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Grade 3 follicular lymphoma (FL3) is thought to have an aggressive clinical course. On the basis of possible biologic differences, the new World Health Organization (WHO) classification of lymphoma suggests further subdivision of FL3 into grades 3a and 3b and states that the percentage of involvement by diffuse large B-cell lymphoma (DLBCL) should also be reported. However, the clinical implications of these features are unclear. Therefore, we studied 190 newly diagnosed patients with lymph node–based FL3 who received anthracycline-containing combination chemotherapy. The follicular component was subclassified as grade 3a (FL3a) or grade 3b (FL3b) according to the WHO criteria, or as follicular large cleaved cell type (FLC). The percentage of a diffuse component, if present, was also recorded. Of the 190 cases, there were 107 FL3a (56%), 53 FL3b (28%), and 30 FLC (16%) cases. Diffuse areas were seen in 72 cases (31 FL3a, 28 FL3b, and 13 FLC). There were no significant differences in the clinical characteristics, overall survival, or event-free survival between patients with grades FL3a, FL3b, or FLC. However, those cases with a predominant diffuse component (> 50% diffuse) had a significantly worse overall survival (P = .0037) and event-free survival (P = .012). Therefore, we conclude that the subdivision of FL3 into cytologic subtypes does not appear to be important clinically. However, patients with FL3 having a diffuse component of more than 50% have an inferior survival that is similar to the survival of those with DLBCL.

Blood stem cell transplantation (BSCT) results in rapid hematopoietic recovery in both the allogeneic and autologous transplant settings. Because of the large numbers of progenitor cells in mobilized blood, the administration of growth factors after transplantation may not provide further acceleration of hematopoietic recovery. A randomized, double-blind, placebo-controlled study was performed to determine the effects of filgrastim (granulocyte colony-stimulating factor; G-CSF) administration on hematopoietic recovery after allogeneic BSCT. Fifty-four patients with hematologic malignancies undergoing a related, HLA-matched allogeneic BSCT were randomly assigned to receive daily filgrastim at 10 µg/kg or placebo starting on the day of transplantation. A minimum of 3?×?106 CD34+ cells/kg in the allograft was required for transplantation. All patients received a standard preparative regimen and a standard regimen for the prevention of graft-versus-host disease (GVHD). The median time to achieve an absolute neutrophil count greater than 0.5?×?109/L was 11 days (range, 9-20 days) for patients who received filgrastim compared with 15 days (range, 10-22 days) for patients who received placebo (P?=?.0082). The median time to achieve a platelet count greater than 20?×?109/L was 13 days (range, 8-35 days) for patients who received filgrastim compared with 15.5 days (range, 8-42 days) for patients who received placebo (P?=?.79). There were no significant differences for red blood cell transfusion independence, the incidence of acute GVHD, or 100-day mortality between the groups. The administration of filgrastim appears to be a safe and effective supportive-care measure following allogeneic BSCT.

Patients with disseminated follicular non-Hodgkin’s lymphoma (NHL) are only occasionally cured with standard chemotherapy regimens. Although most of these tumors are initially responsive to chemotherapy, in 40% to 70% of patients the lymphoma will eventually transform to an NHL of higher grade malignancy and a poorer prognosis. We treated 18 patients having an original diagnosis of follicular NHL with high-dose therapy and autologous bone marrow transplantation. The lymphomas of 10 of the patients had already undergone histologic transformation and eight still had a follicular histologic pattern. The former group had been followed for a longer time from the diagnosis of NHL and had been more extensively treated with conventional chemotherapy regimens. All eight patients with follicular NHL at the time of transplantation are alive for 246+ to 1,804+ days and seven of the patients are in complete remission. In contrast, of the 10 patients in histologic transformation only 1 is alive and in CR. This reflects the inability of these patients to tolerate the high-dose chemotherapy and myelosuppression as well as resistance of their lymphoma to this therapy. This difference in survival between the two groups was highly significant (P= .002). We conclude that the outcome of patients with follicular NHL transplanted early before histologic transformation is better than for those who are transplanted later in the course of their illness. Because of the relapsing behavior of follicular NHL, a longer follow-up is necessary to prove any impact on the natural history of the disease.

Forty patients with refractory Hodgkin's disease (24 patients) or non-Hodgkin's lymphoma (16 patients) who were considered for high-dose therapy but not for autologous bone marrow transplantation (ABMT) due to BM metastases, previous pelvic irradiation, a history of marrow involvement by tumor or hypocellular marrow in conventional harvest sites received high-dose therapy and autologous peripheral blood (PB) hematopoietic stem cell transplantation. Disappearance of circulating neutrophils and development of RBC and platelet transfusion-dependence was followed, in the evaluable patients, by reappearance of 0.5 × 109/L circulating granulocytes and sufficient platelets to obviate the need for platelet transfusions at a median of 25 days after transplantation. Twenty-three patients experienced a clinical complete remission (CR). The projected 2-year event-free survival was 20% for all 40 patients and 49% for the non-Hodgkin's lymphoma patients. The projected 18-month event-free survival for the Hodgkin's disease patients was 15%. PB stem cell transplantation provided an opportunity to administer high-dose salvage therapy to patients with refractory lymphoma who otherwise were not candidates for such therapy. For some of those patients, the high-dose therapy produced prolonged survival, free of tumor progression.

We report nine children with relapsed (n = 8) or high-risk (n = 1) peripheral T-cell lymphoma (PTCL) who underwent autologous (n = 6) or allogeneic (n = 3) bone marrow transplantation (BMT). These children received transplants as part of a prospective phase I/II study of thioTEPA (TT) and total body irradiation (TBI) with escalating doses of VP-16. The median age of these patients at time of BMT was 6.5 years (range 2.5 years to 14 years). Three were transplanted with active disease after failing salvage chemotherapy. Of the other six, one was transplanted in first complete remission (CR) and five in second or subsequent CR. Of these nine patients, eight are free of disease a median of 25 months after BMT (range, 6 to 48 months), with an estimated 2-year relapse-free survival (RFS) of 89%. Six of these eight patients have been followed for 12 or more months after BMT, and in each their current remission exceeds their longest previous remission duration. The toxicity of the TT/TBI ± VP-16 regimens was significant but manageable, predominately consisting of severe mucositis. For a comparison, we reviewed retrospective data on the six additional children and adolescents with PTCL who underwent BMT during the 3-year period preceding this phase I/II study. The median age at BMT of these six patients was 19 years (range 15.5 years to 20 years). These patients were prepared for BMT with a variety of other regimens. One had no response to BMT and the other five relapsed at 1.5 to 5 months after BMT (median, 3 months) with an RFS of 0%. Our data suggest that thioTEPA plus TBI, with or without VP-16, is an effective preparative regimen for BMT for young patients with relapsed or high-stage PTCL and leads to prolonged RFS.

One hundred and twenty-eight patients with non-Hodgkin’s lymphoma (NHL), Hodgkin’s disease (HD), and acute lymphoblastic leukemia (ALL) previously reported from a phase III trial of rhGM-CSF or placebo following autologous bone marrow transplantation (ABMT) were investigated for the development of late toxicities. Median follow-up is 36 months. No apparent long-term deleterious effects on BM function were observed. Moreover, disease-free survival and overall survival were similar for patients on both treatment arms, arguing for the long-term safety of recombinant human granulocyte macrophage-colony-stimulating factor (rhGM-CSF). The only factors predictive for both a high risk of relapse over time and mortality were having the diagnosis of ALL and/or undergoing ABMT in resistant relapse. We attempted to identify clinical variables before BM harvest. at the time of marrow infusion, or events within the first 100 days posttransplant, which might predict speed of neutrophil recovery in the setting of placebo or rhGM-CSF administration after ABMT. Only previous exposure to agents that deplete stem cells led to a significant delay in neutrophil recovery, suggesting their avoidance in patients who may undergo ABMT. Nevertheless, even those patients benefited from rhGM-CSF. For all patients, rhGM-CSF and agents that deplete stem cells were the strongest independent predictors for neutrophil engraftment. With the increasing use of newer hematopoietic growth factors both alone and in combination, long-term follow-up is essential to confirm the same safety that we report with rhGM-CSF.

Between February 1986 and March 1990, 56 patients with relapsed Hodgkin's disease treated with high-dose cyclophosphamide, carmustine, and etoposide (CBV) received an autologous peripheral stem cell transplantation (PSCT) rather than an autologous bone marrow transplantation (ABMT) because each patient had a marrow abnormality, either hypocellularity or tumor involvement. At least 6.5 × 109mononuclear cells/kg patient weight were collected from the peripheral blood of each patient, cyropreserved, and returned intravenously following CBV administration. Three patients had an early death 2,22, and 25 days after PSCT. The actuarial event-free survival for these 56 patients at 3 years was 37% and was as least as good as that reported for relapsed Hodgkin's disease patients treated with CBV and ABMT. The 30 patients who had no marrow metastases at the time of PSC harvesting had an actuarial event-free survival of 47%, while those 26 patients with marrow metastases had a significantly different actuarial event-free survival of 27% (P =.02). CBV and PSCT for patients with relapsed Hodgkin's disease who have marrow hypocellularity in traditional harvest sites or histopathologic evidence of BM metastases can result in long-term event-free survival.

Lunning: Bristol-Myer-Squibb: Consultancy; AbbVie: Consultancy; Pharmacyclics: Consultancy; Juno: Consultancy; TG Therapeutics: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Spectrum: Consultancy; Celgene: Consultancy. Blumel:TG Therapeutics, Inc.: Consultancy. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Vose: Allos Therapeutics/Spectrum: Research Funding; US Biotest, Inc: Research Funding; Janssen Biotech: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte Corp: Research Funding; Acerta Pharma: Research Funding; GlaxoSmithKline: Research Funding. Armitage:Celgene: Consultancy; Ziopharm: Consultancy; Spectrum: Consultancy; Roche: Consultancy; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Conatus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tesaro Bio, Inc: Membership on an entity's Board of Directors or advisory committees. Lunning:Spectrum: Consultancy; Genentech: Consultancy; BMS: Consultancy; Juno: Consultancy; Gilead: Consultancy; TG Therapeutics: Consultancy.

Link: Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding. Kahl:Roche/Genentech: Consultancy; Seattle Genetics: Consultancy; Millennium: Consultancy; Cell Therapeutics: Consultancy; Celgene: Consultancy; Infinity: Consultancy; Pharmacyclics: Consultancy; Juno: Consultancy. Bartlett:Gilead: Consultancy, Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Colgene: Research Funding; Medimmune: Research Funding; Kite: Research Funding; Insight: Research Funding; Seattle Genetics: Consultancy, Research Funding; MERC: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding.

Introduction:Approximately 20% of classical Hodgkin lymphoma (HL) patients are greater than 60 years old at diagnosis. The survival of this subgroup is inferior to that of younger patients, despite most being treated with curative intent. Possible reasons for this difference include: comorbidities, toxicity of treatment (especially bleomycin, Stamatoullas at al. BJH 2015), poorer baseline performance status, different disease biology, and more frequent chemotherapy dose reductions. Recent advances and refinements in treatment have not improved the outcomes of elderly patients with HL significantly (Johnson and McKenzie. Blood 2014). Selection of a regimen for HL should take comorbidities into account. There is not a clear standard of care treatment regimen for elderly patients with HL.

Vose: Millennium Pharmaceuticals, Inc.: Research Funding.

Mantle cell lymphoma (MCL) is among the most aggressive B cell lymphomas with median patient survival of only 3–4 years. Although high dose therapies followed by hematopoietic stem cell transplantation is an option for therapy, it is difficult to successfully treat MCL until the therapeutic strategy is developed to target and eliminate the residual/relapsing tumors after existing chemotherapies. Therefore, characterization of these residual/relapsing tumor cells after chemotherapy as a basis for developing therapeutic strategy to target residual/relapsing MCL cells is essential. Accordingly, we have isolated the residual/relapsing tumor cells by transplanting the human MCL cell line, Granta519, into NOD-SCID mice followed by CHOP+Bortezomib chemotherapy. Isolated residual/relapsing tumor cells from liver and kidney characterized morphologically using microscopy, and immunophenotypically for CD45, CD19 and CD23 expression by flow-cytometry showed no differences. However these cells had a significantly higher growth rate and increased chemo-resistant potential in vitro as determined by MTT and 3[H]-thymidine incorporation assay compared to parental Granta cells. In addition, NOD-SCID mice transplanted with cells isolated from liver had significantly shorter survival compared to parental cells indicating a higher tumorigenic potential of relapsed tumor cells pre-exposed to chemotherapy. There was a higher frequency of side population (SP) cells in relapsed tumor cells compared to parental cells as determined by flow cytometry after Hoechst staining. In addition, there was an increased expression of transcripts associated with maintenance of stem cells, including GLI transcription factors, targets of hedgehog signaling, as determined by microarray and confirmation by real time PCR, suggesting that increased stem cell-like cells in the relapsing tumors may be responsible for the chemo-resistance and increased tumorigenic potential. However, these residual/relapsing cells were susceptible to in vitro generated MCL-specific cytotoxic T lymphocytes (CTLs) against parental cells. We have demonstrated the potential of inhibition of GLI to render the MCL cells sensitive to chemotherapy (Hegde et al., Mol Cancer Ther, 7:1450–60, 2008). Therefore, we have developed a strategy of targeting hedgehog signaling mediators such as GLI transcription factors using GLI-antisense oligonucleotides or the proteosome using Bortezomib, to target residual/relapsing tumor cells after CHOP chemotherapy followed by tumor-specific adoptive T cell therapy (ATT) against human MCL using the mouse model. There was a significantly improved survival and decreased tumor burden in the mice treated with CHOP+GLI-ASO+ATT or CHOP+bortezomib+ATT compared to CHOP only treated controls suggesting the potential of targeting of residual/relapsing tumor cells using this strategy. Together, these results demonstrate the potential of this novel combined therapeutic strategy against human residual/relapsing MCL, which may have future clinical application.

Despite recent therapeutic advances, the treatment of Hodgkin's disease remains controversial. Among the most commonly used regimens are ABVD, Stanford V and BEACOPP. Studies of Stanford V have shown conflicting outcomes with some excellent and some much less good results. To address this discrepancy we reviewed 113 patients with previously untreated Hodgkin's disease, all of whom were HIV negative, who received the Stanford V regimen from physicians in the Nebraska Lymphoma Study Group between January 1997 and January 2006. The median age was 36 years (range 15–88) with only 10 patients over 60 years of age. Fifty-two (46%) of the total were males. Seventy-eight (68%) had nodular sclerosis, subtype and 69 (61%) were stage I and II. Constitutional symptoms were present in 36 (32%) patients. Tumor bulk > 5cm was evident in 68 (60%). Four or more nodes were involved in 57 (50%) and 84 (78%) received radiotherapy. Median follow up was 63 months (range 8–114). Univariate analysis of the data identified 4 adverse risk factors which included age > 60 years, stages III or IV, constitutional symptoms, and mixed cellularity subtype. Complete remission or unconfirmed complete remission was achieved in 82(72%), 21 (18%) had partial response, 2 had progression of disease (PD) and 3 were unable to be evaluated. There were 5 early deaths; 3 of which were definitely related to the treatment. For the entire group, the 5 year overall survival (OS) was 84% and the 5-year event free survival (EFS) was 74%. However, the results were dependent on the presence or absence of the adverse risk factors of age >60, stage III or IV, non-nodular sclerosis histological subtype, and B symptoms as shown below:

Although many patients are successfully treated for DLBCL, relapses can occur especially in the higher risk patients. Relapses in successfully treated DLBCL patients most frequently occur within the first 2–3 years. However in a small number of patients, relapses occurring after 5 years do happen and have been frequently reported to be a relapse of follicular lymphoma. We evaluated 805 patients with DLBCL treated with an anthracycline based chemotherapy through the Nebraska Lymphoma Study Group from 1983–1998. The patients were treated prior to the use of rituximab in this patient population. Two hundred and three patients relapsed from a documented complete remission. Of these, 30 (15%) relapsed more than 5 years after treatment (range 5.3 – 14.5 years, median 6.8 years). The median age at relapse was 71 years (range 32 – 85) and 58% were male. Patients with late relapses had relatively good prognostic features at the time of diagnosis. None had a low performance status, 71% were stage I/II, 78% had no systemic symptoms, 78% had a normal LDH, and 67% had an IPI of 0/1. All patients had biopsies to document relapse. Eighty one percent of the relapses were documented DLBCL, 11% had composite lymphoma with DLBCL and follicular grade 3 (FL3) lymphoma, 4% had FL3 alone, and 4% had follicular grade 1 (FL1). Using immunohistochemistry to predict GCB vs. non-GCB origin, 72% of the patients had a GCB phenotype at diagnosis and 90% had a GCB phenotype at relapse. Four patients had no therapy at relapse and 2 patients had radiotherapy. The remaining patients received a variety of combination chemotherapy regimens with or without rituximab and 2 patients underwent autologous stem cell transplantation. Seven patients had durable complete remissions to their second line chemotherapy regimens (4 with chemo + rituximab and 2 autologous stem cell transplantation). Three of these survivors died of unrelated causes and 4 are alive in remission 19–119 months after the salvage therapy or autologous transplantation. Conclusions: Most patients with late relapses of DLBCL initially present with good prognostic characteristics at the time of the origninal diagnosis. Unlike previous studies, the most common type of histology in this study at the time of late relapse was DLBCL and not follicular lymphoma. However, the vast majority of the late relapse DLBCL patients had a GCB phenotype both at diagnosis and at relapse. Patients with late relapses usually do respond to salvage therapy and can have second prolonged remissions with chemotherapy and/or autologous stem cell transplantation.

Considerable advancements have been made in our understanding of the biology and treatment of CLL/SLL. Despite these advances, CLL/SLL essentially remains an incurable illness. Hematopoietic stem cell transplantation (HSCT) has been used in an attempt to improve remission duration and survival. However little high level data exists on outcomes for patients (pts) undergoing HSCT for CLL/SLL. We evaluated the long-term survival of 65 CLL/SLL pts who underwent allogeneic or autologous HSCT from 1995 until 2006 at the University of Nebraska Medical Center. The median duration of follow-up for surviving pts is 8.8 years. The median age was 49 years and there was no significant difference in age between the autologous and allogeneic groups. Thirty nine pts underwent allogeneic HSCT (n=25 matched related donor, n=14 matched unrelated donor) and 26 pts underwent autologous HSCT. For the group undergoing allogeneic HSCT, the stem cell source was mobilized peripheral blood progenitor cells in 74% and bone marrow in 26%. In the autologous HSCT group, 81% of pts received peripheral blood and 19% received bone marrow as their stem cell source. In the autologous group there were 19 deaths (10 from progression) over the period of follow-up. In the allogeneic group there were 29 deaths (including 8 from acute regimen related toxicity, 9 from infection, 3 from complications of GVHD, 1 from late pulmonary toxicity, one from PTLD, one from MDS/AML) and 10 pts are alive at end of follow-up. One hundred day mortality was significantly higher in the allogeneic group (20% vs. 6%; p=0.05). For the allogeneic group the cumulative incidence of grade II-IV acute graft versus host disease (GHVD) was 64% (95% confidence interval [CI]=47–76) and the cumulative incidence of chronic extensive GHVD was 50% (95% CI=29–68). One-year progression free survival (PFS) was significantly better among autologous SCT when compared to allogeneic HSCT (77% versus 45%; P=0.006), but at 5 years these differences were no longer apparent. Similarly, one-year overall survival (OS) was significantly better for autologous SCT (81% versus 48%; P=0.003) but at 5 years these differences were no longer significant (49% versus 31%; p=0.15). Among all patients undergoing allogeneic HSCT, 5-year PFS was significantly higher for patients with SLL vs. CLL (36% vs. 25%; P=0.04). In addition, 5 year OS was better for pts with SLL compared to CLL (51% vs. 33%, P=0.06). There was no difference in PFS or OS following autologous SCT between patients with a diagnosis of CLL versus SLL. The group of pts undergoing autologous HSCT demonstrates no plateau on the PFS curve, whereas for pts undergoing allogeneic HSCT there is a suggestion of a plateau in PFS at approximately 25%. In conclusion, CLL/SLL patients undergoing allogeneic SCT had a higher incidence of early treatment related mortality, mainly from regimen related toxicity and infection. In a subgroup analysis pts with CLL appear to have an inferior PFS compared with pts with SLL. This difference may be due to a more prominent underlying immune deficiency in CLL patients that leads to a higher probability of treatment related mortality. Pts with CLL/SLL undergoing autologous HSCT had a lower incidence of treatment related mortality, but there is no evidence of a plateau in progression-free survival.

Mantle cell lymphoma (MCL) accounts for 7% of all non-Hodgkin’s lymphomas, with median overall survival in most series of 3–4 years. MCL has been classified into three histological subtypes which include diffuse MCL, nodular MCL, and blastic MCL. A relatively small number of studies have examined the prognostic importance of histology in MCL. The aim of this study was to determine if the progression free survival (PFS) and overall survival (OS) rates in mantle cell lymphoma differ among histological subtypes. A total of 102 patients with MCL, treated by the Nebraska Lymphoma Study Group between January 1986 and June 2006, with a median age of 60 years (range 32–89 years) were available for study. Patients were treated with HyperCVAD or a CHOP like regimen with or without rituximab and autologous hematopoetic stem cell transplant (ASCT). All cases were confirmed using cyclin D1 staining. Regardless of treatment, our study failed to show a significant difference in PFS (p=0.26) or OS (P=0.06) among histological subtypes. There was a trend for better survival in patients with nodular MCL. However, in patients receiving ASCT, there was a significantly higher PFS (P=0.0001) and OS (p=0.0005) compared to patients not receiving ASCT. The 3 year PFS for patients receiving HyperCVAD followed by ASCT was 64% compared to the 3 year PFS for HyperCVAD alone of 0 (p=0.008). In conclusion, we failed to show association between histological subtypes of MCL with outcomes regardless of treatment. However, the use of ASCT improved survival.

Background/Patients and Methods: NST is increasingly being used as a means of establishing a graft-versus-malignancy (GVM) effect with less regimen related toxicity. Between 9/01 and 7/04, 39 patients (pts) with high risk/relapsed/refractory HM who were not candidates for full intensity allogeneic stem cell transplantation underwent NST using Pentostatin/TBI. The median age of pts was 52 years (range 22–70). The median number of prior therapies was 4 (range 0–8) including prior autologous stem cell transplantation in 22 pts. Diseases transplanted included chronic lymphocytic leukemia/indolent non-Hodgkin’s lymphoma (NHL, n=6), aggressive NHL (n=8), mantle cell lymphoma (n=3), Hodgkin’s disease (n=6), myeloproliferative disorders (n=4), myelodysplastic syndromes (n=4), and acute myelogenous leukemia (AML, n=8). Conditioning consisted of Pentostatin 4 mg/m2 daily on day -21, -20, and -19, followed by 200 cGy TBI on day -1. Post-grafting immunosuppression consisted of cyclosporine/mycophenolate mofetil. Results: Stem cell transplantation was from matched related (n=14) or unrelated (n=25) donors. Death prior to 100 days post transplant occurred in 7 patients. Grade III/IV toxicities included hematologic (n=10 pts), infectious (n=5) and other non-infectious (n=4). The median nadir values (day -21 to day 0) for hemoglobin, neutrophil count and platelet count were 10.7 g/dl (range 7.8–12), 1056/mm3 (range 0–5336), and 174/mm3 (range 24–523) respectively. Three pts failed to engraft; two patients with myelofibrosis (both of whom had autologous reconstitution) and one patient with high risk AML (who died of complications of fungal sepsis without hematologic recovery). The median chimerism values for CD3+ cells and WBC at day 28 are 80% and 95% donor cells respectively. The median chimerism values for CD3+ and WBC at day 70 are 95% and 95% respectively. There have been no late graft failures. The cumulative incidence of all grades of acute graft-versus-host disease at day 100 was 40% and was more common in unrelated donor transplants (60% vs. 15%, P=0.012). Chronic graft-versus-host disease has developed in 69% of patients. The cumulative incidence of relapse for all patients is 30%, and is lower for unrelated donor transplants than matched related donor transplants (46% vs. 20%, P=0.02). The probability of event-free and overall survival at two years is 52% and 56% respectively. Conclusions: This regimen is associated with acceptable toxicity. Engraftment has not been an issue with the exception of two pts with myelofibrosis. Pts receiving unrelated donor grafts have a higher incidence of graft-versus-host disease and a lower relapse rate. This represents indirect support for the presence of a GVM effect. A prospective study using a modified Pentostatin schedule (starting at day - 10) is ongoing based on the nadir of host T-cells identified in this study.

B chronic lymphocytic leukemia (B-CLL) is the most common leukemia in the elderly with heterogeneous clinical outcome. Rai stage, immunoglobulin heavy chain mutation status, Zap-70 expression, CD38 expression and chromosome abnormalities are used as prognostic markers. Among these, CD38, a differentiation marker of T lymphocytes, has been reported to have a role in B-CLL pathogenesis. High CD38 expression is associated with an unfavorable clinical course with advanced disease stage, poor responsiveness to therapy, short time to first treatment, and shorter survival, whereas B-CLL patients with low CD38 expression required minimal or no treatment, remained treatment free for longer time and had better survival. However, the molecular basis for the association of CD38 expression and clinical course of B-CLL patients is not known. Therefore, in this study we classified 35 B-CLL patients into CD38 high (>30%) and CD38 low (<30%) expressions, and the clinical course was correlated with gene expression profile using oligonucleotide DNA microarrays consisting 10,000 genes. There was a significant difference in CD38 expression levels in patients with good clinical outcome (mean CD38 ~ 20%) compared to poor clinical outcome (mean CD38 ~ 46%). Median time to treatment with high CD38 expression was 30 months compared to 69 months for low CD38 expressing patients. Significance analysis of microarray (SAM) identified 52 differentially expressed genes. From these genes, Hem1 and CTLA-4 were further studied because the Hem1 expression is limited to hematopoietic cells and CTLA-4 is involved in modulation of immune response. Also, CTLA-4 is a member of the immunoglobulin superfamily involved in the cell cycle regulation and prolongs the progression through the G1 phase of the cell cycle. The differential expression of Hem1 and CTLA-4 was also confirmed by semi-quantitative RT-PCR. Hem1 was found to be over expressed in B-CLL patients with higher CD38 expression compared to lower CD38 expression, whereas CTLA-4, was over expressed in B-CLL patients with lower CD38 expression compared to patients with high CD38 expression thus confirming the microarray results. Furthermore, to determine whether the expression levels of these two genes are associated with disease progression in B-CLL, log rank test was applied across the expression of Hem1 and CTLA-4 and disease progression. The higher expression of Hem1 was associated with shorter time to treatment (Figure 1), whereas lower expression of CTLA-4 was associated with shorter time to treatment (Figure 2). Thus, these results while confirming the prognostic value of CD38 expression, demonstrate the possible molecular basis of CD38 mediated clinical course in B-CLL patients involving key genes such as Hem1 and CTLA-4. Figure 1 Figure 1. Figure 2 Figure 2.

Background: The use of auto-HSCT has expanded to include older patients. Age is a risk factor for the development of AF in the general population. As more elderly patients undergo auto-HSCT, the risk of developing AF post-transplant may also increase. The development of AF may increase morbidity, may prolong hospitalization, and may increase the cost of hospitalization. However, few data exist evaluating the factors that contribute to the development of AF following auto-HSCT. At our institution, we have observed a large number of patients with this complication. Therefore, we performed a retrospective case-control study to determine the incidence of AF following auto-HSCT and to determine risk factors associated with the development of AF. Patients and Methods: We performed a chart review on all patients at our institution who received an auto-HSCT from November 1999 to May 2004. Cases were identified by reviewing EKGs performed post-transplant. Controls consisted of patients with similar age, year of transplant, and underlying hematologic malignancy. The following variables were examined for their association with AF: age, sex, diagnosis, disease stage at transplant, conditioning regimen, year of transplant, previous medical history including cardiac history, pre-transplant cardiology work-up, and electrolyte abnormalities immediately following auto-HSCT. Patients who developed AF were compared to controls. Multivariate logistic regression was done to evaluate the factors associated with the development of AF. Results: During the study period, 44 patients developed AF at a median of four days (range days 1–9) following auto-HSCT; incidence of 8.5%. We identified 516 patients who did not develop AF who had auto-HSCT in the same time period. Of these, 179 patients with similar characteristics were used as controls. The following variables were associated with developing AF in the multivariate model: age at transplant; median age 63 yrs (50–72) for cases vs 57 (49–72) for controls (p<0.001), abnormal renal function as determined by serum creatinine (p=0.008), history of previous arrhythmia (p<0.001), and a history of mediastinal irradiation (p=0.003). Although not significant in the multivariate model, we observed that 45% of the patients who developed AF had increased left atrial size on a pre-transplant echocardiogram as opposed to none in the controls (p<0.001). There was no difference in the length of hospital stay between the cases and controls (p=0.13). We did not detect a significant difference in the 100d survival between those who did and did not develop AF (90% vs 96%, p=0.25). However, patients who did not develop AF had a better overall survival (Log-rank p=0.04). Conclusions: Patients with older age, elevated serum creatinine level, history of previous arrhythmia, or history of previous mediastinal irradiation are more likely to develop AF following an auto-HSCT. Future studies should investigate whether interventions such as prophylactic beta-blockers can decrease the incidence of AF following auto-HSCT.

Background: Given the elective nature of hematopoietic stem cell transplantation (HSCT), the increased mortality and the potential loss of decision making capacity, patients undergoing HSCT are encouraged to have advanced care planning (ACP). This however could result in undue anxiety for the patient and their families since going through the process of having ACP explicitly raises the possibility of death. We compared the outcomes of patients with or without ACP who received HSCT for hematologic malignancies. Study Design: Patients age ≥19 yrs undergoing first allogeneic or autologous HSCT for a hematological malignancy between 2001 and 2003 were included in this study. Psychosocial assessments, including discussions about ACP, defined as having living will, power of attorney for health care, and life support instructions, conducted prior to transplant, were reviewed. Patients were classified according to presence or absence of ACP at HSCT. Multivariate Cox regression analysis was used to compare the risk of 100-day mortality between those with and without ACP while controlling for patient-, disease-, and transplant-related variables. Other outcomes evaluated include: days of hospitalization and in-hospital mortality. Results: Of the 380 eligible patients, psychosocial assessments were available for 343 patients (90%). Of these, 146 either had ACP (n=138, 40%) or completed it (n=8, 2%) during the pre-transplant process, while 197 did not have it but were open to the idea of having it in the future (n=161, 47%) or did not plan to have ACP (n=36, 11%). Older patients (p <0.001), male sex (p <0.01), and patients with lymphoma versus leukemia (p<0.005) were more likely to have ACP. No differences in level of education, role of patient in the family, smoking or alcohol usage, usage of spiritual faith to cope with illness, stage of disease at transplant, type of transplant, and interval from diagnosis to transplant were noted between those with and without ACP. There was no difference in the risk of 100-day mortality (RR: 0.80; 95% CI: 0.36 – 1.81) between patients with or without ACP after adjusting for disease stage and transplant type. Conclusions: The absence of differences in the outcomes of patients with or without ACP suggests that engagement in ACP is not reflective of HSCT risk. Factors other than outcome of HSCT need to be considered while counseling patients regarding ACP. The fact that only 40% of patients engaged in ACP prior to HSCT and 11% were not interested in ACP suggests that other factors determine interest in ACP and that a policy of discussing ACP with all HSCT patients will not result in universal acceptance of ACP. Outcomes following HSCT based on ACP OUTCOME WITHOUT ACP (n = 197) WITH ACP (n = 146) p VALUE Probability of 100-day mortality (95% CI) 8 (4–12) 7 (4–12) 0.79 In-hospital deaths 5 (2%) 3 (2%) 0.94 Median hospital stay in days (range) 13 (8–59) 13 (3–158) 0.7

Previously we have demonstrated that peripheral blood samples with B-cell Chronic Lymphocytic Leukemia (CLL) have different gene expression profiles associated with chromosome aberrations detected by fluorescence in situ hybridization (FISH). In particular, the vast majority of differentially expressed genes were related to the presence of the 11q23 deletion. The 11q23 deletion has previously been shown to be correlated with shortened over-all survival and extensive/bulky lymphadenopathy. In this study we sought to identify genes whose expression may play role in the progression of CLL in patients that carry the 11q23 deletion. Gene expression from 10,700 human gene specific 50-mer oligos (MWG Biotech, Ebersberg, Germany) was compared between two groups of peripheral blood CLL samples. The first group consisted of CLL patients with the 11q23 deletion detected by FISH as well as with the presence of abdominal/mediastinal lymphadenopathy. The second group consisted of CLL patients without the 11q23 deletion and without the presence of known abdominal/mediastinal lymphadenopathy. The non-11q deletion group included CLL patients with the 13q14 deletion, trisomy 12, 17p13 deletion, as well as several without any detectable abnormality. Immunoglobulin heavy chain variable region (IgVH) mutational status was compared in CLL samples in both groups to ensure that resulting expression differences were not the result of this known prognostic marker. Median of ratios was compared between the two groups. Eighty-eight (87) genes had a p-value < 0.01. Gene function was classified at the European Molecular Biology Laboratory (EMBL) Bioinformatic Harvester website. Twenty of these differentially expressed genes were cell cycle/cell signaling related genes that were over-expressed in the 11q23 deletion group. Examples include: activating transcription factor 4, rho-associated coiled-coil containing protein kinase 2, fibroblast growth factor 21 precursor, signal transducing adaptor molecule 1, mad2-like 1, interferon receptor 1, pim-2 oncogene, and zw10 interactor. In comparison, using the same peripheral blood CLL samples, 78 genes were differentially expressed (p < 0.01) between those samples that had a mutated IgVH versus those that had an unmutated IgVH. Therefore, the presence of both the 11q23 deletion and bulky abdominal/mediastinal lymphadenopathy significantly alters the gene expression profile of peripheral blood CLL cells, particularly genes related to the cell cycle and cell signaling related processes. Biological roles of some of these genes may help further elucidate the basis of the clinical behavior of CLL patients

Several studies have now identified that the addition of rituximab (R) to CHOP chemotherapy has increased the complete response, EFS, and overall survival (OS) for patients with previously untreated DLBCL. However, concerns of increased resistance of DLBCL following failure of CHOP-R and the inability to salvage those patients with high-dose chemotherapy and autologous stem cell transplantation have been raised. In an attempt to address this issue, we evaluated 103 patients with high risk, relapsed, or refractory DLBCL receiving high-dose chemotherapy and autologous stem cell transplantation at our center between 1999 and 2003. Fifty-six (54%) of the patients received CHOP as their initial induction therapy and 47 (46%) received CHOP-R. The patients ranged in age from 20–73 years (median 50). Sixty patients were male and 43 female. Sixty two of the patients were transplanted < 12 months from diagnosis and 41 were transplanted ≥ 12 months from diagnosis. The patients had received a median of 2 prior therapies (range 1–4). The majority (81%) were chemotherapy sensitive at the time of transplantation. The median follow-up of surviving patients is 27 months ( range 3–74). All patients received a BEAM (C) - based regimen [carmustine, etoposide, cytarabine, melphalan or cycylophosphamide] +/− anti-CD20 monoclonal antibodies. There was no difference in the 2-year EFS for patients failing CHOP vs. CHOP-R (60% vs. 68%, p=0.49). In addition, there was no difference in the 2-year overall survival (OS) of patients failing CHOP vs. CHOP-R (72% vs. 68%, p=0.63). In a multivariate analysis, the only factor predicting for an event (relapse or death) post-transplant was having received ≥ 2 prior chemotherapies (Relative Risk (RR) 7.5, p=0.048) and predicting for death from any cause was chemotherapy resistance (RR 2.5, p=0.037) and an increased lactic dehydrogenase at transplant (RR 4.1, p=0.002). The additional use of a monoclonal antibody with the transplant regimen did not significantly impact outcome in this analysis. This study demonstrates that patients with DLBCL failing CHOP-R are able to be salvaged with high-dose chemotherapy and autologous stem cell transplantation and have a similar 2-year EFS and OS as patients being transplanted following CHOP failure.

Clinical prognostic factors for grade 3 follicular lymphoma (FL3), using the new WHO classification, have not yet been clearly defined. Hence, we conducted a retrospective study to identify the outcome and clinical features predictive of survival in patients with FL3. Two hundred and two patients diagnosed with FL3 using the Berard criteria, who were staged and treated with various aggressive combination chemotherapy regimens containing either an anthracycline or mitoxantrone, are included in this study. After a median follow-up of 8.4 years (range, 0.5 – 19.5 years), 105 patients (52%) have died and 97 patients (48%) are alive at last contact. The estimated 10-yr event-free survival (EFS) and overall survival (OS) are 34% (95% CI: 26–41%) and 45% (95% CI: 37–53%), respectively. By multivariate analysis, older age (≥60 years; Figure 1) and a low hemoglobin (<12 gm/dL) were independent adverse predictors of OS (RR: 2.3, 95% CI: 1.5–3.7, p=0.0002; and RR: 1.9, 95% CI 1.2–3.0, p=0.0095, respectively). A low hemoglobin and advanced stage (III/IV) at presentation were independent adverse predictors of EFS (RR: 1.8, 95% CI: 1.2–2.8, p=0.0072; and RR: 1.7, 95% CI: 1.1–2.5, p=0.0096 respectively). When patients were compared based on age, there were no significant differences in the distribution of adverse prognostic factors among patients ≥60 years of age as compared to younger patients. There were also no differences in the frequency of relapse/progression (10-year rate of 50% in patients <60 years vs. 44% in patients ≥60 years, p=0.71) or lymphoma-specific/treatment-related deaths between the two age groups (10-year rate of 30% in patients <60 years vs. 35% in patients ≥60 years, p=0.17; Figure 2). Although younger patients (<60 years) had a significantly better OS and EFS as compared to older patients, there were no differences in the relapse/progression rates or lymphoma/treatment-related survival. Thus, aggressive combination chemotherapy led to durable remissions in 50–60% of patients with FL3. Figure Figure Figure Figure

Follicular lymphoma (FL) is the second-most common subtype of non-Hodgkin’s lymphoma. However, data addressing the management of early-stage FL is sparse. Hence we conducted this study in order to try to assess the influence of initial treatment on outcome in patients with stage I follicular lymphoma. One hundred patients, 46 males and 54 females diagnosed with stage I FL and treated on various Nebraska Lymphoma Study Group protocols have been included in this retrospective study. Thirty-eight percent of patients had grade 1, 22% had grade 2 and 40% had grade 3 FL. Sixty percent of patients were older than 60 years of age, 3% had a poor performance status (Karnofsky score <80), 7% had an elevated LDH level, 19% had bulky disease (tumor size ≥5 cm) and 5% had B-symptoms at presentation. Twenty-five percent of patients were treated with radiation alone, 37% with chemotherapy alone and 37% received both chemotherapy and involved-field radiation. Patients who received chemotherapy alone were more likely to have extranodal disease (p<0.01), but all other patient characteristics were similar across the three treatment groups. At a median follow-up of 8.4 years (range, 2.3 – 18.3 years), 45 patients are alive and disease-free, 39 patients have died while 16 patients are alive after progression. Of the 39 deaths that occurred, 13 were due to lymphoma progression, 4 were related to therapy, 11 patients died of unrelated causes (mainly coronary artery disease and its complications), while the cause of death was unknown in 11 patients. The median event-free survival (EFS) for this group of patients is 8.09 years and the median overall survival (OS) is 11.7 years. By multivariate analyses, only treatment with combination chemotherapy and radiation (HR: 0.3, 95% CI: 0.1 – 0.5, p<0.001) as opposed to either modality alone, and surprisingly, presence of B-symptoms at presentation (HR: 0.2, 95% CI: 0.04 – 0.8, p=0.02) predicted for a better EFS. Older age (≥60 years) predicted for an adverse OS (HR: 2.9, 95% CI: 1.3 – 6.3, p<0.01), while combination chemotherapy and radiation predicted for a better OS (HR: 0.4, 95% CI: 0.1– 0.9, p=0.02). However, there was no difference in the relapse rates between the older and younger patients (p=0.42), thereby suggesting that that poor OS in older patients was due to factors other than the disease itself. Patients who received both chemotherapy and radiation had a median EFS of 13.2 years and median OS was not yet reached in these patients. In contrast patients who received chemotherapy or radiation alone had an EFS of 5.54 years and 3.32 years respectively and an OS of 9.95 years and 10.7 years respectively. Thus, after accounting for known confounding factors, combined modality treatment with chemotherapy and radiation was associated with better EFS and OS than either modality alone in patients with Stage I follicular lymphoma.