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Background: The ECOG-ACRIN Cancer Research Group evaluated rituximab treatment schedules for patients with newly-diagnosed low-tumor-burden follicular-lymphoma (FL). All patients received 4-weekly rituximab treatments as induction therapy. Clinically-responding patients were randomized to receive rituximab every 13 weeks ("maintenance") vs. no additional rituximab until progression ("non-maintenance"). Based on "time-to-rituximab-failure (TTRF)", the study-committee reported there was no overall-benefit for maintenance rituximab in this setting. Tumor-reactive mAbs, like rituximab, trigger natural killer (NK) cells. NK-cell responses are regulated, in part, by interactions between killer immunoglobulin-like receptors (KIRs) on NK cells and their interactions with KIR-ligands. In a separate study of children with neuroblastoma treated with a different mAb, we found certain KIR/KIR-ligand genotypes associated with improved outcome. Here, we assessed whether a subset of FL patients show improved outcome from the maintenance rituximab based on these same KIR/KIR-ligand genotypes., Methods: Genotypes for KIR/KIR-ligand were determined and assessed for associations with outcome [duration of response, TTRF and % tumor shrinkage] as a post-hoc analysis of this phase III trial. Our primary objective was to assess specific KIR/KIR-ligand genotype associations, followed by separate prespecified KIR/KIR-ligand genotype associations in follow-up analyses. Statistical analyses for association of genotype with clinical outcome included: Log-rank tests and Cox proportional hazards regression models to assess duration of response and TTRF; analysis of variance (ANOVA) was used for assessment of % tumor shrinkage., Results: We found that patients inheriting KIR2DL2 and its ligand (HLA-C1) along with KIR3DL1 and its ligand (HLA-Bw4) had improved outcome over patients without this genotype. In addition, patients with KIR2DL2 and HLA-C1 along with KIR3DL1 and HLA-Bw4 also showed improved duration of response and tumor shrinkage if they received maintenance, while patients without this genotype showed no such improvement when receiving maintenance., Conclusions: The data presented here indicate that a subset of FL patients, identified by certain KIRs/KIR-ligands, have improved outcome and may benefit from additional rituximab treatment. Taken together, this suggests that the efficacy of tumor-reactive mAb treatment for some patients is influenced by KIRs on NK cells. However, prior to considering these genotypes in a clinically-actionable manner, these findings need independent validation in other studies.

Purpose: Preclinical studies suggest that SNPs in the Fc gamma receptor (FCGR) genes influence response to rituximab, but the clinical relevance of this is uncertain., Experimental Design: We prospectively obtained specimens for genotyping in the rituximab extended schedule or re-treatment trial (RESORT) study, in which 408 previously untreated, low tumor burden follicular lymphoma (FL) patients were treated with single agent rituximab. Patients received rituximab in 4 weekly doses and responders were randomized to rituximab re-treatment (RR) upon progression versus maintenance rituximab (MR). SNP genotyping was performed in 321 consenting patients., Results: Response rates to initial therapy and response duration were correlated with the FCGR3A SNP at position 158 (rs396991) and the FCGR2A SNP at position 131 (rs1801274). The response rate to initial rituximab was 71%. No FCGR genotypes or grouping of genotypes were predictive of initial response. A total of 289 patients were randomized to RR (n = 143) or to MR (n = 146). With a median follow-up of 5.5 years, the 3-year response duration in the RR arm and the MR arm was 50% and 78%, respectively. Genotyping was available in 235 of 289 randomized patients. In patients receiving RR (n = 115) or MR (n = 120), response duration was not associated with any FCGR genotypes or genotype combinations., Conclusions: Based on this analysis of treatment-naïve, low tumor burden FL, we conclude that the FCGR3A and FCGR2A SNPs do not confer differential responsiveness to rituximab., (©2015 American Association for Cancer Research.)

Rituximab, bortezomib, modified hyper-cyclophosphamide, doxorubicin, vincristine, dexamethasone (VcR-CVAD) induction chemoimmunotherapy and maintenance rituximab (MR) were evaluated for efficacy and safety in Eastern Cooperative Oncology Group protocol E1405. Patients with previously untreated mantle cell lymphoma received VcR-CVAD chemotherapy every 21 days for 6 cycles, followed by MR for 2 years. Transplant-eligible patients had the option of autologous stem cell transplantation (ASCT) consolidation instead of MR. The primary end point was the complete response (CR) rate to VcR-CVAD. The secondary end points were overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and toxicities. Seventy-five eligible patients with a median age of 62 (range 40-76) were enrolled. The ORR was 95% and a CR was achieved in 68% of patients. After a median follow-up of 4.5 years, 3-year PFS and OS were 72% and 88%, respectively. No substantial difference in PFS or OS was observed between patients treated with MR (n = 44) vs ASCT (n = 22). There were no unexpected toxicities. VcR-CVAD produced high ORR and CR rates in mantle cell lymphoma. MR after VcR-CVAD induction performed similarly to ASCT and may improve response duration. Randomized clinical trials comparing MR against ASCT should be considered and randomized clinical trials evaluating bortezomib's contribution to conventional therapy are under way. This study was registered at www.clinicaltrials.gov as #NCT00433537.

Background: The role of body mass index (BMI) in survival outcomes is controversial among lymphoma patients. We evaluated the association between BMI at study entry and failure-free survival (FFS) and overall survival (OS) in three phase III clinical trials, among patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Hodgkin's lymphoma (HL)., Patients and Methods: A total of 537, 730 and 282 patients with DLBCL, HL and FL were included in the analysis. Baseline patient and clinical characteristics, treatment received and clinical outcomes were compared across BMI categories., Results: Among patients with DLBCL, HL and FL, the median age was 70, 33 and 56; 29%, 29% and 37% were obese and 38%, 27% and 37% were overweight, respectively. Age was significantly different among BMI groups in all three studies. Higher BMI groups tended to have more favorable prognosis factors at study entry among DLBCL and HL patients. BMI was not associated with clinical outcome with P-values of 0.89, 0.30 and 0.40 for FFS, and 0.64, 0.67 and 0.09 for OS, for patients with DLBCL, HL and FL, respectively. The association remains non-significant after adjusting for other clinical factors in the Cox model. A subset analysis of males with DLBCL treated on R-CHOP revealed no differences in FFS (P = 0.48) or OS (P = 0.58)., Conclusion: BMI was not significantly associated with clinical outcomes among patients with DLBCL, HD or FL, in three prospective phase III clinical trials. The findings contradict some previous reports of similar investigations. Further work is required to understand the observed discrepancies.

Background: Treatment options for patients with nonbulky stage IA-IIA Hodgkin lymphoma include combined modality therapy (CMT) using doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) plus involved-field radiation therapy (IFRT), and chemotherapy with ABVD alone. There are no mature randomized data comparing ABVD with CMT using modern radiation techniques., Patients and Methods: Using German Hodgkin Study Group HD10/HD11 and NCIC Clinical Trials Group HD.6 databases, we identified 588 patients who met mutually inclusive eligibility criteria from the preferred arms of HD10 or 11 (n = 406) and HD.6 (n = 182). We evaluated time to progression (TTP), progression-free (PFS) and overall survival, including in three predefined exploratory subset analyses., Results: With median follow-up of 91 (HD10/11) and 134 (HD.6) months, respective 8-year outcomes were for TTP, 93% versus 87% [hazard ratio (HR) 0.44, 95% confidence interval (CI) 0.24-0.78]; for PFS, 89% versus 86% (HR 0.71, 95% CI 0.42-1.18) and for overall survival, 95% versus 95% (HR 1.09, 95% CI 0.49-2.40). In the exploratory subset analysis including HD10 eligible patients who achieved complete response (CR) or unconfirmed complete response (CRu) after two cycles of ABVD, 8-year PFS was 87% (HD10) versus 95% (HD.6) (HR 2.8; 95% CI 0.64-12.5) and overall survival 96% versus 100%. In contrast, among those without CR/CRu after two cycles of ABVD, 8-year PFS was 88% versus 74% (HR 0.35; 95% CI 0.16-0.79) and overall survival 95% versus 91%, respectively (HR 0.42; 95% CI 0.12-1.44)., Conclusions: In patients with nonbulky stage IA-IIA Hodgkin lymphoma, CMT provides better disease control than ABVD alone, especially among those not achieving complete response after two cycles of ABVD. Within the follow-up duration evaluated, overall survivals were similar. Longer follow-up is required to understand the implications of radiation and chemotherapy-related late effects., Clinical Trials: The trials included in this analysis were registered at ClinicalTrials.gov: HD10 - NCT00265018, HD11 - NCT00264953, HD.6 - NCT00002561.

In July 2012, Congress passed the Food and Drug Administration Safety and Innovation Act (FDASIA). The Advancing Breakthrough Therapies for Patients Act was incorporated into a Title of FDASIA to expedite clinical development of new, potential "breakthrough" drugs or treatments that show dramatic responses in early-phase studies. Using this regulatory pathway, once a promising new drug candidate is designated as a "Breakthrough Therapy", the U.S. Food and Drug Administration (FDA) and sponsor would collaborate to determine the best path forward to abbreviate the traditional three-phase approach to drug development. The breakthrough legislation requires that an FDA guidance be drafted that details specific requirements of the bill to aid FDA in implementing requirements of the Act. In this article, we have proposed criteria to define a product as a Breakthrough Therapy, and discussed critical components of the development process that would require flexibility in order to enable expedited development of a Breakthrough Therapy., (©2013 AACR.)

Recent studies report an improvement in overall survival (OS) of patients with follicular lymphoma (FL). Previously untreated patients with grade 1 to 2 FL treated at Stanford University from 1960-2003 were identified. Four eras were considered: era 1, pre-anthracycline (1960-1975, n = 180); era 2, anthracycline (1976-1986, n = 426); era 3, aggressive chemotherapy/purine analogs (1987-1996, n = 471); and era 4, rituximab (1997-2003, n = 257). Clinical characteristics, patterns of care, and survival were assessed. Observed OS was compared with the expected OS calculated from Berkeley Mortality Database life tables derived from population matched by gender and age at the time of diagnosis. The median OS was 13.6 years. Age, gender, and stage did not differ across the eras. Although primary treatment varied, event-free survival after the first treatment did not differ between eras (P = .17). Median OS improved from 11 years in eras 1 and 2 to 18.4 years in era 3 and has not yet been reached for era 4 (P < .001), with no suggestion of a plateau in any era. These improvements in OS exceeded improvements in survival in the general population during the same period. Several factors, including better supportive care and effective therapies for relapsed disease, are likely responsible for this improvement.

Epstein-Barr virus (EBV) is associated with Hodgkin lymphoma (HL) and can be detected by in situ hybridization (ISH) of viral nucleic acid (EBER) in tumor cells. We sought to determine whether plasma EBV-DNA could serve as a surrogate for EBER-ISH and to explore its prognostic utility in HL. Specimens from the Cancer Cooperative Intergroup Trial E2496 were used to compare pretreatment plasma EBV-DNA quantification with EBV tumor status by EBER-ISH. A cutoff of >60 viral copies/100 µL plasma yielded 96% concordance with EBER-ISH. Pretreatment and month 6 plasma specimens were designated EBV(-) or EBV(+) by this cutoff. Patients with pretreatment EBV(+) plasma (n = 54) had inferior failure-free survival (FFS) compared with those with pretreatment EBV(-) plasma (n = 274), log-rank P = .009. By contrast, no difference in FFS was observed when patients were stratified by EBER-ISH. Pretreatment plasma EBV positivity was an independent predictor of treatment failure on multivariate analyses. At month 6, plasma EBV(+) patients (n = 7) had inferior FFS compared with plasma EBV(-) patients (n = 125), log-rank P = .007. These results confirm that plasma EBV-DNA is highly concordant with EBER-ISH in HL and suggest that it may have prognostic utility both at baseline and after therapy. This trial was registered at www.clinicaltrials.gov as #NCT00003389.

Introduction: To assess the efficacy of an abbreviated Stanford V regimen in patients with early-stage Hodgkin lymphoma (HL). PATIENTS AND METHODS PATIENTS: with untreated nonbulky stage I-IIA supradiaphragmatic HL were eligible for the G4 study. Stanford V chemotherapy was administered for 8 weeks followed by radiation therapy (RT) 30 Gy to involved fields (IF). Freedom from progression (FFP), disease-specific survival (DSS) and overall survival (OS) were estimated., Results: All 87 enrolled patients completed the abbreviated regimen. At a median follow-up of 10 years, FFP, DSS and OS are 94%, 99% and 94%, respectively. Therapy was well tolerated with no treatment-related deaths., Conclusions: Mature results of the abbreviated Stanford V regimen in nonbulky early-stage HL are excellent and comparable to the results from other contemporary therapies.

Increased tumor-associated macrophages (TAMs) are reported to be associated with poor prognosis in classic Hodgkin lymphoma (CHL). We investigated the prognostic significance of TAMs in the E2496 Intergroup trial, a multicenter phase 3 randomized controlled trial comparing ABVD and Stanford V chemotherapy in locally extensive and advanced stage CHL. Tissue microarrays were constructed from formalin-fixed, paraffin-embedded tumor tissue and included 287 patients. Patients were randomly assigned into training (n = 143) and validation (n = 144) cohorts. Immunohistochemistry for CD68 and CD163, and in situ hybridization for EBV-encoded RNA were performed. CD68 and CD163 IHC were analyzed by computer image analysis; optimum thresholds for overall survival (OS) were determined in the training cohort and tested in the independent validation cohort. Increased CD68 and CD163 expression was significantly associated with inferior failure-free survival and OS in the validation cohort. Increased CD68 and CD163 expression was associated with increased age, EBV-encoded RNA positivity, and mixed cellularity subtype of CHL. Multivariate analysis in the validation cohort showed increased CD68 or CD163 expression to be significant independent predictors of inferior failure-free survival and OS. We demonstrate the prognostic significance of TAMs in locally extensive and advanced-stage CHL in a multicenter phase 3 randomized controlled clinical trial.

Autologous hematopoietic cell transplantation with augmented BCNU regimens is effective treatment for recurrent or refractory Hodgkin lymphoma (HL); however, BCNU-related toxicity and disease recurrence remain challenges. We designed a conditioning regimen with gemcitabine in combination with vinorelbine in an effort to reduce the BCNU dose and toxicity without compromising efficacy. In this phase I/II dose escalation study, the gemcitabine maximum tolerated dose (MTD) was determined at 1250 mg/m(2), and a total of 92 patients were treated at this dose to establish safety and efficacy. The primary endpoint was the incidence of BCNU-related toxicity. Secondary endpoints included 2-year freedom from progression (FFP), event-free survival (EFS), and overall survival (OS). Sixty-eight patients (74%) had 1 or more previously defined adverse risk factors for transplant (stage IV at relapse, B symptoms at relapse, greater than minimal disease pretransplant). The incidence of BCNU-related toxicity was 15% (95% confidence interval, 9%-24%). Only 2% of patients had a documented reduction in diffusing capacity of 20% or greater. With a median follow-up of 29 months, the FFP at 2 years was 71% and the OS at 2 years was 83%. Two-year FFP was 96%, 72%, 67%, and 14% for patients with 0 (n = 24), 1 (n = 37), 2 (n = 23), or 3 (n = 8) risk factors, respectively. Regression analysis identified PET status pretransplant and B symptoms at relapse as significant prognostic factors for FFP. This new transplant regimen for HL resulted in decreased BCNU toxicity with encouraging FFP and OS. A prospective, risk-modeled comparison of this new combination with other conditioning regimens is warranted.

Purpose: To prospectively investigate the prognostic significance of p21 and p53 expression in diffuse large B-cell lymphoma in the context of the U.S. Intergroup trial comparing conventional cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy to rituximab-CHOP (R-CHOP) induction, with or without maintenance rituximab., Experimental Design: Immunohistochemical staining of 197 paraffin-embedded biopsy specimens was scored by an independent panel of experts., Results: The cyclin-dependent kinase inhibitor, p21, was expressed in 55% of cases examined. In a multivariable analysis adjusting for International Prognostic Index score and BCL2 status, p21 expression was a significant, independent, favorable predictive factor for failure-free survival (relative risk, 0.3; P = 0.001) and overall survival (relative risk, 0.3; P = 0.003) for patients treated with R-CHOP. Expression of p21 was not predictive of outcome for CHOP-treated patients. Only p21-positive cases benefited from the addition of rituximab to CHOP. Among p21-positive patients, treatment with R-CHOP was associated with a higher failure-free survival rate at 5 years compared with CHOP (61% versus 24%; P = 0.01). In contrast, no significant differences were detected in failure-free survival according to treatment arm for p21-negative patients. Expression of p53, alone or in combination with p21, did not predict for outcome in univariable or multivariable analyses., Conclusions: In this study, p21 protein expression emerged as an important independent predictor of a favorable clinical outcome when rituximab was added to CHOP therapy. These data suggest that rituximab-related effects on lymphoma survival pathways may be functionally linked to p21 activity.

Positive interim positron emission tomography (PET) scans are thought to be associated with inferior outcomes in diffuse large B-cell lymphoma. In the E3404 diffuse large B-cell lymphoma study, PET scans at baseline and after 3 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone were centrally reviewed by a single reader. To determine the reproducibility of interim PET interpretation, an expert panel of 3 external nuclear medicine physicians visually scored baseline and interim PET scans independently and were blinded to clinical information. The binary Eastern Cooperative Oncology Group (ECOG) study criteria were based on modifications of the Harmonization Criteria; the London criteria were also applied. Of 38 interim scans, agreement was complete in 68% and 71% by ECOG and London criteria, respectively. The range of PET(+) interim scans was 16% to 34% (P = not significant) by reviewer. Moderate consistency of reviews was observed: kappa statistic = 0.445 using ECOG criteria, and kappa statistic = 0.502 using London criteria. These data, showing only moderate reproducibility among nuclear medicine experts, indicate the need to standardize PET interpretation in research and practice. This trial was registered at www.clinicaltrials.gov as #NCT00274924 [corrected].

The peripheral T cell lymphomas (PTCL) carry a worse prognosis compared to B cell non-Hodgkin lymphoma. There is no uniform standard therapy for PTCL, and autologous hematopoietic cell transplant (AHCT) is often offered as consolidation in first remission or at relapse because of the poor outcomes with conventional therapy. We conducted a retrospective review of patients who underwent AHCT for PTCL from 1989 to 2006. Fifty-three cases were identified consisting of systemic anaplastic large cell (n = 18), PTCL unspecified (n = 17), angioimmunoblastic (n = 9), nasal type extranodal NK/T (n = 7), hepatosplenic (n = 2), and adult T cell leukemia/lymphoma (n = 1). Fifteen patients were transplanted in first complete or partial response (CR1/PR1), 32 in second or beyond CR or PR (CR2/PR2+), and 11 with primary refractory disease (REF). With a median follow-up was 5 years (range: 1.0-11.5), the 5-year progression-free survival (PFS) and overall survival (OS) were 25% and 48%, respectively. Disease status at AHCT had a significant impact on PFS and OS. The 5-year PFS for patients in CR1/PR1, CR2/PR2+, and REF was 51%, 12%, and 0%, respectively, and the corresponding figures for OS were 76%, 40%, and 30%, respectively. The pretransplant factors that impacted survival were disease status and the number of prior regimens. Histology, age, sex, stage, B symptoms, bone marrow involvement, and duration of first response did not significantly affect PFS or OS. Based on these results, AHCT as consolidation therapy in first complete or partial response may offer a durable survival benefit. However, AHCT with conventional salvage chemotherapy has minimal durable benefit in patients with relapsed or refractory PTCL, and thus novel strategies and/or allogeneic HCT should be more aggressively explored in lieu of AHCT for relapsed/ refractory PTCL.

Background: In the National Cancer Institute of Canada Clinical Trials Group/Eastern Cooperative Oncology Group HD.6 trial, progression-free survival was better in patients randomized to therapy that included radiation, compared to doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD) alone. We now evaluate patterns of progression and subsequent outcomes of patients with progression., Patients and Methods: After a median of 4.2 years, 33 patients have progressed. Two radiation oncologists determined whether sites of progression were confined within radiation fields. Freedom from second progression (FF2P) and freedom from second progression or death (FF2P/D) were compared., Results: Reviewers agreed for the extended (kappa = 0.87) and involved field (kappa = 1.0) analyses. Progression after ABVD alone was more frequently confined within both the extended (20/23 vs. 3/10; P = 0.002) and involved fields (16/23 vs. 2/10; P = 0.02). There was no difference in FF2P between groups [5-year estimate 99% (radiation) versus 96% (ABVD alone)] [hazard ratio (HR) = 3.14, 95% confidence interval (CI) 0.63-15.6; P = 0.14]; the 5-year estimates of FF2P/D were 94% in each group (HR = 1.04, 95% CI 0.41-2.63; P = 0.93)., Conclusion: Treatment that includes radiation reduces the risk of progressive Hodgkin lymphoma in sites that receive this therapy, but we are unable to detect differences in FF2P or FF2P/D.

The proceedings of a workshop focusing on a project to evaluate the use of fluorodeoxyglucose-positron emission tomography (FDG-PET) as a tool to measure treatment response in non-Hodgkin lymphoma (NHL) are described. Sponsored by the Leukemia & Lymphoma Society, the Foundation of the National Institutes of Health, and the National Cancer Institute, and attended by representatives of the Food and Drug Administration, the Centers for Medicare and Medicaid Services, and scientists and clinical researchers from academia and the pharmaceutical and medical imaging industries, the workshop reviewed the etiology and current standards of care for NHL and proposed the development of a clinical trial to validate FDG-PET imaging techniques as a predictive biomarker for cancer therapy response. As organized under the auspices of the Oncology Biomarker Qualification Initiative, the three federal health agencies and their private sector and nonprofit/advocacy group partners believe that FDG-PET not only demonstrates the potential to be used for the diagnosis and staging of many cancers but in particular can provide an early indication of therapeutic response that is well correlated with clinical outcomes for chemotherapy for this common form of lymphoma. The development of standardized criteria for FDG-PET imaging and establishment of procedures for transmission, storage, quality assurance, and analysis of PET images afforded by this demonstration project could streamline clinical trials of new treatments for more intractable forms of lymphoma and other cancers and, hence, accelerate new drug approvals.

Current therapy for Hodgkin disease is aimed at high cure rates and optimal survivorship. Although intensified chemotherapy with the escalated BEACOPP regimen resulted in higher rates of cure and survival compared with COPP/ABVD in the high-profile HD9 randomized controlled trial (RCT), this regimen has not been universally adopted by patients and physicians due to the attendant increased risks of early and late complications. Appropriately, questions emerge as to whether the results of this trial should be interpreted as establishing the superiority of BEACOPP over the current standard ABVD therapy, and whether clinical or biologic prognostic factors can better select patients for more intensive treatment. The widespread availability and high predictive accuracy of functional imaging with PET scans has led to promising, preliminary studies assessing early response to therapy with this diagnostic tool. In this review, the characteristics and outcomes of patients treated with ABVD in RCT will be made and compared with COPP/ABVD in HD9; clinical and biologic prognostic factors will be discussed, including PET imaging; and newer strategies targeted at minimizing treatment complications while maximizing cure rates will be discussed. Although enthusiasm for PET imaging is great, the challenges for using this diagnostic tool for risk-adapted therapies are substantial. Importantly, physicians and patients should be aware of these challenges, support the RCT that seek to address them, and carefully weigh risks and benefits for individual patients.

Allogeneic hematopoietic cell transplantation (HCT) has been shown to be curative in a group of patients with aggressive non-Hodgkin lymphoma (NHL). A previous study has demonstrated equivalent outcomes with a conditioning regimen based on total body irradiation and another not based on total body irradiation with preparative therapy using cyclophosphamide, carmustine, and etoposide (CBV) in autologous HCT. We investigated the safety and efficacy of using CBV in an allogeneic setting. Patients were required to have relapsed or be at high risk for subsequent relapse of NHL. All patients had a fully HLA-matched sibling donor. Patients received carmustine (15 mg/kg), etoposide (60 mg/kg), and cyclophosphamide (100 mg/kg) on days -6, -4, and -2, respectively, followed by allogeneic HCT. All patients were treated with cyclosporine and methylprednisolone as prophylaxis for graft-versus-host disease (GVHD). Thirty-one patients (median age, 46 years) who were felt to be inappropriate candidates for autologous transplantation were enrolled. Each subject had a median of 3 previous chemotherapy regimens. All patients engrafted. Fifteen of 31 patients are alive. Median follow-up time was 11.5 months (range, .4-126). There were 8 deaths due to relapse. Nonrelapse mortality (n = 8) included infection (n = 3), GVHD (n = 2), diffuse alveolar hemorrhage (n = 1), veno-occlusive disease in the setting of concurrent acute GVHD of the liver (n = 1), and leukoencephalopathy (n = 1). Probabilities of event-free survival and overall survival were, respectively, 44% (95% confidence interval, 26%-62%) and 51% (33%-69%) at 1 year and 44% (26%-62%) and 47% (29%-65%) at 5 years. Probability of relapse was 33% (15%-51%) at 1 year and 5 years. Probability of nonrelapse mortality was 31% (13%-49%) at 1 year and 5 years. Incidences were 29% for acute GVHD and 39% for chronic GVHD. None of the 12 patients who developed chronic GVHD has disease recurrence. Patients who had required >3 previous chemotherapy regimens before HCT had an increased probability of relapse. CBV is an effective preparative regimen for patients with aggressive NHL who undergo allogeneic HCT.

Bcl-6 protein expression, a marker of germinal center origin, has been associated with a favorable prognosis in diffuse large B-cell lymphoma (DLBCL). To determine the prognostic significance of this marker when rituximab (R) was added to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy, we prospectively studied Bcl-6 protein expression by immunohistochemical staining of 199 paraffin-embedded specimens from patients enrolled in the US Intergroup phase 3 trial comparing R-CHOP to CHOP with or without maintenance R. In Bcl-6(-) patients, failure-free survival (FFS) and overall survival (OS) were prolonged for those treated with R-CHOP alone compared to CHOP alone (2-year FFS 76% versus 9%, P < .001; 2-year OS 79% versus 17%, P < .001). In contrast, no differences in FFS and OS were detected between treatment arms for Bcl-6(+) cases. In the multivariate analysis, treatment arm (CHOP versus R-CHOP) was the major determinant of both FFS (P < .001) and OS (P < .001) for the Bcl-6(-) subset, whereas the International Prognostic Index risk group was the only significant predictor of outcome among Bcl-6(+) cases. Bcl-2 protein expression was not predictive of outcome in either group. In this study, we observed a reduction in treatment failures and death with the addition of R to CHOP in Bcl-6(-) DLBCL cases only. Our finding that Bcl-6(+) cases did not benefit from the addition of R to CHOP requires independent confirmation.

Based on the favorable safety profile and the independent activity of rituximab in B-cell lymphoma, we evaluated its efficacy and toxicity after high-dose therapy (HDT) and autologous hematopoietic cell transplantation (HCT). Thirty-five patients with diffuse large cell (25 patients), mantle cell (3 patients), transformed (3 patients), or other (4 patients) subtypes of B-cell lymphoma received HDT followed by a purged autologous graft. The rituximab schedule was 4 weekly infusions (375 mg/m(2)) starting at day 42 after HCT and, for patients 5 to 35, a second 4-week course 6 months after HCT. All planned therapy was completed in 29 patients. With 30 months' median follow-up, the 2-year event-free survival (EFS) rate was 83% and the overall survival (OS) rate was 88%. For 21 patients with relapsed or refractory large cell lymphoma, the EFS rate was 81% and the OS rate was 85%. Grades 3 to 4 neutropenia occurred in 19 (54%) patients. A prospective study of immune reconstitution included measurements of lymphocyte subsets, immunoglobulins, and response to vaccination. Serious infections were not observed despite delayed B-cell recovery in all patients and suppressed immunoglobulin G (IgG) levels and low pneumococcus antibody titers in a subset. Rituximab after HDT and HCT is feasible, and these phase 2 data support the current US Intergroup phase 3 trial in recurrent/refractory diffuse large cell lymphoma.

Lymphocyte-predominant Hodgkin disease (LPHD) is a unique clinical entity characterized by indolent nodal disease that tends to relapse after standard radiotherapy or chemotherapy. The malignant cells of LPHD are CD20+ and therefore rituximab may have activity with fewer late effects than standard therapy. In this phase 2 trial, 22 patients with CD20+ LPHD received 4 weekly doses of rituximab at 375 mg/m2. Ten patients had previously been treated for Hodgkin disease, while 12 patients had untreated disease. All 22 patients responded to rituximab (overall response rate, 100%) with complete response (CR) in 9 (41%), unconfirmed complete response in 1 (5%), and partial response in 12 (54%). Acute treatment-related adverse events were minimal. With a median follow-up of 13 months, 9 patients had relapsed, and estimated median freedom from progression was 10.2 months. Progressive disease was biopsied in 5 patients: 3 had recurrent LPHD, while 2 patients had transformation to large-cell non-Hodgkin lymphoma (LCL). All 3 patients with recurrent LPHD were retreated with rituximab, with a second CR seen in 1 patient and stable disease in 2. Rituximab induced prompt tumor reduction in each of 22 LPHD patients with minimal acute toxicity; however, based on the relatively short response duration seen in our trial and the concerns about transformation, rituximab should be considered investigational treatment for LPHD. Further clinical trials are warranted to determine the optimal dosing schedule of rituximab, the potential for combination treatment, and the possible relationship of rituximab treatment to the development of LCL.

Advanced stage follicular small cleaved and mixed cell lymphoma is characterized by relapse from remission and survival ranging from 6 to 12 years. Because young patients have the greatest compromise in longevity, the efficacy and toxicity of high-dose radiochemotherapy and bone marrow transplantation after conventional chemotherapy was evaluated in a prospective phase II clinical trial. Thirty-seven patients in a minimal disease state after conventional chemotherapy received fractionated total body irradiation and high-dose etoposide and cyclophosphamide, followed by purged autologous bone marrow. A reference sample of 188 patients of similar age, stage, and histology managed at this institution before 1988 was identified for comparison of patient characteristics and outcomes. Compared with reference patients, transplant recipients had a higher tumor burden at diagnosis. With a median follow-up of 6.5 years, the estimated 10-year survival after transplantation was 86%. There was a single lymphoma death yielding a 10-year disease-specific survival of 97%. There were 2 early transplant-related deaths and 2 late acute leukemia deaths. Ten patients relapsed, one with microscopic disease only. High tumor burden at diagnosis and incomplete response to chemotherapy adversely influenced survival in the reference but not in the transplanted patients. The estimated risk of death of 14% and relapse of 30% at 10 years in our transplanted follicular lymphoma patients, the majority of whom had high tumor burdens, compares favorably with our observations in appropriately matched reference patients.

This paper examines the evidence available to guide treatment decisions in three areas of Hodgkin's lymphoma management. In Section I Dr. Evert Noordijk describes evolving strategies for patients with early stage disease outlining the eras during which the focus has changed from initially accomplishing cure through refining and intensifying the treatment to one of maximizing cure rates and finally into a patient-oriented era in which the twin goals of maintaining high rates of cure and minimizing late toxicity are being achieved. In Section II Dr. Sandra Horning reviews the way in which the cooperative groups of North America and Europe have built upon initial observations from single centers to assemble the trials that have defined the treatment for advanced stage Hodgkin's lymphoma. Over a period of almost three decades, these well-constructed trials have defined a current standard of treatment, ABVD chemotherapy and are now investigating innovative approaches to move beyond this standard. She also indicates the need to appreciate diagnostic factors and the implications of prognostic factor models for the design and interpretation of clinical trials. In Section III Dr. Joseph Connors summarizes the evidence available to inform our choice of treatment for the uncommon but important entity of lymphocyte predominance Hodgkin's lymphoma. Once again, the guidance that can be derived from carefully conducted clinical investigation is used to address the issues surrounding choice of treatment, reasonable monitoring in long term follow-up and the clear-cut need to base diagnosis on objective immunohistochemical evidence.

High-dose CBV (cyclophosphamide, carmustine, and etoposide) in combination with autologous HCT achieves survival rates of approximately 50% at 5 years in recurrent or refractory Hodgkin's disease (HD). However, carmustine (BCNU) dose-dependent pulmonary toxicity occurs in 20% to 30% of patients. A decreased incidence of interstitial pneumonitis as well as a possible benefit in efficacy has been reported with lomustine (CCNU) compared to BCNU in the standard dose setting. In a dose-escalation study, we substituted CCNU for BCNU in the CBV regimen for 16 patients with HD (n = 12) or non-Hodgkin's lymphoma (n = 4). Based on the promising results, an additional 47 consecutive patients with HD were treated with the following regimen: CCNU (15 mg/kg) orally on day -6, etoposide (60 mg/kg) intravenously on day -4, and cyclophosphamide (100 mg/kg) intravenously on day -2. Peripheral blood progenitor cells and/or bone marrow were infused on day 0. With a median follow-up for the surviving patients of 3.2 years (range, 0.8-9.9 years), the 3-year overall survival rate was 57% (CI, +/-15%), event-free survival was 52% (CI, +/-14%), and freedom from progression was 68% (CI, +/-14%). There were 21 deaths, 10 due to HD. Six patients died due to respiratory failure. Interstitial pneumonitis occurred in 63% of patients and could not be correlated with prior chest radiotherapy. This regimen demonstrated survival rates similar to those of historical studies that used the CBV regimen. However, the incidence of interstitial pneumonitis was in excess of expected.

Background: Oncologic literature cites many different definitions of critical response measurements., Patients and Methods: Response criteria (RC) for non-Hodgkin's lymphoma (NHL) were developed by lymphoma experts, endorsed by international lymphoma clinicians, and applied to a 166-patient rituximab (Rituxan, MabThera) trial by a third-party, blinded panel of NHL experts (LEXCOR). Retrospectively, we analyzed this data using variations of the original RC and comparing with recently published RC., Results: The definition of a 'normal' lymph node affected the complete response (CR) rate (< or = 1.0 x 1.0 cm, 6%; < or = 1.5 x 1.5 cm, 18%; < or = 2.0 x 2.0 cm, 28%); overall response rate (ORR) was not affected. CR rates increased progressively without > or = 28 days response confirmation: 12% vs. 6% (< or = 1.0 x 1.0 cm), 26% vs. 18% (< or = 1.5 x 1.5 cm), and 36% vs. 28% (< or = 2.0 x 2.0 cm). CR rate and duration of response (DR) were unaffected when only the six largest, rather than all lesions, were measured. When the new RC were applied, CR rate (32%) was higher and DR (13.9 months) and time to progression (15.6 months) were shorter in complete responders., Conclusions: Standard RC must be consistently and rigorously applied for accurate comparisons between studies.

Central nervous system (CNS) involvement by non-Hodgkin's lymphoma (NHL) carries a poor patient prognosis whether it occurs as a primary site of disease or secondarily in patients with systemic disease. In a group of 481 patients undergoing high-dose therapy with hematopoietic cell transplantation (HCT) for NHL, 15 patients (3.1%) were identified with CNS involvement. Two patients had primary CNS lymphoma, and 13 had secondary disease. All patients received intrathecal chemotherapy, and 13 received CNS radiotherapy before transplantation. Fourteen patients received systemic chemotherapy. At the time of transplantation, both patients with primary CNS lymphoma and 8 patients with secondary disease had achieved a complete response, 3 patients had achieved a partial response, 1 had failed induction therapy, and 1 had progression of CNS disease before high-dose therapy. Fourteen patients received carmustine, etoposide, and cyclophosphamide as the preparative regimen, and 1 patient received fractionated total body irradiation instead of carmustine. The 2 patients with primary CNS lymphoma were alive and free of disease, 1 at 1,085 days after HCT and 1 at 3,704 days after HCT. The actuarial 5-year event-free survival (EFS) was 46% +/- 26%, and overall survival (OS) was 41% +/- 28%. The median EFS and OS were 2.2 and 1.5 years, respectively. Three patients experienced symptomatic memory loss or intellectual decline after therapy, 1 patient developed paraplegia, and 1 patient had a thrombotic stroke 20 months after HCT. Despite treatment-related toxicities, 7 patients responding to quality-of-life questions at approximately 1 year after HCT gave their overall quality of life a median rating of 9 out of a possible 10 (range, 6-10). High-dose therapy with autologous HCT can produce extended EFS in patients with secondary CNS lymphoma and possibly in those with primary CNS NHL.

Purpose: This survey was designed to confirm the prevalence and duration of fatigue in the cancer population and to assess its physical, mental, social, and economic impacts on the lives of patients and caregivers. Patients and Methods. A 25-minute telephone interview was completed with 379 cancer patients having a prior history of chemotherapy. Patients were recruited from a sample of 6, 125 households in the United States identified as having a member with cancer. The median patient age was 62 years, and 79% of respondents were women. Patients reporting fatigue at least a few times a month were asked a series of questions to better describe their fatigue and its impact on quality of life., Results: Seventy-six percent of patients experienced fatigue at least a few days each month during their most recent chemotherapy; 30% experienced fatigue on a daily basis. Ninety-one percent of those who experienced fatigue reported that it prevented a "normal" life, and 88% indicated that fatigue caused an alteration in their daily routine. Fatigue made it more difficult to participate in social activities and perform typical cognitive tasks. Of the 177 patients who were employed, 75% changed their employment status as a result of fatigue. Furthermore, 65% of patients indicated that their fatigue resulted in their caregivers taking at least one day (mean, 4.5 days) off work in a typical month. Physicians were the health care professionals most commonly consulted (79%) to discuss fatigue. Bed rest/ relaxation was the most common treatment recommendation (37%); 40% of patients were not offered any recommendations., Conclusions: Cancer-related fatigue is common among cancer patients who have received chemotherapy and results in substantial adverse physical, psychosocial, and economic consequences for both patients and caregivers. Given the impact of fatigue, treatment options should be routinely considered in the care of patients with cancer.

The use of HDT and AHCT in Hodgkin's disease patients with early relapsed and refractory disease is supported by historical comparisons. In regard to the late relapsed patient or the newly diagnosed high-risk patient, the role AHCT plays would ideally be answered by well-controlled phase 3 trials. A surrogate approach would be the comparison of AHCT data with well-matched historical controls. It is important, however, to be mindful of the changes that have occur red in the therapy of the newly diagnosed and relapsed HD patient (ABVD replacing MOPP regimens) and the impact these changes may or may not have on nonrelapse mortality in the autografted and nonautografted setting. In addition, the incorporation of consistent prognostic factors in any trial design may identify groups of relapsed or refractory and high-risk HD patients who may or may not gain benefit from HDT. The most effective and efficient route to answering these treatment questions is enrollment of patients in well-controlled and well-designed clinical trials.

We conducted a pilot study in 20 patients with high-risk or recurrent/refractory non-Hodgkin's lymphoma (NHL) using high-dose sequential chemotherapy (HDSC) and autologous hematopoietic cell transplantation (AHCT). After cytoreduction with standard salvage therapy, HDSC/AHCT was administered in 4 phases at 2- to 4-week intervals. Phase 1 consisted of cyclophosphamide 7 g/m2 followed by granulocyte colony-stimulating factor (G-CSF) at 10 microg/kg per day and leukapheresis upon recovery from white blood cell nadir. The hematopoietic cell product was enriched by Percoll gradient separation and purged with a B-cell or T-cell monoclonal antibody panel and complement. Phase 2 consisted of methotrexate 8 g/m2 with leucovorin rescue and vincristine 1.4 mg/m2. Phase 3 was etoposide 2 g/m2 with G-CSF 5 microg/kg per day. In phase 4, the preparative regimen of mitoxantrone 60 mg/m2 and melphalan 180 mg/m2 was administered followed by AHCT. The NHL histologies were diffuse large cell, follicular/diffuse mixed, small noncleaved cell, T-cell-rich B-cell, lymphoblastic, and peripheral T cell. The remission status was first partial remission (PR1; n = 1) or beyond first complete remission (post-CR1; n = 19). Of the 20 patients enrolled, 11 proceeded through all 4 phases. Nine were removed from the study after the first or second phase because of progressive disease (n = 5), poor hematopoietic cell mobilization (n = 1), excessive toxicity (n = 2), and chronic active hepatitis C (n = 1). Treatment-related toxicities in the remaining 11 transplant recipients were cardiomyopathy, hemorrhagic cystitis, persistent cytopenias, acute renal failure, abnormal liver function test results, and infectious complications. There were no treatment-related deaths. Eight of the 11 transplant recipients were alive, 6 without disease, at a median follow-up of 2.7 years. The estimated median 2-year event-free survival was 55%, and overall survival was 70%. We conclude that HDSC/AHCT in refractory/recurrent NHL is associated with considerable acute and chronic toxicities. Given the toxicity profile, efficacy data were not sufficiently promising to warrant further study.

Follicular lymphomas are characterized by relatively long median survivals and a continuous pattern of relapse. The heterogeneity in these diseases is increasingly appreciated, leading to concerted efforts to define prognostic factors and risk-adapted strategies. The status of multiple options for treatment including interferon, fludarabine, dose intensification with autologous transplantation, therapy targeting the CD20 antigen and novel approaches is reviewed. The long natural history of follicular lymphoma requires mature data for accurate analysis. However, the achievement of molecular remission as a surrogate endpoint is under active investigation. This is an exciting era for the clinical investigation of follicular lymphoma given the large number of candidate therapies and their potential combinations and permutations. Although the goal of primary treatment remains durable remission and cure, the sequential application of effective, non-cross-resistant treatments may also result in a prolongation of median survival time. It is essential that physicians treating patients with follicular lymphoma demonstrate restraint in the application of new treatments and cooperate in the study of new therapies in carefully designed phase II and phase III trials.

Primary refractory Hodgkin's disease may generally be defined as progression of disease during induction treatment or a partial or transient response (< 60 days) to induction therapy. Salvage chemotherapy is inadequate in this patient population; fewer than 10% of patients survive for 10 years or longer. Improved outcomes after failure of primary induction therapy have been reported with myeloablative therapy and autografting. The projected event-free survivals ranged from 18%-49% at four years. Highly selected patients may benefit from salvage radiotherapy, but this may be best accomplished in combination with transplantation. A number of strategies might be considered for increasing the cure rate for the small subset of patients with primary refractory Hodgkin's disease. Among these, identification of patients at high risk for induction failure and modifications of primary treatment to address this risk hold the greatest promise for success.

One hundred nineteen patients with relapsed or refractory Hodgkin's disease (HD) received high-dose therapy followed by autologous hematopoietic progenitor cell transplantation. Three preparatory regimens, selected on the basis of prior therapy and pulmonary status, were employed. Twenty-six patients without a history of prior chest or pelvic irradiation were treated with fractionated total body irradiation, etoposide (VP) 60 mg/kg and cyclophosphamide (Cy) 100 mg/kg. Seventy-four patients received BCNU 15 mg/kg with identical doses of VP and Cy. A group of 19 patients with a limited diffusing capacity or history of pneumonitis received a novel high-dose regimen consisting of CCNU 15 mg/kg, VP 60 mg/kg and Cy 100 mg/kg. Twenty-nine patients (24%) had failed induction therapy and 35 (29%) had progressive HD within 1 year of initial chemotherapy. At 4 years actuarial survival was 52%, event-free survival was 48% and freedom from progression (FFP) was 62%. No significant differences were seen in survival data with the three preparatory regimens. Six patients died within 100 days of transplantation and 5 died at a later date of transplant-related complications. Secondary malignancies have developed in 6 patients, including myelodysplasia/leukemia in four patients and solid tumors in two patients. Regression analysis identified systemic symptoms at relapse, disseminated pulmonary or bone marrow disease at relapse and more than minimal disease at the time of transplantation as significant prognostic factors for overall and event-free survival and FFP. Patients with none of these factors enjoyed an 85% FFP at 4 years compared with 41% for patients with one or more unfavorable prognostic factors (P = .0001). Our results confirm the efficacy of high-dose therapy and autografting in recurrent or refractory HD. Although longer follow-up is necessary to address ultimate cure rates and toxicity, our data indicate that a desire to reduce late effects should drive future research efforts in favorable patients whereas new initiatives are needed for those with less favorable prognoses.

Sixty patients with Hodgkin's disease, refractory to or at first recurrence after chemotherapy, received cytoreductive therapy followed by high-dose etoposide, cyclophosphamide and either total body irradiation or carmustine and autografting (median follow-up, 3.6 years; range, 1.1 to 7.5 years). A matched conventional salvage group of 103 patients was selected from patients treated at Stanford University Medical Center between January 1976 and January 1989 (median follow-up, 10.3 years; range, 3.0 to 15.7 years). Overall survival (OS), event-free survival (EFS), and freedom from progression (FFP) at 4 years follow-up favored patients who received high-dose therapy compared with conventional salvage treatment (OS: 54% v 47%, P = .25; EFS: 53% v 27%, P < .01; FFP: 62% v 32%, P < .01). In Cox regression analysis, response to cytoreductive or salvage therapy and B symptoms at relapse were the most important predictors of OS. The use of high-dose therapy at relapse, a longer duration of remission, and favorable response to cytoreductive or salvage therapy were most predictive of superior FFP and EFS. These data from a single institution comparing conventional and high-dose therapy in matched patients demonstrate an advantage for high-dose therapy and autografting in the sustained control of Hodgkin's disease. As with primary therapy, it is difficult to demonstrate a statistically significant survival advantage, despite an apparently superior cure rate. However, patients failing induction therapy or relapsing within 1 year benefited significantly from high-dose therapy by all outcome measures (OS, EFS, FFP). As the transplant-related mortality rates decline in Hodgkin's disease, it is predicted that cure rates and late effects will become ultimate determinants of the success of high-dose therapy and autografting.

From May 1989 to August 1995, 94 previously untreated patients with Hodgkin's disease stage II with bulky mediastinal involvement (n = 28) or stage III or IV (n = 66) received an abbreviated chemotherapy regimen, Stanford V, +/-radiotherapy (RT). Chemotherapy was given weekly for 12 weeks followed by consolidative RT to sites of initial bulky disease. With a median follow-up of 3 years, the actuarial 6-year survival is 93% and the freedom from progression is 89%. There have been no relapses or deaths among the 28 patients with stage II bulky mediastinal disease. Eight relapses and three deaths have occurred in the group of 66 patients with stage III-IV disease. The abbreviated chemotherapy regimen, Stanford V, in combination with RT is well tolerated and highly effective therapy for bulky, limited stage and advanced stage HD. Lower cumulative exposure to alkylating agents, doxorubicin, bleomycin and limited use of radiation is expected to improved the prospects for fertility and decrease the risks for second neoplasms and late cardiopulmonary toxicity.

In an area of lymphoma classification still being defined, marginal-zone lymphomas have distinctive immunohistochemical and cytogenetic features that distinguish them from mantle-cell and follicular lymphomas. There are three subtypes: the extranodal mucosa-associated lymphoid tissue (MALT) lymphomas, the nodal monocytoid B-cell (MBCL) lymphomas, and the splenic marginal-zone lymphomas. The MALT lymphomas represent the neoplastic counterpart of the gut-associated lymphoid tissue, which extends from the jejunum to the rectum. They arise in sites usually containing no lymphoid tissue, such as the stomach, thyroid, and salivary gland. Gastric MALT lymphomas, the most common, are associated with Helicobacter pylori. The MBCL lymphomas closely resemble MALT lymphomas and unlike other non-Hodgkin's lymphomas are commonly composite. Therapy for these lymphomas may include radiation therapy or surgery when disease is of limited extent. However, gastrectomy for gastric MALT lymphomas is not in favor because of the efficacy of antibiotic regimens that can eliminate H. pylori infection. Splenectomy may be indicated for splenic lymphomas. Purine analogs are promising therapeutic agents because they are specific for lymphoid cells. Also, they may prove useful in indolent cancers such as these, because of their activity against dividing and resting cells. Purine analogs may be considered as second-line therapy after alkylating agents for these lymphomas.

Molecular typing of HLA class II loci has been performed on a sample of 196 patients with Hodgkin lymphoma. Division of patients into two histological categories--nodular sclerosing Hodgkin disease versus all other types--shows significant overall association of the nodular sclerosing group with the HLA class II region. Haplotypes and alleles defined for the four loci typed--DRB1, DQA1, DQB1, and DPB1--were present in both excess and deficit in the nodular sclerosing sample. Some of the effects are attributable to particular DRB1 and DQB1 alleles, while other effects are best explained by haplotypes marking the entire class II region. The latter effects might be due to variation in additional, as-yet-unexamined loci in the class II region or to particular combinations of alleles from two or more loci. These data also explain why earlier studies showed HLA linkage but not association, and they substantiate the specific involvement of the immune system in certain neoplastic diseases.