Unmet needs in the first-line treatment of follicular lymphoma.

For the majority of patients with newly diagnosed follicular lymphoma (FL), current treatments, while not curative, allow for long remission durations. However, several important needs remain unaddressed. Studies have consistently shown that ∼20% of patients with FL experience disease progression within 2 years of first-line treatment, and consequently have a 50% risk of death in 5 years. Better characterization of this group of patients at diagnosis may provide insight into those in need of alternate or intensive therapies, facilitate a precision approach to inform clinical trials, and allow for improved patient counseling. Prognostic methods to date have employed clinical parameters, genomic methods, and a wide assortment of biological and biochemical markers, but none so far has been able to adequately identify this high-risk population. Advances in the first-line treatment of FL with chemoimmunotherapy have led to a median progression-free survival (PFS) of approximately 7 years; creating a challenge in the development of clinical trials where PFS is a primary end point. A surrogate end point that accurately predicts PFS would allow for new treatments to reach patients with FL sooner, or lessen toxicity, time, and expense to those patients requiring little to no therapy. Quality of response to treatment may predict PFS and overall survival in FL; as such complete response rates, either alone or in conjunction with PET imaging or minimal residual disease negativity, are being studied as surrogates, with complete response at 30 months after induction providing the strongest surrogacy evidence to date. A better understanding of how to optimize quality of life in the context of this chronic illness is another important focus deserving of further study. Ongoing efforts to address these important unmet needs are herein discussed.

Disease characteristics, treatment patterns, and outcomes of follicular lymphoma in patients 40 years of age and younger: an analysis from the National Lymphocare Study†.

BACKGROUND: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma, with median age at diagnosis in the seventh decade. FL in young adults (YAs), defined as diagnosis at ≤40 years, is uncommon. No standard approaches exist guiding the treatment of YA FL, and little is known about their disease characteristics and outcomes. To gain further insights into YA FL, we analyzed the National LymphoCare Study (NLCS) to describe characteristics, initial treatments, and outcomes in this population versus patients aged >40 years. PATIENTS AND METHODS: Using the NLCS database, we stratified FL patients by age: 18-40 (YA), 41-60, 61-70, 71-80, and >80 years. Survival probability was estimated using Kaplan-Meier methodology. We examined associations between age and survival using hazard ratios and 95% confidence intervals (CIs) from multivariable Cox models. RESULTS: Of 2652 eligible FL patients in the NLCS, 164 (6%) were YAs. Of YA patients, 69% had advanced disease, 80% had low-grade histology, and 50% had good-risk disease according to the Follicular Lymphoma International Prognostic Index (FLIPI). Nineteen percent underwent observation, 12% received rituximab monotherapy, and 46% received chemoimmunotherapy [in 59% of these: R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone)]. With a median follow-up of 8 years, overall survival (OS) at 2, 5, and 8 years was 98% (95% CI 93-99), 94% (95% CI 89-97), and 90% (95% CI 83-94), respectively. Median progression-free survival (PFS) was 7.3 years (95% CI 5.6-not reached). CONCLUSIONS: In one of the largest cohorts of YA FL patients treated in the rituximab era, disease characteristics and outcomes were similar to patients aged 41-60 years, with favorable OS and PFS in YAs. Longer-term outcomes and YA-specific survivorship concerns should be considered when defining management. These data may not support the need for more aggressive therapies in YA FL. CLINICAL TRIAL NUMBER: Roche/Genentech ML01377 (U2963n).

Examination of the follicular lymphoma international prognostic index (FLIPI) in the National LymphoCare study (NLCS): a prospective US patient cohort treated predominantly in community practices.

BACKGROUND: Because follicular lymphoma (FL) patients have heterogeneous outcomes, the FL international prognostic index (FLIPI) was developed to risk-stratify patients and to predict survival. However, limited data exist regarding the role of FLIPI in the era of routine first-line rituximab (R) and R-chemotherapy regimens and in the setting of community oncology practices. PATIENTS AND METHODS: We evaluated the outcome data from the National LymphoCare Study (NLCS), a prospective, observational cohort study, which collects data on patients with FL in the United States (US) community practices. RESULTS: Among 1068 male and 1124 female patients with FLIPI data, most were treated in US community practices (79%); 35% were FLIPI good risk, 30% intermediate risk, and 35% poor risk. FLIPI risk groups were significant predictors of overall survival (OS) and progression-free survival (PFS) for patients who undergo watchful waiting (WW), and those who receive non-R-containing regimens, R-alone, and R-chemotherapy combinations. CONCLUSIONS: In the setting of contemporary practice with routine R use, stratifying patients into good, intermediate, and poor FLIPI risk groups predicts distinct outcomes in terms of OS and PFS. FLIPI remains an important prognostic index in the R era and should be used in clinical practices to support discussions about prognosis.

Bortezomib and gemcitabine in relapsed or refractory Hodgkin's lymphoma.

BACKGROUND: Given the significant activity and tolerability of gemcitabine in patients with relapsed Hodgkin's lymphoma (HL), the critical role that nuclear factor kappa B (NF-kappaB) appears to play in the pathogenesis of this tumor, the ability of bortezomib to inhibit NF-kappaB activity, and laboratory studies suggesting synergistic antitumor effects of gemcitabine and bortezomib, we hypothesized that this combination would be efficacious in patients with relapsed or refractory HL. PATIENTS AND METHODS: A total of 18 patients participated. Patients received 3-week cycles of bortezomib 1 mg/m(2) on days 1, 4, 8, and 11 plus gemcitabine 800 mg/m(2) on days 1 and 8. RESULTS: The overall response rate for all patients was 22% (95% confidence interval 3% to 42%). Three patients developed grade III transaminase elevation: one was removed from the study and two had doses of gemcitabine held. Almost all patients exhibited inhibition of proteasome activity with treatment. CONCLUSIONS: The combination of gemcitabine and bortezomib is a less active and more toxic regimen in relapsed HL than other currently available treatments. It poses a risk of severe liver toxicity and should be pursued with caution in other types of cancer.

Outcome in patients with myelodysplastic syndrome after autologous bone marrow transplantation for non-Hodgkin's lymphoma.

PURPOSE: The absolute risk of myelodysplastic syndrome (MDS) after autologous bone marrow transplant (ABMT) for non-Hodgkin's lymphoma (NHL) exceeds 5% in several reported series. We report the outcome of a large cohort of patients who developed MDS after ABMT for NHL. PATIENTS AND METHODS: Between December 1982 and December 1997, 552 patients underwent ABMT for NHL, with a uniform ablative regimen of cyclophosphamide and total body irradiation followed by reinfusion of obtained marrow purged with monoclonal antibodies. MDS was strictly defined, using the French-American-British classification system, as requiring bone marrow dysplasia in at least two cell lines, with associated unexplained persistent cytopenias. RESULTS: Forty-one patients developed MDS at a median of 47 months after ABMT. The incidence of MDS was 7.4%, and actuarial incidence at 10 years is 19.8%, without evidence of a plateau. Patients who developed MDS received significantly fewer numbers of cells reinfused per kilogram at ABMT (P =.0003). Karyotypes were performed on bone marrow samples of 33 patients, and 29 patients had either del(7) or complex abnormalities. The median survival from diagnosis of MDS was 9.4 months. The International Prognostic Scoring System for MDS failed to predict outcome in these patients. Thirteen patients underwent allogeneic BMT as treatment for MDS, and all have died of BMT-related complications (11 patients) or relapse (two patients), with a median survival of only 1.8 months. CONCLUSION: Long-term follow-up demonstrates a high incidence of MDS after ABMT for NHL. The prognosis for these patients is uniformly poor, and novel treatment strategies are needed for this fatal disorder.

Phase I study for poor-prognosis lymphoma: augmentation of the "BEAM" regimen with escalating dose melphalan using amifostine cytoprotection and autologous hematopoietic stem cell transplantation--a preliminary report.

We and others have previously shown that the use of amifostine (Ethyol; MedImmune Inc, Gaithersburg, MD) can ameliorate certain regimen-related toxicities of high-dose melphalan (HD-MEL) in the autologous hematopoietic stem cell transplant setting. Our recent experience indicated that the maximum tolerated dose of HD-MEL plus autologous hematopoietic stem cell transplant could be increased from approximately 200 mg/m2 to at least 280 mg/m2 with amifostine. Although a dose-limiting toxicity was not clearly identified, atrial fibrillation was noted in several patients. Phase II trials using this regimen have been reported in lymphoma and myeloma. Nonetheless, it is unlikely that single agent therapy, regardless of dose, will be highly curative in advanced hematologic malignancy. Thus, we used amifostine to permit dose escalation of HD-MEL within the BEAM (BCNU/etoposide/arabinosylcytosine/HD-MEL) combination chemotherapy regimen before autologous hematopoietic stem cell transplant in selected patients with lymphoma. Patient entry at the starting dose (ie, HD-MEL 140 mg/m2) has been completed without the development of severe regimen-related toxicities. This trial is ongoing.

Ex vivo B cell depletion using the Eligix B Cell SC system and autologous peripheral blood stem cell transplantation in patients with follicular non-Hodgkin's lymphoma.

One limitation of ASCT is the potential reinfusion of tumor cells contaminating PBSC. The Eligix B cell SC system consists of high-density microparticles coated with anti-B cell antibodies. To determine if this system eliminates B cells and lymphoma cells from PBSC, immunocytochemistry and PCR of the bcl-2/IgH rearrangement were performed, and correlated with patient outcome after ASCT. Eligible patients (n=29) had relapsed or transformed follicular NHL with bone marrow involvement <20%, and all lymph nodes <5 cm. PBSCs were mobilized with cyclophosphamide/G-CSF (n=21), and patients were conditioned with cyclophosphamide, carmustine and etoposide. Using immunocytochemistry on PBSC, the median number of CD20+ cells pre-purge was 310/10(6) (range 0-16692) and post-purge was 0.75/10(6); the median log B cell depletion was 2.7 (range 1.4-3.9). B cell depletion correlated with PFS after ASCT (P=0.06). Of 17 available samples for PCR, only four had a detectable t(14;18) breakpoint. After purging, all four remained PCR+; two had a 1-3 log depletion of lymphoma cells. At median follow-up of 18 months, 10 patients, including five infused with PCR-negative PBSC, have had disease progression. The paucity of PCR-informative patients, possibly related to in vivo rituximab therapy, limited the utility of minimal residual disease as a surrogate marker of clinical outcome.

High-dose therapy for follicular lymphoma.

Most patients with advanced-stage follicular non-Hodgkin's lymphoma (NHL) are not cured with conventional therapy. The use of high-dose therapy and autologous stem-cell transplantation in patients with relapsed follicular NHL has received increasing attention. Several large studies suggest a disease-free survival rate of approximately 40% among patients transplanted during sensitive relapse, although the role of autologous transplantation in first remission remains controversial. Patients with histologic transformation from low-grade to diffuse large B-cell lymphoma whose disease remains sensitive to conventional therapy have a similar disease-free survival rate. Allogeneic transplantation has achieved relapse, overall survival, and treatment-related death rates of approximately 15%, 50%, and 40%, respectively, in patients with follicular NHL. Studies of minimal residual disease suggest that the presence of lymphoma cells in the autologous graft and within the patient before clinically apparent relapse is predictive of later recurrence. Therefore, treatment of minimal residual disease may improve the outcome of high-dose therapy. Use of a tumor-free stem-cell product through improved purging or allogeneic stem cells is one approach, although the morbidity and mortality of allogeneic transplantation remain high. Immunomodulatory strategies with monoclonal antibodies, vaccines, or adoptive immunotherapy may be particularly well suited to patients at high risk for relapse following high-dose therapy.

Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin's lymphoma: CALGB 59804.

BACKGROUND: Because of high single-agent activity and modest toxicity, we hypothesized the combination of gemcitabine (G), vinorelbine (V), and pegylated liposomal doxorubicin (D) would be an effective salvage therapy for Hodgkin's lymphoma (HL). PATIENTS AND METHODS: A total of 91 patients participated. GVD was administered on days 1 and 8 every 21 days at doses of G 1000 mg/m(2), V 20 mg/m(2), and D 15 mg/m(2) for transplant-naive patients, and G 800 mg/m(2), V 15 mg/m(2), and D 10 mg/m(2) for post-transplant patients. RESULTS: The dose-limiting toxicity was mucositis for the transplant-naive patients and febrile neutropenia for post-transplant patients. The overall response rate (RR) for all patients was 70% [95% confidence interval (CI) 59.8, 79.7], with 19% complete remissions. The 4-year event-free and overall survival rates in transplant-naive patients treated with GVD followed by autologous transplant were 52% (95% CI 0.34, 0.68) and 70% (95% CI 0.49, 0.84), and in the patients in whom prior transplant failed, these were 10% (95% CI 0.03, 0.22) and 34% (95% CI 0.17, 0.52), respectively. CONCLUSIONS: GVD is a well-tolerated, active regimen for relapsed HL with results similar to those reported for more toxic regimens. High RRs in patients in whom prior transplant failed confirms this regimen's activity even in heavily pretreated patients.

A phase I/II study of galiximab (an anti-CD80 monoclonal antibody) in combination with rituximab for relapsed or refractory, follicular lymphoma.

BACKGROUND: Galiximab is a monoclonal antibody that targets CD80, a costimulatory molecule constitutively expressed on follicular and other lymphomas. Modest single-agent clinical activity and tolerability were demonstrated in a phase I study in relapsed or refractory, follicular non-Hodgkin's lymphoma (NHL). A phase I/II study was conducted to evaluate galiximab in combination with a standard course of rituximab. Safety, pharmacokinetics, and efficacy were evaluated. PATIENTS AND METHODS: Patients with follicular NHL who had relapsed or failed primary therapy were enrolled. Rituximab-refractory patients (no response or a response with time to progression <6 months) were excluded. Patients received 4 weekly i.v. infusions of galiximab (125, 250, 375, or 500 mg/m(2)) and rituximab (375 mg/m(2)). International Workshop Response Criteria (IWRC) were used to evaluate response. RESULTS: Seventy-three patients received treatment. All had received at least one prior lymphoma therapy; 40% were rituximab naive. Infusions were delivered in an outpatient setting and were well tolerated. The most common study-related adverse events (AE) were lymphopenia, leukopenia, neutropenia, fatigue, and chills. The overall response rate at the recommended phase II dose of galiximab (500 mg/m(2)) was 66%: 19% complete response, 14% unconfirmed complete response, and 33% partial response. The median progression free survival was 12.1 months. Combination therapy did not appear to alter pharmacokinetics. CONCLUSION: These results indicate that galiximab can be safely combined with a standard course of rituximab. This doublet biologic approach offers the potential to avoid or delay chemotherapy or to integrate with other lymphoma therapies. A phase III, randomized study evaluating clinical benefit of rituximab versus the combination has been initiated.

High-dose therapy and stem cell transplantation in follicular lymphoma.

Indolent follicular lymphomas are diseases which are generally incurable with conventional therapy. Although patients can survive for prolonged periods, the median duration of first remissions is about 2.5 years, and subsequent remissions progressively shorten with time. High-dose therapy with hematopoietic stem cell support leads to prolonged disease-free and overall survival in a subset of patients with aggressive non-Hodgkin's lymphoma. Mounting evidence suggests similar findings for selected patients with indolent follicular non-Hodgkin's lymphoma. It is still unclear as to when this approach should be used; however, inferior results have been seen in heavily pretreated patients. In contrast, encouraging results are being reported in patients undergoing such treatment early in the course of their disease. Despite these data, many patients continue to relapse, and investigations are now focused on eradication of minimal residual disease, allogeneic transplantation, novel ablative regimens, and improvements in stem cell purging.

Clozapine-caused eosinophilic colitis.

Four patients with diarrhea and eosinophilia associated with clozapine therapy are presented. In two cases clozapine therapy was interrupted but then restarted; all patients eventually tolerated clozapine well. A syndrome of clozapine-induced eosinophilic colitis is suggested.

Uptake of radiolabeled somatostatin analog is detectable in patients with metastatic foci of sarcoma.

BACKGROUND: Somatostatin receptors are present on many types of epithelial tumors, and ligands targeting these receptors are used to treat patients with neuroendocrine malignancies. Preclinical studies have demonstrated the presence of somatostatin receptors on a variety of mesenchymal tumors by in vitro receptor autoradiography. The use of radiolabeled somatostatin analogs to assess the presence of somatostatin receptors in vivo has been established, but use of this technique to evaluate human sarcomas has not been reported previously. METHODS: Seventeen patients (13 females and 4 males) with metastatic sarcoma underwent imaging via somatostatin-receptor scintigraphy. Scans were performed using indium -111 pentetreotide. Planar studies and single photon emission computed tomography imaging were performed at 4 and 24 hours, and results of scintigraphy were correlated with computed tomography findings. RESULTS: Twelve of 17 scans showed increased uptake in regions of known metastatic disease. There was no apparent correlation with scan positivity and patient age, histology, site of disease, or duration of diagnosis. CONCLUSIONS: Seventy-one percent of patients with advanced soft-tissue sarcomas had positive scintigraphy scans demonstrating tumor expression of somatostatin receptors subtype 2 in vivo. Imaging with indium-111 pentetreotide could be studied as an adjunct to conventional imaging modalities for assessment of sarcoma patients. Further research is needed to determine the prognostic implications of somatostatin receptor subtype 2 positivity, including larger studies to evaluate any potential correlation with metastatic behavior and other clinical outcomes.

The impact of external beam radiation therapy prior to autologous bone marrow transplantation in patients with non-Hodgkin's lymphoma.

External beam radiation therapy (XRT) is frequently used to treat refractory disease sites or consolidate remission in patients with relapsed non-Hodgkin's lymphoma (NHL) prior to autologous bone marrow transplantation (ABMT). We report the long-term outcome and toxicities associated with this therapy. We uniformly treated 552 patients with NHL with total body irradiation, high-dose chemotherapy, and anti-B-cell monoclonal antibody-purged ABMT. Of these patients, 152 received XRT to the mediastinum, abdomen, or pelvis (n = 102) or other sites (n = 50) prior to ABMT. In this nonrandomized series, there was no difference in progression-free survival between patients treated with XRT and those not treated with XRT. For patients with indolent histology, there was no difference in overall survival between patients treated with XRT and those not treated with XRT. For patients with aggressive histology, the median overall survival time was 64 months in the XRT patients and 79 months in the patients not treated with XRT (P= .09). The risk of acute transplantation-related deaths was not influenced by prior XRT (P = .68). Of patients who received XRT, 12.5% developed secondary myelodysplasia compared with 5.8% of patients not receiving XRT (P = .01). Patients receiving XRT to the mediastinum or axilla had a significantly higher risk of late respiratory death (P = .002). In conclusion, XRT allows refractory patients to become eligible for transplantation and experience a disease-free survival interval equivalent to that of patients who do not receive XRT. However, a higher incidence of non-relapse-associated deaths was observed in patients who received XRT. Future work should explore alternative conditioning strategies and altered timing of XRT, in an attempt to limit these late toxicities.

Autologous bone marrow transplantation after histologic transformation of indolent B cell malignancies.

The role of high-dose therapy and autologous stem cell transplantation in diffuse large B cell lymphoma (DLBCL) after transformation is controversial. We have retrospectively analyzed patients with chemosensitive disease and a history of follicular lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma who underwent high-dose chemoradiotherapy and bone marrow transplantation (BMT) with anti-B cell monoclonal antibody-purged autologous marrow for DLBCL. Between December 1982 and August 1997, 27 patients underwent autologous BMT using a uniform ablative regimen with cyclophosphamide, total-body irradiation, and bone marrow purging. All patients received multiple chemotherapy regimens before autologous BMT. At bone marrow (BM) harvest, only 44% of patients were in complete remission, and overt BM infiltration was present in 37%. After cyclophosphamide and total-body irradiation, no treatment-related deaths were seen. Eleven of the 27 patients relapsed, and four patients developed myelodysplasia/acute myelogenous leukemia. In seven patients in whom pathologic studies were available after relapse, the histology remained DLBCL. Twelve patients remained alive and in complete remission with a median follow-up of 36 months (range 10-132). The disease-free survival and overall survival are estimated to be 46% (90% confidence interval 28-64) and 58% (40-76) at 5 years, respectively. Patients whose disease underwent histologic transformation within 18 months of their initial diagnosis of indolent lymphoma had significantly better overall survival. Selected patients with histologic transformation, particularly those whose transformation occurs early in the course of their disease and who remain chemosensitive, may experience prolonged survival after autoBMT.