Effect of remission status and induction chemotherapy regimen on outcome of autologous stem cell transplantation for mantle cell lymphoma.

We analysed the outcomes of autologous stem cell transplantation (ASCT) following high-dose therapy with respect to remission status at the time of transplantation and induction regimen used in 56 consecutive patients with mantle cell lymphoma (MCL). Twenty-one patients received induction chemotherapy with HyperCVAD with or without rituximab (+/-R) followed by ASCT in first complete or partial remission (CR1/PR1), 15 received CHOP (+/-R) followed by ASCT in CR1/PR1 and 20 received ASCT following disease progression. Estimates of overall and progression-free survival (PFS) at 3 years among patients transplanted in CR1/PR1 were 93% and 63% compared with 46% and 36% for patients transplanted with relapsed/refractory disease, respectively. The hazard of mortality among patients transplanted with relapsed/refractory disease was 6.09 times that of patients transplanted in CR1/PR1 (P = 0.006). Patients in the CHOP (+/-R) group had a higher risk of failure for PFS compared with patients in the HyperCVAD (+/-R) group, though the difference did not reach statistical significance (hazard ratio 3.67, P = 0.11). These results suggest that ASCT in CR1/PR1 leads to improved survival outcomes for patients with MCL compared to ASCT with relapsed/refractory disease, and a HyperCVAD (+/-R) induction regimen may be associated with an improved PFS among patients transplanted in CR1/PR1

A Phase I/II Study of Chemotherapy Followed by Donor Lymphocyte Infusion plus Interleukin-2 for Relapsed Acute Leukemia after Allogeneic Hematopoietic Cell Transplantation

The efficacy of donor lymphocyte infusion (DLI) for treatment of relapsed acute leukemia after allogeneic hematopoietic cell transplantation is limited. We hypothesized that interleukin-2 (IL-2) combined with DLI after chemotherapy might augment graft-versus-leukemia effects. To identify a safe and effective IL-2 regimen, a phase I/II study of DLI plus IL-2 therapy was performed for such patients. After chemotherapy, 17 patients received DLI (1 × 108 CD3/kg for patients with related donors, and 0.1 × 108 CD3/kg for those with unrelated donors) and an escalating dose of induction IL-2 (1.0, 2.0, or 3.0 × 106 IU/m2/day representing levels I [n = 7], Ia [n = 9], and II [n = 1]) for 5 days followed by maintenance (1.0 × 106 IU/m2/day) for 10 days as a continuous intravenous infusion. Unacceptable IL-2–related toxicities developed in 1 patient at level I, 2 at level Ia, and 1 at level II. Grades III-IV acute graft-versus-host disease (aGVHD) developed in 5 patients, and extensive chronic GVHD (cGVHD) developed in 8. Eight patients had a complete remission after chemotherapy prior to DLI, and 2 additional patients had a complete remission after DLI plus IL-2 therapy. In conclusion, the maximal tolerated induction dose of IL-2 combined with DLI appears to be 1.0 × 106 IU/m2/day. IL-2 administration after DLI might increase the incidence of cGVHD

Association of immunophenotype with expression of topoisomerase II α and β in adult acute myeloid leukemia.

Anthracyclines used in the treatment of acute myelogenous leukemia (AML) inhibit the activity of the mammalian topoisomerase II (topo II) isoforms, topo II α and topo IIβ. In 230 patients with non-M3 AML who received frontline ara-C/daunorubicin we determined expression of topo IIα and topo IIβ by RT-PCR and its relationship to immunophenotype (IP) and outcomes. Treatment outcomes were analyzed by logistic or Cox regression. In 211 patients, available for analysis, topo IIα expression was significantly lower than topo IIβ (P \u3c 0.0001). In contrast to topo IIα, topo IIβ was significantly associated with blast percentage in marrow or blood (P = 0.0001), CD7 (P = 0.01), CD14 (P \u3c 0.0001) and CD54 (P \u3c 0.0001). Event free survival was worse for CD56-negative compared to CD56-high (HR = 1.9, 95% CI [1.0-3.5], p = 0.04), and overall survival was worse for CD-15 low as compared to CD15-high (HR = 2.2, 95% CI [1.1-4.2], p = 0.02). Ingenuity pathway analysis indicated topo IIβ and immunophenotype markers in a network associated with cell-to-cell signaling, hematological system development/function and inflammatory response. Topo IIβ expression reflects disease biology of highly proliferative disease and distinct IP but does not appear to be an independent variable influencing outcome in adult AML patients treated with anthracycline-based therapy

Modulation of Human Mesenchymal Stem Cell Immunogenicity through Forced Expression of Human Cytomegalovirus US Proteins

BACKGROUND: Mesenchymal stem cells (MSC) are promising candidates for cell therapy, as they migrate to areas of injury, differentiate into a broad range of specialized cells, and have immunomodulatory properties. However, MSC are not invisible to the recipient's immune system, and upon in vivo administration, allogeneic MSC are able to trigger immune responses, resulting in rejection of the transplanted cells, precluding their full therapeutic potential. Human cytomegalovirus (HCMV) has developed several strategies to evade cytotoxic T lymphocyte (CTL) and Natural Killer (NK) cell recognition. Our goal is to exploit HCMV immunological evasion strategies to reduce MSC immunogenicity. METHODOLOGY/PRINCIPAL FINDINGS: We genetically engineered human MSC to express HCMV proteins known to downregulate HLA-I expression, and investigated whether modified MSC were protected from CTL and NK attack. Flow cytometric analysis showed that amongst the US proteins tested, US6 and US11 efficiently reduced MSC HLA-I expression, and mixed lymphocyte reaction demonstrated a corresponding decrease in human and sheep mononuclear cell proliferation. NK killing assays showed that the decrease in HLA-I expression did not result in increased NK cytotoxicity, and that at certain NK∶MSC ratios, US11 conferred protection from NK cytotoxic effects. Transplantation of MSC-US6 or MSC-US11 into pre-immune fetal sheep resulted in increased liver engraftment when compared to control MSC, as demonstrated by qPCR and immunofluorescence analyses. CONCLUSIONS AND SIGNIFICANCE: These data demonstrate that engineering MSC to express US6 and US11 can be used as a means of decreasing recognition of MSC by the immune system, allowing higher levels of engraftment in an allogeneic transplantation setting. Since one of the major factors responsible for the failure of allogeneic-donor MSC to engraft is the mismatch of HLA-I molecules between the donor and the recipient, MSC-US6 and MSC-US11 could constitute an off-the-shelf product to overcome donor-recipient HLA-I mismatch

Prediction Of CR On Reinduction In Patients With Newly Diagnosed Acute Myeloid Leukemia Given Intensive Induction Regimens: A Report From SWOG and Cleveland Clinic

Abstract 3+7” (3 days of daunorubicin or idarubicin + 7 of cytarabine) is the most frequently used intensive induction regimen for newly diagnosed AML. While it is common practice to reinduce patients (pts) who do not achieve marrow ablation by day 14 with the same agents, it remains unclear whether any particular disease or treatment-related factors can predict for CR with such a strategy, or can identify pts who should more appropriately be considered to have primary refractory disease at day 14 and treated with different agents. This analysis was designed to address this question. Methods We analyzed 1505 pts given 3+7 on SWOG studies S8600 (n = 534), S9031 (n= 215), S9333 (n = 161), and S0106 (n = 595) and 235 treated at Cleveland Clinic from 2006-2010 of whom 54 were reinduced with anthracycline-based therapy. In the SWOG cohort, 49% of pts achieved CR on course 1. Of the 734 patients who were alive at day 28 but did not achieve CR on course 1, 336 (53%) had received a reinduction course of 3+7. We used multivariate logistic regression to identify covariates associated with achievement of CR to reinduction in these 336 pts. The area under receiver operating characteristic curves (AUC) were used to quantify the effectiveness of the multivariate models at predicting CR in reinduction (AUC 1.0 = perfect prediction, AUC 0.5 = “coin flip”). Numerical covariates examined were [median (range)]: age (51, 15-83), day the first post-induction marrow was examined (hereafter “day 14”, 15, 7-48), day 14 blasts % (20, 0-95), day 14 % cellularity (37, 1-85), and their product (infiltrate, 5, 0-74), change in % blasts from day 1 (-44, -96,50), change in cellularity from day 1 (-5, -99-80), change in infiltrate from day 1 (-2, 93-41), and days from start of course 1 to start of course 2 (21, 13-67). Categorical covariates examined were: pre-treatment performance status (PS, ECOG scale) and pre-treatment cytogenetics (SWOG criteria). Results 40% of the 336 SWOG pts achieved CR to 3+7 reinduction, while 14% died during the first 28 days following reinduction, and 45% neither died during this time nor achieved CR (resistant). Age was associated with reinduction CR rate (median 47 for CR, 56 for no CR, p<0.001), as was day of reinduction (median 24 for CR, 20 for no CR, p=0.005), cytogenetics (CR rates 75% for favorable, 35% for intermediate, 18% for unfavorable, and 9% for unknown, p=0.04), and AML status (CR rate 42% for de novo and 16% for secondary AML). However, the AUC for age was 0.63, day of second induction was 0.59, cytogenetics was 0.60, and AML status was 0.53. Day 14 marrow blast % was similar in pts who did and did not achieve CR to reinduction (medians 20% and 22% respectively, p = 0.8). Similarly, day 14 cellularity, day 14 infiltrate, change in blast %, cellularity, infiltrate from pretreatment, and day when course 2 began were not associated with reinduction CR rate. On multivariate analysis, none of these covariates nor SWOG protocol was associated with second course CR rate, and the AUC for this multivariate model was only 0.70. There was no evidence that the effects of covariates differed in the different protocols. In the Cleveland Clinic cohort, 53% of pts achieved a CR on their reinduction or 3rd induction course, 11% died during the first 28 days of reinduction, and 33% were resistant. In this cohort, no covariates were associated with CR on reinduction or 3rd induction and AUC values were uniformly low and similar to the SWOG cohort. Conclusion In AML pts treated with 3+7 regimens, our findings indicate that bone marrow parameters, specifically day 14 blasts %, marrow cellularity, and treatment-related changes do not predict for subsequent CR with a reinduction Perhaps too few patients not in CR after a first course of 3+7 receive reinduction with 3+7. ClinicalTrials.gov Identifier: NCT00085709 (others precede registry reporting) Funding This work was supported by PHS Cooperative Agreement grants awarded by the National Cancer Institute, CA32102 and CA38926 Disclosures: No relevant conflicts of interest to declare

High-dose therapy and autologous stem cell transplantation for chemoresistant Hodgkin lymphoma: the Seattle experience.

BACKGROUND: High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the standard treatment for patients with chemosensitive relapsed/refractory Hodgkin lymphoma (HL), but this therapy is commonly denied to patients with resistant disease. We explored the utility of HDT and ASCT for chemoresistant HL because there are few established therapies for these patients. METHODS: Sixty-four chemoresistant HL patients underwent HDT followed by ASCT at our center. Baseline characteristics included median age = 35 years (range, 14-59 years), stage III/IV = 49 (77%), nodular sclerosis histology = 51 (80%), and prior radiation = 32 (50%). Twenty-six patients (41%) received total body irradiation (TBI)-based regimens, and 38 (59%) underwent non-TBI conditioning. RESULTS: The estimated 5-year overall survival (OS) and progression-free survival (PFS) were 31% and 17%, respectively (median follow-up = 4.2 years). Multivariate analysis only identified year of transplant as independently associated with improved OS (P = .008) and PFS (P = .04), with patients receiving transplants in later years having better outcome. The probabilities of 3-year PFS for patients receiving transplants during 1986 to 1989, 1990 to July 1993, August 1993 to 1999, and 2000 to 2005 were 9%, 21%, 33%, and 31%, respectively. CONCLUSIONS: These data suggest that HDT and ASCT may result in prolonged remissions and survival for a subset of chemoresistant HL patients, with improved outcomes in patients receiving transplants more recently