can correct congenital immunodeficiencies including variants of SCID, WAS, and CHS, with an acceptably low incidence of transplant-related complications, principally GVHD.