Introduction: Recently, we described a 23-gene gene expression-based biomarker that was prognostic for overall survival (OS) in patients (pts) with locally extensive and advanced stage classical Hodgkin lymphoma treated with ABVD chemotherapy (Scott et al. J Clin Oncol2013). The observation that the results of PET scan after 2 cycles (PET2) of ABVD is highly prognostic of progression free survival (PFS) has led to the design of response-adapted trials, where pts with a positive PET2 receive more intensive regimens aiming to improve outcomes. The purpose of this study was to test whether the 23-gene assay could predict PET2 results, allowing rational selective escalation of treatment from the time of diagnosis. The US Intergroup S0816 trial was a response-adapted trial in advanced stage (III and IV) classical Hodgkin lymphoma, with escalation to escBEACOPP where the PET2 was Deauville 4 or 5 (Press et al. J Clin Oncol 2016). Methods: The 23-gene assay was applied to RNA extracted from the formalin-fixed paraffin-embedded (FFPE) diagnostic biopsies of 276 pts from the S0816 trial. Patients were categorized into low- and high-risk groups using previously described assay thresholds. The primary endpoint was the comparison of the proportion of PET2 positive pts in the two risk groups. The secondary endpoint explored whether the risk groups were predictive of PFS in the context of response-adapted treatment. Results: Adequate gene expression was obtained in 217/276 (79%) biopsies – 119/164 (73%) from archival slides and 98/112 (88%) FFPE blocks. The patient characteristics of the 217 pts were not significantly different from the remainder of the total trial population of 336 pts. 142 (65%) pts were assigned to the low- and 75 (35%) to the high-risk gene expression group. 38 (18%) pts had a positive PET2. The assay did not identify pts at greater risk of PET2 positivity with 21% and 11% of pts having a positive PET2 in the low- and high-risk group, respectively. To test whether this was the result of a suboptimal threshold, we examined the area under the curve (AUC) of the receiver operator characteristic curve. The AUC of 0.41 (95% CI 0.31 – 0.51) demonstrates that the assay is not predictive of PET2 positivity. Furthermore, the assay was not predictive of PFS, with a 2-year PFS of 80% and 84% in the low- and high-risk groups, respectively (log rank P = 0.65). There were not sufficient events to test the prognostic power of the assay for OS. Conclusions: The 23-gene assay, trained on the endpoint of OS, was not predictive of PET2 results. Furthermore, it was not predictive of PFS in this trial of response-adapted treatment. These results provide strong evidence that this assay should not be used for risk stratification where response-adapted therapy is utilized. Support: National Cancer Institute (NCI), National Clinical Trials Network (NCTN) grants CA180888, CA180819, CA180821, and CA180820; Lymphoma Research Foundation. Keywords: classical Hodgkin lymphoma (cHL); gene expression profile (GEP); positron emission tomography (PET).

Hospital readmissions increase healthcare cost and are a target of ways to improve cost and quality of medical care. Patients (pts) who undergo allogeneic hematopoietic progenitor cell transplant require a high level of care and are often readmitted. Thirty-day hospital readmissions following allogeneic HPCT, however, are associated with poor survival. In this retrospective review, we evaluated our 30-day readmissions for allogeneic HPCT occurring in 2010 at our institution. The analysis included pts who were not only transplanted in 2010 but also those who had been previously transplanted (ranging from 1994-2010), and later hospitalized again in 2010 and subsequently readmitted within 30 days. There were 83 total readmissions for allogeneic transplant pts within 30 days of a prior hospitalization in 2010. Only 47 pts, however, accounted for these readmissions and 19 (23%) pts were admitted multiple times (range 2-5 times), accounting for 55 (66%) of the readmissions. Initial diagnoses for pts admitted more than once included: 7 refractory NHL, 4 AML, 3 ALL, 2 MDS, 2 AA and 1 CML. Donor type included 4 UCB, 5 MUD and 10 MSD. Fifty-two percent (n = 10) had a CIBMTR transplant co-morbidity index score of >2. Fifty-three (64%) of the 30d readmissions after allogeneic HPCT were due to infection or unexplained fever, followed by 9 (11%) for symptoms related to GVHD, 7 (8%) due to cardiac complications (CHF, arrhythmias), and 14 (17%) others related to symptom management (pain, nausea/vomiting, diarrhea not related to infection or GVHD). Looking specifically at reasons for subsequent repeated readmissions demonstrated a similar distribution with the majority of re-hospitalizations being for infection or unexplained fever, followed by symptom management, cardiac complications, and GVHD. There were 13 deaths, all related to infection or complications from GVHD. Median time to death after readmission was 27 days (range, 0 to 96). Readmissions for allogeneic HPCT are associated with worse survival. In this retrospective review we have found that the majority of readmissions were from pts admitted multiple times. About half of these pts were identified as having higher co-morbidity index scores. Further prospective studies of readmission trends in allogeneic transplant and identification of high risk pts who may be susceptible to multiple readmissions may help decrease readmission rates, transplant outcomes, and improve overall quality of care.

Background: The purpose was to examine the prognostic impact of features of tumor cells and immune microenvironment in patients with follicular lymphoma treated with and without anti-CD20 monoclonal antibody therapy.Patients and methods: Tissue microarrays were constructed from archived tissue obtained from patients on three sequential Southwest Oncology Group (SWOG) trials for FL. All three trials included anthracycline-based chemotherapy. Anti-CD20 monoclonal antibodies were included for patients in the latter two trials. Immunohistochemistry was used to study the number and distribution of cells staining for forkhead box protein P3 (FOXP3) and lymphoma-associated macrophages (LAMs) and the number of lymphoma cells staining for myeloma-associated antigen-1 (MUM-1). Cox proportional hazards regression was used to evaluate the association between marker expression and overall survival (OS).Results: The number or pattern of infiltrating FOXP3 cells and LAMs did not correlate with OS in sequential SWOG studies for FL. The presence of MUM-1 correlated with lower OS for patients who received monoclonal antibody but not for those treated with chemotherapy alone.Conclusions: Immune cell composition of lymph nodes did not correlate with OS in this analysis of trials in FL. The mechanism of the observed correlation between MUM-1 expression and adverse prognosis in patients receiving monoclonal antibody therapy requires confirmation.

The standard approach for relapsed diffuse large B-cell lymphoma (DLBCL) involves auto-SCT. However, studies that established this approach were conducted before the inclusion of rituximab (R) with first-line therapy became routine. Whether DLBCL patients (pts) relapsing after first-line chemoimmunotherapy including R derive a comparable benefit from auto-SCT to pts in the pre-R era is unknown. We analyzed outcomes after auto-SCT for relapsed DLBCL among pts receiving initial R and those who did not. We reviewed 257 consecutive pts with relapsed DLBCL treated at our institution with auto-SCT. In all, 226 pts were included in the analysis, of whom 161 had received no R and 65 received R as part of first-line therapy (Planned R). Median OS and relapse-free survival, measured from transplant, were similar between No R vs Planned R groups: 67 vs 44 months (P=0.3) and 25 vs 27 months (P=0.8), respectively. A further analysis was carried out between two cohorts matched by propensity analysis. Again, no differences in outcomes were observed. This suggests that auto-SCT may be equally effective in pts relapsing after first-line therapy including R, and should remain the standard of care for relapsed DLBCL.

J.I. Martin-Subero, M. Kreuz, M. Bibikova , S. Bentink , W. Klapper, E. Wickham-Garcia, M. Rosolowski , J. Richter, L. Lopez-Serra, O. Ammerpohl, E. Ballestar, H. Berger , J.B. Fan , M. Loeffler, L. Trümper, H. Stein , R. Spang, M. Esteller, D. Barker, D. Hasenclever, R. Siebert Institute of Human Genetics, Christian-Albrechts University, Kiel, Germany, Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany, Illumina Inc, San Diego, United States, Institute of Functional Genomics, University of Regensburg, Regensburg, Germany, Institute of Pathology, Christian-Albrechts University, Kiel, Germany, Cancer Epigenetics Laboratory, Spanish National Cancer Centre, Madrid, Spain, Department of Hematology and Oncology, Georg-August University of Göttingen, Göttingen, Germany, Institute of Pathology, Charité– Universitätsmedizin Berlin, Berlin, Germany

Granulocyte colony-stimulating factor (G-CSF) is widely used following myeloablative chemotherapy (high-dose therapy; HDT) and peripheral blood progenitor cell rescue (PBPCR) to reduce neutrophil engraftment time. The dose and duration required to gain maximum clinical and economic benefit has not been fully investigated. This double blind placebo-controlled randomised trial was performed to determine whether short course low-dose or standard-dose Lenograstim (L) would influence recovery of haematopoiesis following HDT and PBPCR. Sixty-one patients were randomised between May 1999 and November 2004, to receive standard-dose lenograstim (263 microg/d), low-dose lenograstim (105 microg/d) or placebo injections. These commenced on day +5 following PBPCR and continued until neutrophil engraftment [absolute neutrophil count (ANC)] > or = 0.5 x 10(9)/l. Patients received standard supportive care until haemopoietic recovery. Both standard- and low-dose lenograstim resulted in a significantly shorter median time to neutrophil recovery (ANC > or = 0.1 x 10(9)/l:10.0 vs. 11.0 d, P = 0.025; ANC > or = 0.5 x 10(9)/l:11.0 vs. 14.0 d, P = 0.0002) compared with placebo. There was no significant difference in blood product support, antibiotic usage, documented infection, overall survival or relapse-free survival between the groups. Short course low-dose lenograstim is as effective as standard-dose in reducing neutrophil engraftment time following HDT and PBPCR.

8061 Background: Recent studies have suggested that OS for patients (pts) with FL is improving compared with older reports in which median OS was typically 8 to 10 years. We analyzed outcomes for pts with FL undergoing ASCT at any time in the course of the disease to determine whether this contributes to improved OS. Unlike previously reported transplant series, we calculated OS from the date of diagnosis to determine the potential effect of ASCT on the overall course of the disease. Methods: Between 1/79 and 10/05, 188 pts with FL underwent ASCT at our center. Male/female = 103/85. Median age = 47yrs (20–73). Other pt characteristics are summarized in the table . The International Prognostic Index (IPI) was used since data for the FLIPI were only available for a minority of pts. All pts received chemotherapy-only conditioning regimens, most commonly with busulfan, cyclophosphamide and etoposide (82%). OS was calculated from the date of diagnosis, and survival comparisons were made using the logrank test. Results: 120 pts (64%) are alive at a median follow-up of 8.2 years (0.8–23.7 years). Median follow-up from date of transplant is 5.2 years (0.1–15.3 years). The median OS from the date of diagnosis is 15.2 years. IPI at diagnosis was predictive of OS (low-risk median not reached, low-intermediate = 18.3 yrs, high-intermediate = 4.9yrs) (p = <0.001). Status at transplant (CR/PR1 vs CR/PR2 vs CR/PR3 vs relapsed/refractory) had no effect on OS (p = 0.36). Conclusions: The use of ASCT as part of the overall treatment strategy for pts with FL is associated with prolonged OS and may in part be responsible for the reported improvement in survival for FL reported in recent years. Further prospective evaluation of the role of ASCT in the context of treatment regimens which include monoclonal antibodies is required. No significant financial relationships to disclose. [Table: see text]

The cellular composition of an autologous graft may influence autologous stem cell transplantation (ASCT) outcome. Etoposide (VP) plus filgrastim (G) frequently mobilizes high numbers of CD34+ cells for autologous transplantation. We investigated whether patients collecting high numbers of CD34+ cells (‘super mobilizers’) have a better outcome than other patients. We reviewed 350 consecutive adult patients with NHL or Hodgkin's lymphoma receiving an ASCT from January 1994 to December 2005, mobilized with VP+G. Super mobilizers were defined as collecting a minimum of 8 × 106 CD34+ cells/kg. Two hundred and three patients were super mobilizers, while 147 collected between 2.0 and 7.95 CD34+ cells/kg. Super mobilizers were younger and more likely to have received two or fewer prior chemotherapy regimens (80 versus 63%, P<0.001). Median CD34+ cell dose for the super mobilizing group was 13.7 × 106 versus 4.4 × 106/kg in the standard collecting group. The super mobilizer group had a superior overall survival (P=0.006). In multivariable analysis, favorable disease status and younger age at transplant, and super mobilization were associated with improved survival. We conclude that patients had an improved ASCT outcome if large numbers of CD34+ cells were mobilized and infused. The explanation for this observation is unknown.

The role of high-dose therapy and autologous stem cell transplantation (ASCT) for patients with peripheral T-cell lymphoma (PTCL) is poorly defined. Comparisons of outcomes between PTCL and B-cell non-Hodgkin's lymphoma (NHL) have yielded conflicting results, in part due to the rarity and heterogeneity of PTCL. Some retrospective studies have found comparable survival rates for patients with T- and B-cell NHL. In this study, we report our single-center experience of ASCT over one decade using a uniform chemotherapy-only high-dose regimen. Thirty-two patients with PTCL-unspecified (PTCL-u; 11 patients) and anaplastic large-cell lymphoma (21 patients) underwent autologous stem cell transplant, mostly for relapsed or refractory disease. The preparative regimen consisted of busulfan, etoposide and cyclophosphamide. Kaplan–Meier 5-year overall survival (OS) and relapse-free survival (RFS) are 34 and 18%, respectively. These results suggest a poor outcome for patients with PTCL after ASCT, and new therapies for T-cell lymphoma are needed.

Autologous stem-cell transplantation (ASCT) has been used in follicular lymphoma (FL) to achieve durable responses in first remission or in the relapsed or refractory settings. Addition of rituximab to chemotherapy for FL has been shown to improve survival. The impact of prior therapy with rituximab upon the effectiveness of high-dose therapy (HDT) and ASCT in patients with FL is unknown. We retrospectively reviewed consecutive patients with FL who underwent HDT and ASCT. Patients were categorized according to prior therapy with rituximab. Outcomes were compared between groups in all patients and in a well-matched subset. In all 35 patients received prior rituximab and 71 rituximab-naive patients were analyzed. The rituximab-naive group had a median overall survival (OS) that was not reached during follow-up, with a median relapse-free (RFS) survival of 49.9 months. The prior rituximab group also did not reach median OS and had a median RFS of 24.6 months. Survivals were not significantly different in this group or in the well-matched subset. In conclusion, these results suggest that the use of rituximab-based regimens for the treatment of FL does not compromise the effectiveness of HDT and ASCT as a salvage strategy in patients with FL.

7624 Background: This trial was performed to determine whether low-dose or standard dose L would influence recovery of haematopoiesis following HDT and PBPCR. Methods: 61 patients (pts) with non-Hodgkin lymphoma (40) or Hodgkin’s disease (21) undergoing HDT were randomised. Pts had normal peripheral blood counts prior to HDT (Hb ≥100g/L, total white cell count ≥ 3.0, neutrophils (N) ≥ 1.0 and platelets ≥ 50, and had a minimum 2.5 million CD34+ cells/kg PBPC previously collected following mobilisation with Cyclophosphamide 3g/m2 and G-CSF. All received HDT with BCNU 300mg/m2 d-7, Etoposide 200mg/m2 od d-5-d-2, Cytosine arabinoside 200mg/m2 bd d-5-d-2 and Melphalan 140mg/m2 d-1 before return of PBPC on D0. Pts were allocated standard dose L 263mcg daily (20 pts), low dose L 105mcg daily (21 pts) or placebo injections (20 pts). These commenced on day +5 following PBPCR and continued until N≥0.5. Pts received standard supportive care including prophylactic Fluconazole and Acyclovir, but not routine antibacterial prophylaxis, until haemopoietic recovery. Results: L at any dose resulted in a significantly shorter median time to N recovery ≥0.1 (10.0 vs 11.0 days, P=0.02) and ≥0.5 (11.0 vs 14.0 days, p=0.0003) compared to placebo. The only significant difference between standard- and low-dose L was in hospital stay (21.0 vs 22.0 days, p=0.04), however L at any dose showed a significant reduction over placebo (22.0 vs 23.0 days, p=0.01). Conclusions: Short course low dose L is as effective as standard dose in reducing neutrophil engraftment time following HDT and PBSCR. L at any dose reduces hospital stay when compared to placebo. This approach should be considered for those patients in whom growth factor support is indicated. Long-term follow-up data will be presented. [Table: see text] No significant financial relationships to disclose.

We report outcomes in advanced lymphoma patients (n = 32) who enrolled in a trial of prospectively planned combined autologous/reduced-intensity transplantation (RIT) (n = 25) or who received RIT shortly after prior autografting because of high relapse risk or progressive disease (n = 7). Nine patients on the autologous/RIT transplant protocol did not proceed to planned RIT because of patient choice (n = 4), disease progression (n = 3), toxicity (n = 1), or no adequate donor (n = 1). Among the 23 other patients, RIT was started a median of 59 days (range 31-123) after autologous transplant. Fifteen patients had related donors, five patients had unrelated donors, and three patients had cord blood donors. Among all patients completing RIT, the median overall survival time was 385 days (95% CI 272-792), and the median relapse-free survival time was 157 days (95% CI 119-385). At the time of reporting, six patients (26%) remain alive and three patients (13%) remain alive without relapse. The 100-day transplant-related mortality (TRM) was 9% among all patients and was 0% among matched sibling donors. Overall TRM was 43%. Tandem transplant is feasible in advanced lymphoma with low early TRM. However, practical challenges associated with the strategy were significant and high levels of late TRM due to graft-versus-host disease and infections suggest that modifications of the procedure will be needed to improve outcomes and patient retention.

Background The ABVD regimen (doxorubicin, bleomycin, vinblastine, dacarbazine) is widely accepted as standard treatment for patients with advanced HL. There are potential long term cardiac and pulmonary toxicites, particularly in combination with mediastinal radiotherapy. The SV regimen comprises brief duration combination chemotherapy, with relatively low cumulative doses of alkylating agents, doxorubicin and bleomycin, followed by consolidation radiotherapy to sites of bulk disease. High response and disease free survival rates are reported in single institution and multi-centre phase II studies. This randomized phase II trial comparing SV with ABVD was designed to determine 1) the feasibility of the SV regimen; 2) response rate compared with ABVD; and 3) acute toxicity of SV.

Purpose: To compare results of syngeneic, allogeneic, and autologous hematopoietic stem-cell transplantation for non-Hodgkin’s lymphoma (NHL). Patients and Methods: The databases of the International Bone Marrow Transplant Registry (IBMTR) and the European Group for Blood and Marrow Transplantation were used to identify 89 NHL patients who received syngeneic transplants. These patients were compared with NHL patients identified from the IBMTR and the Autologous Blood and Marrow Transplant Registry who received allogeneic (T-cell depleted and T-cell replete) and autologous (purged and unpurged) transplants. Results: No significant differences in relapse rates were observed when results of allogeneic transplantation were compared with syngeneic transplantation for any histology. T-cell depletion of allografts was not associated with a higher relapse risk, but was associated with improved overall survival for patients with low-grade and intermediate-grade histology. Patients who received unpurged autografts for low-grade NHL had a five-fold (P = .008) greater risk of relapse than recipients of syngeneic transplants, and recipients of unpurged autografts had a two-fold (P = .0009) greater relapse risk than patients who received purged autografts. Among low-grade NHL patients, the use of purging was associated with significantly better disease-free survival (P = .003) and overall survival (P = .04) when compared with patients who received unpurged autografts. Conclusion: These analyses failed to find evidence of a graft-versus-lymphoma effect, but do provide indirect evidence to support the hypothesis that tumor contamination may contribute to lymphoma relapse, and that purging may be beneficial for patients undergoing autologous hematopoietic stem-cell transplantation for low-grade NHL.

Advances in the treatment of Hodgkin's disease (HD) have resulted in cure rates of greater than 80%. This remarkable achievement has occurred in the past 50 years secondary to improvements in combination chemotherapy and radiotherapy. Over the last several decades, with the increase in long-term survivors of HD, it has become evident that cure is not the only issue, and late side-effects of treatment, including secondary malignancies and impaired fertility, are of major concern as well. As a result, attempts to improve response and survival rates by intensifying therapy must be countered against the potential for long-term toxicity.

PURPOSE: To determine whether a combination of high-dose therapy and autologous stem-cell transplantation (ASCT) is superior to conventional-dose consolidation and maintenance chemotherapy as postremission therapy in adults with lymphoblastic lymphoma. PATIENTS AND METHODS: One hundred nineteen patients were entered onto this prospective randomized trial from 37 centers. Patients received standard remission induction therapy, and responding patients were randomized either to continue with a conventional consolidation/maintenance protocol (CC) or to receive high-dose therapy and ASCT. In some centers, patients with HLA-identical sibling donors were registered on the trial but proceeded to allogeneic bone marrow transplantation (BMT) without randomization. RESULTS: Of the 119 patients entered, 111 were assessable for response to induction therapy. The overall response rate was 82% (56% complete response, 26% partial response). Of the 98 patients eligible for randomization, 65 were randomized, 31 to ASCT and 34 to CC. Reasons for failure to randomize included patient refusal (12 patients), early progression or death on induction therapy (eight patients), excessive toxicity of induction regimen (six patients), and elective allogeneic BMT (12 patients). With a median follow-up of 37 months, the actuarial 3-year relapse-free survival rate is 24% for the CC arm and 55% for the ASCT arm (hazards ratio = 0.55 in favor of the ASCT arm; 95% confidence interval [CI], 0.29 to 1.04; P = .065). The corresponding figures for overall survival are 45% and 56%, respectively (hazards ratio = 0.87 in favor of the ASCT arm; 95% CI, 0.42 to 1.81; P = .71). CONCLUSION: The use of ASCT in adults with lymphoblastic lymphoma in first remission produced a trend for improved relapse-free survival but did not improve overall survival compared with conventional-dose therapy in this small randomized trial.

The outlook for patients with mantle cell lymphoma is poor. The reported median survival in most published series is only 3 to 4 years, and even the most favorable prognostic groups have median survival rates of only 5 years, with no evidence of cure. The use of autologous and allogeneic stem cell transplantation in this disease has increased dramatically in recent years. Despite encouraging reports from single centers and registries, the impact of stem cell transplantation on the outcome for mantle cell lymphoma is unclear. Optimal first-line regimens for mantle cell lymphoma have yet to be defined, and it is therefore difficult to place the role of first remission transplantation in an appropriate context. Prospective randomized trials have been difficult to design and conduct in the absence of a well-defined ‘standard’ treatment. The role of stem cell transplantation as a salvage strategy is also unknown, although available data suggest that it does not improve survival in heavily pre-treated patients. In the absence of clear evidence for a survival advantage for patients receiving stem cell transplants for mantle cell lymphoma, entry into clinical trials should be a priority. Bone Marrow Transplantation (2001) 28, 813–820.