Academic literature on the topic 'B 20.5 UL 2009 B859'

Abstract Background: NK alloreactivity based on KIR (Killer Immunoglobulin-like Receptor) expression by natural killer cells has been reported to decrease the risk of leukemia relapse after HLA-haploidentical stem cell transplantation (SCT). The use of donors with high KIR B-content score has been correlated with a decreased risk of relapse. Objective: We examined the outcome of leukemia relapse following CD34-positive selected T-cell depleted haploidentical donor peripheral blood SCT followed by donor lymphocyte infusion with methotrexate prophylaxis. Methods: Between 2009-2015, twenty patients underwent haploidentical donor CD34-selected, T cell-depleted peripheral blood SCT on an IRB-approved protocol. Nine patients had acute lymphoblastic leukemia (ALL), and eleven had myeloid leukemia (10 AML, 1 JMML). Among ALL patients, remission status was CR1 in 5, with either induction failure or MRD+ after consolidation, 3 were in CR2 and 1 was CR3. Four patients had T-cell disease. Among AML patients, 5 were in CR1, one had refractory disease and 5 were CR2 or beyond. Ligand-ligand NK alloreactivity based on HLA typing was available for all patients. Receptor-ligand NK alloreactivity based on immunophenotyping of KIR was available in 16 patients and KIR B-content score was available in twelve patients. Patients were considered to have receptor-ligand NK alloreactivity if immunophenotyping of the donor had >5 (cells/uL) expressing KIR2DL1 (recognizes C2 group) or KIR2DL1/2DL13 (recognizes C1 group). Patients with alloreactive KIR only recognizing BW4 were not considered alloreactive due to predicted weak alloreactivity. All patients received a uniform conditioning regimen including TBI 1200cGy, thiotepa 10mg/kg, fludarabine 200mg/m2, and rabbit-anti-thymocyte globulin (rATG) 6mg/kg, with no post-transplant immunosuppression. All patients received a planned donor lymphocyte infusion (DLI) 3-5 x 104 CD3+ cells/kg between days 30- 42 after transplant and received weekly IV methotrexate prophylaxis following DLI. The incidence of relapse and GVHD was evaluated. Results: Based on a ligand-ligand model of NK alloreactivity, only 4/20 patients had NK alloreactivity predicted. Seven patients expressed all 3 ligands and blocked all possible NK alloreactivity. Median follow-up was 306 days (range 45 days-5 years). Four of 20 patients relapsed (1/4 with predicted NK alloreactivity and 3/16 without). Median time to relapse was 110 days (range 124-455 days). NK alloreactivity based on receptor-ligand as defined above was present in 5/16 patients and relapse occurred in 2/5 with and 1/11 without. Donor KIR B-content was >=2 in 4 patients and 0-1 in 8 patients. Relapse occurred in 1/4 with 2 and 2/8 with 0-1. No donors had KIR B-content score of 3-4. The incidence of grade II-IV acute graft-versus-host disease after prophylactic DLI was 25%, with 2 grade II, 3 grade III and no grade IV GVHD. Three patients developed cGVHD, two mild and one severe by NIH consensus criteria. Conclusion: An approach using a DLI followed by methotrexate prophylaxis after a CD34-selected, T-cell depleted SCT for pediatric leukemia diminishes the effect of NK alloreactivity and KIR B-content. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 2523 Background: Rituximab is a chimeric human-murine anti CD 20 antibody that results in B cell depletion. In patients with ITP, the current regimen of 375mg/m2 once a week for 4 weeks, has been shown to result in disease improvement in up to 60% of patients and a complete response in 30–40% of patients. In patients who relapse, a repeat course of rituximab is given but there is no data currently available on its use as a maintenance therapy. In 2009 Hasan et al reported on 20 patients who relapsed following an initial response to rituximab, treating them with the standard regimen (4 infusions). Repeat standard dose rituximab resulted in significant responses in 15 of the 20 patients, which were similar in duration of effect to those seen with the initial infusions (1). Since it thus seemed predictable that there would be a relapse after a second response and the approximate time to relapse could be estimated, we elected to study a maintenance rituximab regimen in patients who had responded to rituximab previously and relapsed. Recent data on the safety of prolonged rituximab use has been shown that it prolongs survival in patients with lymphoma with minimal additional side effects. Results: Ten patients (6 male and 4 female) with refractory ITP who had previously responded to rituximab were included in this study. The median age at diagnosis was 14.5 years and the median time to treatment with maintenance rituximab was 78 months. Five out of the 10 patients had Evans syndrome and 7 of the patients had had a prior splenectomy. The median starting platelet count was 7×109/l. Five of the patients received the first round of 4 weekly doses followed by 1 dose of rituximab every 4 months for 6 doses. All 5 of these patients remain in remission and do not require any treatment currently. They range from having finished the last infusion 2 months ago to 26 months ago; thus far 3 of the patients are past their expected relapse time based on their duration of response to their previous cycle of rituximab. One patient relapsed on treatment, received 2 doses of IVIG, and maintains a platelet count > 100,000/uL, more than 3 years from last treatment. Two patients are still on treatment. Two female patients discontinued rituximab after 4 maintenance infusions due to pregnancy or an expectation of pregnancy. No patient suffered any bleeding episodes, nor did any of them suffer from unusual infectious complications, hepatitis B, or progressive multifocal leukoencephalopathy (PML). One patient is mildly hypogammaglobulinemic but is not on IVIG. Conclusion: In this group of 10 of patients with refractory ITP, all followed for more than 2 years on study and who all previously responded to their initial 4 infusions of rituximab before relapsing, it appears that rituximab maintenance is a safe and effective therapeutic option. If the responses continue to be substantially longer than those seen with the initial rituximab course, this could become an optimal therapeutic approach to patients with ITP who respond to but relapse after rituximab treatment. One potential mechanism is that with B cell depletion by rituximab, autoreactive B cells are also depleted, thereby resulting in decreased “cross talk” between autoreactive B and T cells. Other mechanisms are possible and under study. Reference: 1) Am. J. Hematol. 84:661-665,2009 Patient Characteristics Disclosures: Off Label Use: use of rituximab as a therapy in ITP. Bussel:Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy.

Abstract Abstract 4117 Background Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, and the handful of studies that investigate ethnic differences in childhood ALL consistently report an increased incidence and worse survival in African-American and Latino children. Studies examining clinical features (high white count) and biological prognostic factors (ploidy, immunophenotype, chromosomal abnormalities) by ethnicity could find no contribution that explained poor outcome among African-Americans. However, investigations exclusively focused on biological factors contributing to worse outcome in Latino children with ALL have been limited. The Latino population in Utah is approximately 10% and Latino children account for 15-20% of new ALL diagnoses treated at Primary Children's Medical Center (PCMC), the only children's hospital located in Utah. As the Latino population continues to expand in Utah and the surrounding states, it will become increasingly important to understand what biological differences, if any, exist between Latino and non-Latino children with ALL. Objective To investigate whether Latino children with ALL in Utah have different clinical and biological features compared to non-Latino children. Methods For this pilot study, we conducted a retrospective chart review of clinical and biological risk factors in 90 pediatric patients (Latino, n=40 and Caucasian, n=50) diagnosed with ALL at PCMC between 1997-2009. We included all Latino children treated during this time and randomly-selected Caucasian children for ∼ 1:1 comparison. Over 50 clinical and biological variables were recorded for each patient and compared with Fisher's Exact Test (2-tailed) and logistic regression models. Results We found no statistical differences between the Latino and Caucasian cohort in our univariate analysis for the following features: age ≥ 10 years old (Latino 27.5% vs. Caucasian 26%), initial WBC > 50 × 10-3/uL (Latino 22.5% vs. Caucasian 14%), NCI-Rome High Risk Group (Latino 37.5% vs. Caucasian 46%), initial hemoglobin < 11.5 gm/dL (Latino 85% vs. Caucasian 80%), initial platelet count < 150 × 10-3/uL (Latino 87.5% vs. Caucasian 80%), precursor B-cell phenotype (Latino 98% vs. Caucasian 86%), slow early response (SER) marrow defined as >5% blasts (M2 or M3) for day 8 (Latino 66.6% vs. Caucasian 57.4%), day 15 (Latino 15.4% vs. Caucasian 15.8%), and day 29 (Latino 2.8% vs. Caucasian 0%), minimal residual disease (MRD) ≥ 0.1% on Day 29 (Latino, n=4 vs. Caucasian, n=7), FISH cytogenetic results (Chr. 4 hyperdiploidy: Latino, n=5 vs. Caucasian, n=9; Chr. 10 hyperdiploidy: Latino, n=2 vs. Caucasian, n=10; Chr. 17 hyperdiploidy: Latino, n=3 vs. Caucasian, n=9; Chr. 21 hyperdiploidy: Latino, n=7 vs. Caucasian, n=16), t(12;21) status (Latino, n=1 vs. Caucasian, n=7), t(9;22) status (Latino, n=2 vs. Caucasian, n=0), hepatomegaly (Latino 10% vs. Caucasian 4%), splenomegaly (Latino 18% vs. Caucasian 16%), combined hepatosplenomegaly (Latino 18% vs. Caucasian 36%), CNS disease defined as ≥ CNS 2 (Latino 12.5% vs. Caucasian 12%), DNA index <1 (Latino 10.8% vs. Caucasian 8.3%), DNA index >1 (Latino 27% vs. Caucasian 27%), patients enrolled in COG clinical trial (Latino 75% vs. Caucasian 75%), and relapse rate (Latino 15% vs. Caucasian 8%). Logistic regression found no differences between the Latino and Caucasian cohort for: age (Latino median = 5 yrs vs. Caucasian median = 4 yrs), platelet count at diagnosis (Latino median = 51 vs. Caucasian median = 56), hemoglobin at diagnosis (Latino median = 8.2 vs. Caucasian median = 8.0), WBC at diagnosis (Latino median = 10.3 vs. Caucasian median = 7.0), and initial absolute blast count (% x WBC count) (Latino median = 3024 vs. Caucasian median = 1680). Conclusion We have performed the first comprehensive evaluation of ethnic variation in clinical and biological features in pediatric ALL in Utah. Surprisingly, we found no significant differences between the Latino and Caucasian patients in the features that we examined (although several variables did show a trend). This lack of difference could be explained by: 1) lack of adequate power, 2) lack of any true difference (our Latino vs. Caucasian relapse rate in Utah was similar), or 3) ethnic variation in molecular biology beyond the level of detection for collected variables. We are now preparing to expand our patient numbers and to interrogate clinical samples from each patient using high-resolution, genome-wide technology as we continue our pilot study. Disclosures: No relevant conflicts of interest to declare.

Abstract Introduction. Bone marrow transplantation from an HLA-matched related or unrelated donor remains the only curative treatment for patients with thalassemia. Although one third of patients with thalassemia can find a matched unrelated donor (MUD) few patients were treated by MUD transplantation. Early experience with the use of MUD transplant in class 3 patients with thalassemia resulted in high rates of graft rejection and transplant-related mortality with thalassemia-free (TFS) survival of 53% (La Nasa G et al. Blood 2002). Significant improvements in MUD transplantation in recent years have prompted us to consider it also for high risk patients with thalassemia. Methods . All patient-donor pairs were typed at high resolution for HLA-A, -B, -C, -DRB1, -DQA1, -DQB1, and DPB1. Fourteen consecutive patients with a median age of 5 years (range, 2-17.2) received unrelated bone marrow transplantation for thalassemia. Four patients were in class 1, 2 were in class 2 and 8 were in class 3 of risk. All patients were treated with the conditioning regimen consisting of weight-based IV Bu, thiotepa (10 mg/kg/d), CY (200 mg/kg) and thymoglobulin (10 mg/kg) preceded by preconditioning with hydroxyurea (30 mg/kg/d), azathioprine (3 mg/kg/d) from D −45, and fludarabine (30 mg/m2/d) from D −16 through D −12. Patients received CSA, methylprednisolone and a short course of MTX as GVHD prophylaxis. Results. Between May 2009 and December 2017 un unrelated donor search was performed for 47 patients at our Institute. Forty one patients were Caucasian and 6 patients black African origin. Among Caucasians 16/41 (39%) found a 10/10 and 5/41 (12%) a 9/10 HLA allele-matched unrelated donor, while 1 of 6 black African patients (16.6%) found a 10/10 HLA-matched donor. Among 22 patients with a suitable donor (10/10 or 9/10 HLA allele-matched) 14 received transplantation, 2 patients withdrew consent, 1 patient's donor refused donation, and the remaining 5 patients are awaiting transplant. Twelve patients received 10/10 and 2 patients 9/10 HLA allele-matched grafts. Eight patients had permissive DPB1 mismatches while 2 patients had non-permissive mismatches in the HvG direction and 4 patients in the GvH direction. Median TNC/kg and CD34+/kg infused were 7.2x108 (range, 3.95-12.5) and 7.75x106 (range, 3.47-16.4), respectively. Sustained engraftment occurred in all patients. The median time to neutrophil and platelet recovery was 20 days (range, 15-27) and 19 days (range, 15-28), respectively. All but one patient showed 100% donor chimerism. The patient with stable mixed chimerism (48% donor DNA) has remained transfusion independent for over 3 years with hemoglobin levels >13.5-14 g/dL. Grade 2 and 3-4 acute GVHD occurred in 3 (21%) and 2 (14%) patients, respectively. Two patients developed mild (skin) or severe (skin, gut and liver) chronic GVHD. There was no association between non permissive DPB1 mismatches in the GvH direction and GVHD. All but one patient are alive and are off immunosuppressive therapy. One patient died due to chronic GVHD-related complications. The median follow-up among surviving patients was 2.8 years (range, 0.8-8.6). The 5-year OS and TFS probabilities were 90% (95% CI 47 to 99%) (Figure 1). Patients showed suboptimal CD4+ recovery within the first year: absolute (mean±SEM) cells/ul of CD4+ at 6 months was 223±48. At 12 and 24 months recovery of CD4+, CD8+, CD19+ and CD56+ were 597±122, 1077±228, 331±75, 229±64 and 812±284, 1067±405, 218±82, 112±22, respectively. One patient developed mild to moderate hepatic sinusoidal obstruction syndrome which resolved with supportive care. CMV reactivation occurred in 9 patients and none developed CMV disease. One patient developed adenovirus gastroenteritis. EBV reactivation occurred in 4 patients; one developed posttransplant lymphoproliferative disorder that was successfully treated with Rituximab. Bacterial infections were common: 5 (38%) patients developed gram negative or gram positive sepsis and 4 (29%) patients pneumonia. Probable invasive fungal infections occurred in 2 (14%) patients. Conclusions. This study showed that unrelated donor BMT can successfully cure a proportion of patients with thalassemia. Remarkably, despite 57% of patients were in class 3 of risk the 5-year OS and TFS rates were 90%. We conclude that class 3 patients with thalassemia who have a suitably matched unrelated donor should not be denied the option of transplantation. Disclosures No relevant conflicts of interest to declare.

Introduction: High dose chemotherapy (HDT) and autologous hematopoietic cell transplantation (AHCT) are considered standard of care as first line therapy in mantle cell lymphoma (Dreyling et al., 2005; Geisler et al., 2012) and in first line refractory and chemosensitive relapse Non-Hodgkin Lymphoma (NHL) (Philip et al., 1995) . The development of hematopoietic cell transplant comorbidity index (HCT-CI) (Sorror et al., 2009) for recipient selection and transplant risk evaluation have impacted on patient selection. Over the last decade, most transplant program have seen an increase in the median age of AHCT recipients(McCarthy et al., 2013). Limited data are available to optimise elderly patients selection for transplantation while minimising the risk of treatment related toxicity and mortality (TRM). The goal of this study was to identify factors impacting the safety and efficacy of AHCT in the elderly NHL patients in order to better select those who will benefit from this intervention. Method: This is a single center, retrospective study examining outcomes of AHCT in elderly patients (≥60 years old) with NHL. Between January 1st, 2008 and January 1st, 2015, 90 patients met the inclusion criteria and were included in the study. Patients signed an informed consent and the ethics committee of our institution approved the study. Progression-free-survival (PFS) and overall survival (OS) were analyzed according to age at time of transplantation, HCT-CI, lymphoma histology and disease status at time of transplant. Toxicities were analyzed according to age and HCT-CI. Results: Median age at time of NHL diagnostic was 60 years (range 42 to 68) and 63 years at time of transplant (range 60 to 69). One third (33%) of our cohort was ≥65 years old. Histologic sub-type was mainly composed of follicular (36%), mantle cell (20%) and large B-cell lymphoma (38%). 50% of patients had high-risk disease and 31% had low risk disease. HCT-CI was low-risk in 34%, intermediate risk in 40% and high-risk disease in 26%. BEAM/BEAC conditioning regimen was used in 94%. The median graft CD34+/kg cell dose infused was 4.87. The median time to neutrophil engraftment was 10 days (range 8 to 14 days) and platelet recovery was 16 days (range 11 to 43 days). The incidence of febrile neutropenia was 92% with 2% admission to the intensive care unit (ICU) with no difference between patients younger or ≥65 years old. Our cohort received a median of 8 days of antibiotics (range 0 to 41 days). Absolute lymphocyte count < 0,3 X 103 cells/uL at 14 days after transplant was associated with higher incidence of septic choc (p=0,024) and ICU admission (p=0,034). Age ≥65 year was not associated with an increase TRM and was surprisingly associated with less total parenteral nutrition (p=0,046) and narcotics uses (P=0,011). The median length of stay was 26 days. The median follow-up was 27 months (range, 1 to 87), median PFS of 46 months (Confidence Interval (CI); 95%, 24,4-67,6) (graph 1) and OS not reached (graph 2). The estimated 5 years OS is 62% and PFS is 40%. Transplant related mortality (TRM) was only 1% at 100 days and 2% at 1year after transplant. The only 2 patients who died from TRM died from cardiac arrest (1 month) and from an unknown cause (3 months). The 1-year progression rate was 30% (graph 3) and mortality rate only 12%. Progressive disease status following first line therapy was associated with a worse PFS compared to the achievement of a complete remission (Hazard Ratio (HR) 2,77; CI 95%, 1,18; 6,49). Progressive disease status at time of transplant was also associated with a lower PFS (HR 9,30: CI 95% 2,55 to 33,92) and OS (HR 13,44: CI 95% 2,68 to 67,48). HCT-CI score did not correlate with OS. International Prognostic Index (IPI), age and treatment type did not influence PFS or OS. Surprisingly, HCT-CI score did not correlate with toxicities, morbidity or mortality. Conclusion: In this single center retrospective study of elderly patients with NHL, AHCT was proven to be safe and effective. Progressive disease at the time of transplant was associated with worse PFS and OS. HCT-CI did not allow the categorization of patients in different prognostics group. Lymphocyte count at day 14 could identify patients at significant risk of complications. Our data suggest that age alone should not exclude patients from transplantation. However, HDT and AHCT should be reserved to chemosensitive patients and avoided in the elderly patient with progressive disease. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures No relevant conflicts of interest to declare.