Patients with classical Hodgkin lymphoma experiencing disease progression after treatment with brentuximab vedotin have poor outcomes.

BACKGROUND: Brentuximab vedotin (BV) is a key therapeutic agent for patients with relapsed/refractory classical Hodgkin lymphoma (cHL). The outcomes of patients experiencing disease progression after BV are poorly described. PATIENTS AND METHODS: We reviewed our institutional database to identify patients with cHL treated with BV who were either refractory to treatment or experienced disease relapse. We collected clinicopathologic features, treatment details at progression and outcome. RESULTS: One hundred patients met inclusion criteria, with a median age of 32 years (range 18-84) at progression after BV. The median number of treatments before BV was 3 (range 0-9); 71 had prior autologous stem cell transplant. The overall response rate (ORR) to BV was 57%, and the median duration of BV therapy was 3 months (range 1-25). After disease progression post-BV, the most common treatment strategies were investigational agents (n = 30), gemcitabine (n = 15) and bendamustine (n = 12). The cumulative ORR to therapy was 33% (complete response 15%). After a median follow-up of 25 months (range 1-74), the median progression-free (PFS) and overall survival (OS) were 3.5 and 25.2 months, respectively. In multivariate analysis, no factors analyzed were predictive of PFS; age at progression >45 years and serum albumin <40 g/l at disease progression were associated with increased risk of death. Among patients who achieved response to therapy, allogeneic stem cell transplantation was associated with a non-significant trend toward superior OS (P = 0.11). CONCLUSIONS: Patients with BV-resistant cHL have poor outcomes. These data serve as a reference for newer agents active in BV-resistant disease.

Factors influencing outcome in advanced stage, low-grade follicular lymphoma treated at MD Anderson Cancer Center in the rituximab era.

BACKGROUND: The optimal initial therapy of follicular lymphoma (FL) remains unclear. The aims of this study were to compare primary treatment strategies and assess the impact of maintenance rituximab and patterns of treatment failure. PATIENTS AND METHODS: We retrospectively analyzed patients with treatment-naive advanced stage, grade 1-2 FL treated at our center from 2004 to 2014. We included 356 patients treated on clinical trials or standard of care with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP, n = 119); R-CHOP with maintenance (R-CHOP + M, n = 65); bendamustine/rituximab (BR, n = 45); BR with maintenance (BR + M, n = 35); R(2) (n = 94). We compared baseline characteristics, progression-free survival (PFS), overall survival (OS) and analyzed prognostic factors using univariate and multivariate analysis adjusted for treatment. RESULTS: After a median follow-up of 4 years (range 0.2-15.0), the 3-year PFS was 60% [95% confidence interval (CI) 51% to 69%] for R-CHOP, 72% (59% to 82%) for R-CHOP + M, 63% (42% to 78%) for BR, 97% (80% to 100%) for BR + M and 87% (78% to 93%) for R(2). Patients treated with R-chemotherapy had more high-risk features than patients treated with R(2) but, by adjusted multivariate analysis, treatment with R(2) [hazard ratio (HR) 0.39 (0.17-0.89), P = 0.02] was associated with a superior PFS. Eastern Cooperative Oncology Group Performance status of one or more predicted inferior OS. Among patients treated with R-chemotherapy, maintenance was associated with the superior PFS [HR 0.38 (95% CI 0.21-0.68)]. By adjusted multivariate analysis, disease progression within 2 years [HR 5.1 (95% CI 1.57-16.83)] and histologic transformation (HT) [HR 11.05 (95% CI 2.84-42.93)] increased risk of death. CONCLUSION: Induction therapy with R(2) may result in disease control which is comparable with R-chemotherapy. Early disease progression and HT are predictive of inferior survival.

Patients with mantle cell lymphoma failing ibrutinib are unlikely to respond to salvage chemotherapy and have poor outcomes.

BACKGROUND: Although ibrutinib is highly effective in patients with relapsed/refractory mantle cell lymphoma (MCL), a substantial proportion of patients have resistant disease. The subsequent outcomes of such patients are unknown. PATIENTS AND METHODS: We carried out a retrospective review of all patients with MCL treated with ibrutinib at MD Anderson Cancer Center between January 2011 and January 2014 using pharmacy and clinical databases. Patients who had discontinued ibrutinib for any reason were included in the study. RESULTS: We identified 42 patients with MCL who discontinued therapy due to disease progression on treatment (n = 28), toxicity (n = 6), elective stem-cell transplant in remission (n = 4) or withdrawn consent (n = 4). The median age was 69 years, 35 (83%) were male; the median number of prior treatments was 2 (range 1-8) and the median time from initial diagnosis of MCL to commencing ibrutinib was 3.0 (range 0.5-15.5) years. Patients had received a median of 6.5 (range 1-43) cycles of ibrutinib. Among 31 patients who experienced disease progression following ibrutinib and underwent salvage therapy, the overall and complete response rates were 32% and 19%, respectively. After a median follow-up of 10.7 (range 2.4-38.9) months from discontinuation of ibrutinib, the median overall survival (OS) among patients with disease progression was 8.4 months. By univariate analysis, elevated serum lactate dehydrogenase at progression was associated with inferior OS. CONCLUSION: The outcome of patients with MCL who experience disease progression following ibrutinib therapy is poor, with both low response rates to salvage therapy and short duration of responses. Further studies to better understand and overcome ibrutinib resistance are urgently needed.

A randomized trial of a single-dose rasburicase versus five-daily doses in patients at risk for tumor lysis syndrome.

BACKGROUND: Tumor lysis syndrome (TLS) is a life-threatening disorder characterized by hyperuricemia and metabolic derangements. The efficacy of rasburicase, administered daily for 5 days, has been well established. However, the optimal duration of therapy is unknown in adults. PATIENTS AND METHODS: We evaluated the efficacy of rasburicase (0.15 mg/kg) administered as single dose followed by as needed dosing (maximum five doses) versus daily dosing for 5 days in adult patients at risk for TLS. RESULTS: Eighty of the 82 patients enrolled received rasburicase; 40 high risk [median uric acid (UA) 8.5 mg/dl; range, 1.5-19.7] and 40 potential risk (UA = 5.6 mg/dl; range, 2.4-7.4). Seventy-nine patients (99%) experienced normalization in their UA within 4 h after the first dose; 84% to an undetectable level (<0.7 mg/dl). Thirty-nine of 40 (98%) patients in the daily-dose arm and 34 of 40 (85%) patients in single-dose arm showed sustained UA response. Six high-risk patients within the single-dose arm required second dose for UA >7.5 mg/dl. Rasburicase was well tolerated; one patient with glucose-6-phosphate dehydrogenase deficiency developed methemoglobinemia and hemolysis. CONCLUSIONS: Rasburicase is highly effective for prevention and management of hyperuricemia in adults at risk for TLS. Single-dose rasburicase was effective in most patients; only a subset of high-risk patients required a second dose.

The addition of rituximab to CHOP chemotherapy improves overall and failure-free survival for follicular grade 3 lymphoma.

BACKGROUND: The benefit of adding rituximab to anthracycline-based therapy for follicular lymphoma grade 3 has not been studied. PATIENTS AND METHODS: We retrospectively reviewed the records of 45 patients with follicular grade 3 lymphoma who were treated with rituximab and the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) at The University of Texas MD Anderson Cancer Center. Response rate, failure-free survival (FFS), and overall survival (OS) were estimated and a historical comparison to CHOP-only-treated patients was made. RESULTS: The International Prognostic Index (IPI) distribution was 47% low, 36% low intermediate, 13% high intermediate, and 4% high risk. The complete response rate was 96%. Forty-four of 45 patients are still alive. Median follow-up for the alive patients is 3.5 years. The 3-year FFS rate according to the IPI was 80% [95% confidence interval (CI) 64% to 100%] in low, 81% in low intermediate (95% CI 64% to 100%), and 50% (95% CI 25% to 100%) in high-intermediate/high-risk patient group. The addition of rituximab to CHOP improved both 5-year FFS, 71% (95% CI 58% to 87%) compared with 44% (95% CI 36% to 55%) with P value of 0.019, and 5-year OS, 98% (95% CI 93% to 100%) compared with 75% (95% CI 67% to 84%) with P value of 0.0034. CONCLUSION: The addition of rituximab to CHOP provided a high response rate and excellent early survival. Poor-risk patients continue to demonstrate a high rate of failure despite the use of rituximab.

Is there an increased rate of additional malignancies in patients with mantle cell lymphoma?

PURPOSE: To examine the frequency of additional neoplasms preceding and following the diagnosis of mantle cell lymphoma (MCL). PATIENTS AND METHODS: A total of 156 patients with MCL treated on the hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternated with methotrexate and cytosine arabinoside (Hyper-CVAD/M-A) program with or without rituximab from 1994 to 2000 were the subjects of this report. RESULTS: These patients were followed for a median time of 26 months, and a total of 32 (21%) additional neoplasms were diagnosed, 21 preceding the diagnosis of MCL and 11 following MCL. After excluding certain types of non-invasive neoplasms, including basal cell carcinoma, meningioma and cervical intraepithelial neoplasia, we observed seven second malignancies after the diagnosis of MCL, and the 5-year cumulative incidence rate of second malignancy was 11%. The observed-to-expected (O/E) ratio was 7/0.07 = 100 [95% confidence interval (CI) 49.3 to 186.6; P <0.0001]. Of the 21 malignancies diagnosed prior to MCL, 16 were invasive and five non-invasive. There were a total of 10 urologic malignancies occurring before or after the diagnosis of MCL was established. CONCLUSIONS: Our findings suggest that there is an increased incidence of second malignancies in patients with MCL. In addition, the high number of cases with urinary tract cancer in our series may substantiate prior reports describing a possible association between lymphoma and urologic malignancies.

Non-Hodgkin's lymphoma affecting the testis: is it curable with doxorubicin-based therapy?

This study was designed to determine response, outcome, and patterns of failure of patients with non-Hodgkin's lymphoma who presented with a testicular mass. Consecutive patients presenting to M.D. Anderson Cancer Center between 1969 and 1999 treated with doxorubicin-based regimens and with radiotherapy and/or intrathecal therapy were considered for this study. We identified 43 patients whose median age was 61 years. Ann Arbor stage (AAS) was I in 22 patients, II in 7 patients, III in 1 patient, and IV in 13 patients. All 43 patients had intermediate-grade lymphomas according to the Working Formulation, and all 31 tumors assessed immunophenotypically were large B-cell lymphoma according to the World Health Organization classification. The International Prognostic Index score was > or = 2 in 18 patients (42%). Thirty-four patients achieved complete remission, 19 of whom relapsed, and 5 failed initial therapy. At 10 years, progression-free survival (PFS) was 20% +/- 9% and survival was 33% +/- 9%. Progression-free survival for patients with AAS I/II vs. III/IV was 36% +/- 13% vs. 0%, respectively (P = 0.004). At 10 years, the actuarial probability of failure in the central nervous system was 34% +/- 9% and was 21% +/- 9% in contralateral testis. Using the intent-to-treat method, patients receiving cyclophosphamide/doxorubicin/ vincristine/prednisone (CHOP), with additional scrotal radiotherapy and intrathecal methotrexate, had a 5-year PFS of 91% +/- 9% vs. 30% +/- 15% vs. 41% +/- 12% for those receiving only one or neither of these additional modalities (P = 0.053). Doxorubicin-based regimens alone appear unable to cure most patients with lymphoma involving the testis, but CHOP with prophylactic intrathecal therapy and adjuvant scrotal radiotherapy appears promising. This should be confirmed with prospective clinical trials and longer follow-up.

Primary hepatic lymphoma: favorable outcome after combination chemotherapy.

BACKGROUND: Primary hepatic non-Hodgkin lymphoma (PHL) is a rare and difficult to diagnose lymphoproliferative disorder of unknown etiology. It is believed that the prognosis in affected patients is dismal, consisting of early recurrence and short survival. METHODS: A retrospective cohort review of patients with PHL diagnosed between 1974 and 1995 at a university cancer center was performed. RESULTS: Twenty-four patients with PHL were identified. Typically, the disease occurred in middle-aged men (median age, 50 years). The primary presenting complaint was right upper quadrant abdominal pain, with hepatomegaly found at physical examination. Serum liver enzymes, lactate dehydrogenase, and beta-2-microglobulin levels all were elevated, but alpha-fetoprotein and carcinoembryonic antigen levels were within normal range. Hypercalcemia was found in 6 of 15 patients who were tested. Six of 10 patients who were tested were positive for the hepatitis C virus (HCV). Liver scans demonstrated either a solitary lesion or multiple lesions. Pathologic examination revealed diffuse large cell lymphoma in 23 patients (96%). Combination chemotherapy was the mainstay of treatment; surgery consisted of diagnostic biopsy. The complete remission rate was 83.3%, and the 5-year cause specific and failure free survival rates were 87.1% and 70.1%, respectively. HCV infection did not appear to influence the outcome of therapy. CONCLUSIONS: The outcome of patients with PHL who are treated with combination chemotherapy may be more favorable than that reported elsewhere. The frequent association of PHL with HCV infection observed in this series warrants further investigation.

Paclitaxel plus topotecan treatment for patients with relapsed or refractory aggressive non-Hodgkin's lymphoma.

BACKGROUND: Used as single agents, paclitaxel and topotecan have demonstrated promising activity in treating patients with relapsed aggressive non-Hodgkin's lymphoma (NHL). We conducted a phase II clinical trial to investigate the activity and tolerability of the combination of both drugs. PATIENTS AND METHODS: Patients with refractory or relapsed aggressive NHL who had previously been treated with a maximum of two prior chemotherapeutic regimens were given intravenous infusions of paclitaxel 200 mg/m2 over three hours on day one and topotecan 1 mg/m2 over 30 minutes daily from days one to five. All patients received daily subcutaneous injections of filgrastim (granulocyte colony-stimulating factor) 5 microg/kg starting 24 hours after the last dose of chemotherapy until neutrophil recovery. Treatments were repeated every three weeks for a maximum of six courses. Patients who achieved partial remission or complete remission (CR) after at least two courses were offered stem cell transplantation, if eligible. RESULTS: Of the 71 patients eligible for this trial, 66 (93%) were evaluable for treatment response. The median age was 53 years (range 23 to 74 years). Thirty-six percent of the patients had previously been treated with ara-C/platinum-based regimens, and 48% failed to achieve CR after primary induction therapy. Sixty-seven percent of the patients had elevated lactate dehydrogenase levels at the time of treatment initiation. The overall response rate was 48% (95% confidence interval (95% CI): 36%-61%). Patients who had primary refractory disease had a response rate of 31%, compared with 65% for patients who did not. Similarly, the response rate of patients who failed to achieve CR after their most recent previous therapy was 37%, compared with a 65% response rate in patients who relapsed from a first or second CR. The median duration of response was six months. A total of 199 courses were given, with a median of three courses per patient. Neutropenia at levels < or = 500 leukocytes per microliter was observed after 32% of the courses, and thrombocytopenia at levels < or = 20,000 platelets per microliter was observed after 17% of the courses. Grade 3-4 neutropenic fever occurred after 6% of the courses. Non-hematologic toxic effects were predominantly grade 1-2. CONCLUSION: The combination of paclitaxel and topotecan is an effective first or second line salvage therapy for patients with relapsed or refractory aggressive NHL who had prior anthracycline- or platinum-based chemotherapy.

Primary effusion lymphoma in an HIV-negative patient with no serologic evidence of Kaposi's sarcoma virus.

Primary effusion lymphoma (PEL) is a newly described high-grade B cell lymphoma which develops in association with Kaposi's sarcoma-associated herpesvirus (KSV) in human immunodeficiency virus (HIV)-infected individuals. We hereby describe a very unusual presentation of PEL that developed in the abdominal cavity of an HIV negative, KSV negative patient with a 1-year history of refractory ascites due to alcohol-related liver cirrhosis. Possible factors aiding lymphomagenesis in the cirrhotic state are discussed.

Mantle-cell lymphoma.

During the past decade, mantle-cell lymphoma has been established as a new disease entity. The normal counterparts of the cells forming this malignant lymphoma are found in the mantle zone of the lymph node, a thin layer surrounding the germinal follicles. These cells have small to medium-sized nuclei, are commonly indented or cleaved, and stain positively with CD5, CD20, cyclin D1, and FMC7 antibodies. Because of its morphological appearance and a resemblance to other low-grade lymphomas, many of which grow slowly, this lymphoma was initially thought to be an indolent tumour, but its natural course was not thoroughly investigated until the 1990s, when the BCL1 oncogene was identified as a marker for this disease. Mantle-cell lymphoma is a discrete entity, unrelated to small lymphocytic or small-cleaved-cell lymphomas.

Untreated aggressive mantle cell lymphoma: results with intensive chemotherapy without stem cell transplant in elderly patients.

Aggressive mantle cell lymphoma has a poor prognosis with current therapy and occurs frequently in an elderly population which cannot receive stem cell transplantation. Newer aggressive therapies are needed. In this study, 25 consecutive previously untreated patients 65 years or older with MCL were enrolled in two sequential phase II trials. The program included fractionated cyclophosphamide 1,800 mg/m2 administered with doxorubicin, vincristine and dexamethasone (hyper-CVAD), alternating every 3 weeks with high doses of methotrexate and cytarabine (M-A) for up to 8 cycles. Cytarabine was given as 1 gram/m2/dose. Six of 14 patients tested (50%) presented with gastrointestinal (GI) involvement, but only one had GI symptoms. The overall response rate was 92% (95% C.I. 73-99) and the complete remission (CR) rate was 68% (95% C.I. 46-85). With a median follow-up of 17 months, the median FFS for the entire group is 15 months. Hematologic toxicity was significant but only 5% of the cycles were associated with grade 3 infection. Treatment-related death occurred in 2 patients. In conclusion, GI involvement by MCL is common in this age group. Hyper-CVAD alternating with M-A with adjustment of the cytarabine is an active regimen in this elderly group of patients with untreated MCL and the toxicity is manageable. Strategies for eradicating minimal residual disease are still needed.

Nasal-type T/NK lymphomas: a clinicopathologic study of 13 cases.

Natural Killer (NK) cell lymphomas, which include the nasal and the "nasal type" varieties, are defined as angiocentric lymphomas in the revised European American Lymphoma (R.E.A.L.) classification. This group of diseases is rare in the United States and Europe but is more common in Asia and Central America. It is associated with the Epstein-Barr virus (EBV) and its response to treatment and prognosis are usually very poor. The aim of this study was to describe our experience with 13 patients with angiocentric lymphomas seen at The University of Texas M. D. Anderson Cancer Center (UTMDACC) over the last 14 years. Thirteen patients with a diagnosis of nasal NK cell lymphoma were treated at UTMDACC from 1987 to 1999. Eleven patients were treated initially with doxorubicin based chemotherapy with or without radiotherapy. One patient received interferon (IFN)-alpha and vitamin A and another methotrexate, vincristine, L-Asparaginase, and radiotherapy. The median age was 44 years (range 15-76); there were four women and nine men. All patients presented with local disease involving the sinonasal region. Typical immunophenotypes expressing CD2+, CD3- and CD56+ surface markers as well as non rearrangement of T-receptors were present in all patients. Eight patients (62%) responded to therapy; six (46%) with complete response (CR) and two (16%) with partial response (PR). Five patients (38%) were alive, four with no evidence of disease (NED) at 1, 2, 3, and 9 years after treatment, and one patient was alive with disease (AWD) at the time of publication. One patient died while in CR from complications from allogeneic bone marrow transplant. Six patients had disease progression to extranodal sites including: testis (2), central nervous system (2), lung (1), bone marrow (2), liver (2), peripheral blood (2), and skin (2). In conclusion, the response to doxorubicin-containing regimens is inferior to that of patients with other non-Hodgkin's lymphomas and similar prognostic factors. Because the disease is associated with EBV virus in 90%-100% of the cases and the prognosis is poor, innovative therapies should be tried including immunotherapy that targets the expression of EBV by the tumor with or without myeloablative procedures.

Detection of chromosome 11q13 breakpoints by interphase fluorescence in situ hybridization. A useful ancillary method for the diagnosis of mantle cell lymphoma.

We assessed cytologic specimens from 11 mantle cell lymphomas (MCLs) and 32 other B-cell non-Hodgkin lymphomas (NHLs) for 11q13 breakpoints using a 2-color fluorescence in situ hybridization (FISH) assay that uses an 11q13 probe centered on the CCND1 gene and a centromeric chromosome 11 probe (CEP11). The number of nuclei in 200 cells were counted, and results were expressed as an 11q13/CEP11 ratio. All MCLs showed a high percentage of interphase nuclei with 3 or more 11q13 signals (mean, 74.8%; range 57%-90%). In contrast, in other B-cell NHLs the mean percentage of cells with 3 or more 11q13 signals was 9.2%. All MCLs had an elevated 11q13/CEP11 ratio (mean, 1.38). The mean ratio for other B-cell NHLs was 0.99. Two non-MCL cases, 1 large B-cell and 1 B-cell unclassified NHL, had high 11q13/CEP11 ratios of 1.15 and 1.30, respectively. Conventional cytogenetic analysis performed on the former case revealed a t(5;11)(q31;q13). Interphase FISH analysis using 11q13 and CEP11 probes is a convenient ancillary method for assisting in the diagnosis of MCL. This commercially available assay is simple to use on cytology or imprint specimens, and results can be obtained within 24 hours.

The outcome of combined-modality treatments for stage I and II primary large B-cell lymphoma of the mediastinum.

PURPOSE: Primary mediastinal large B-cell lymphoma (PML) has clinicopathologic features distinct from those of other diffuse large-cell lymphomas. However, the optimal treatment for this tumor is evolving, and in particular, the role of radiation therapy remains undefined. We conducted a retrospective review to evaluate the role of radiation therapy in this disease. METHODS AND MATERIALS: The medical records of 40 consecutive patients with Ann Arbor Stage I or II PML treated at our institution from January 1980 to December 1995 were reviewed. There were 18 patients with Stage I disease and 22 patients with Stage II disease; 62.5% were women and 37.5% were men. The median age was 32.4 years (range, 17-74 years). The tumor scores were 0 in 1 patient, I in 5 patients, II in 13 patients, III in 7 patients, IV in 4 patients, and unknown in 10 patients. The International Prognostic Index (IPI) was 0 in 10 patients, I in 26 patients, II in 2 patients, and unknown in 2 patients. All patients were treated with doxorubicin-based chemotherapy, and 35 patients received radiation therapy. For most patients who received radiation therapy, an involved field or a modified-mantle field was used, and a dose of 40 Gy in 20 fractions or 39.6 Gy in 22 fractions was administered. Univariate analysis was performed to identify prognostic factors. RESULTS: The median follow-up in surviving patients was 56 months (range, 19-194 months). The actuarial 5-year relapse-free survival (RFS) rate and overall survival (OS) rate for all patients were 67% and 72%, respectively. Thirty-five patients achieved a complete response; 32 of these patients received radiation therapy. The patterns of failure for the complete responders were as follows: locoregional failure alone for 1 patient (at the margin of the radiation field); distant failure alone for 5 patients; and both locoregional (in-field) and distant failure for 1 patient. There were no failures after 2.5 years. None of the 5 patients who never achieved a complete response had local control, and all died with disease. Only 2 of the 5 completed the planned course of radiation therapy; both had massive mediastinal disease. There was no treatment-related death from the initial chemotherapy or radiation therapy. One patient developed a second malignancy (sarcoma) within the radiation field after 13 years. The tumor score was a significant predictor of RFS (p = 0.016) and OS (p = 0.006), but the IPI did not prove to be a significant predictor. CONCLUSION: We recommend consolidative radiation therapy in view of the excellent local control and the lack of significant toxicity. Modified mantle or involved field appears to be an adequate volume, and 39.6-40 Gy appears to be an adequate dose. The tumor score is a significant prognostic factor.

Molecular response assessed by PCR is the most important factor predicting failure-free survival in indolent follicular lymphoma: update of the MDACC series.

BACKGROUND: We have observed that molecular response, as defined by a PCR-negative status during the first year of therapy, along with beta 2-microglobulin (beta 2M), was the most important variable associated with failure-free survival (FFS) in follicular lymphoma (FL). Herein, we present an update of the previously published MDACC series. PATIENTS AND METHODS: A total of 116 patients (male:female ratio 64:52; median age: 52 years) with indolent FL and BCL-2 rearrangement (at MBR or mcr breakpoints) assessable in peripheral blood (pb) by PCR prior to treatment, and with two or more PCR determinations during the first year, were selected for the present study. RESULTS: Of the 116 patients, 4 who presented with progression and 1 who died of unrelated causes during the first year were excluded from the landmark analysis. One hundred patients (86%) achieved clinical CR and 80 (69%) achieved a negative PCR status within first year. Median FFS was 6.4 years. Five-year FFS was 73% and 28% for molecular responders and nonresponders, respectively (P = 0.001). In spite of this strikingly higher FFS favoring molecular responders, no clearcut plateau was evident in this group. Molecular response assessed in pb (P = 0.001) and serum beta 2M (P < 0.001) were the most important factors to predict FFS in the multivariate analysis. In the subset of patients with normal beta 2M and molecular CR, there was a trend for a plateau in the FFS curve. No significant difference between the groups has been observed so far in terms of survival. CONCLUSIONS: Molecular response assessed in pb using a PCR technique is, along with beta 2M, the most important factor to predict FFS in FL.

Safety of fludarabine, mitoxantrone, and dexamethasone combined with rituximab in the treatment of stage IV indolent lymphoma.

Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA) is an effective agent for the treatment of CD20-positive B-cell lymphomas. Because its toxicities are minimal and do not overlap with the toxicities of standard chemotherapy, it is an appealing agent to use in combination with chemotherapy. Moreover, there is evidence for synergy between rituximab and some chemotherapeutic agents. The combination of fludarabine/ mitoxantrone/dexamethasone (FND) has been a well-tolerated and effective regimen for the treatment of indolent lymphomas. When given together with prophylaxis for Pneumocystis carinii, infectious complications with FND have been modest. We report on preliminary safety data using FND in conjunction with rituximab, along with maintenance alpha interferon. Toxicity has been modest. The concurrent use of rituximab with FND modestly increases neutropenia, but has not resulted in any change in the pattern of infectious or other toxicity that occurs with FND alone.

Real-time 5'-->3' exonuclease-based PCR assay for detection of the t(11;14)(q13;q32).

We describe the usefulness of a real-time polymerase chain reaction (PCR) assay for detection of the t(11;14)(q13;q32), most commonly present in mantle cell lymphoma (MCL). This assay is based on the 5'-->3' exonuclease activity of Taq polymerase, which cleaves an internal probe labeled with a reporter dye at its 5' end and a quencher dye at its 3' end during PCR. The real-time t(11;14) PCR assay was established using DNA from a case of MCL with the t(11;14), amplifiable using conventional PCR and primers specific for the major translocation cluster (MTC) region of the bcl-1 locus and the immunoglobulin heavy chain joining region gene (JH). The specificity was determined by analyzing DNA from 82 cases: 50 MCL, 27 other types of non-Hodgkin lymphoma (NHL), and 5 reactive lymphoid proliferations. The real-time t(11;14) PCR results were correlated with data obtained by a conventional PCR assay. By using the real-time assay, bcl-1 MTC/JH DNA fusion sequences were detected in 25 of 50 MCLs but not in other NHLs or reactive lymphoid proliferations. Concordance between real-time and conventional PCR methods for MCL was 96% and for all samples was 98%. The results demonstrate that this real-time PCR method to detect bcl-1 MTC/JH DNA fusion sequences is specific and reliable. In addition, the results are available immediately following amplification, without standard post-PCR manipulations.

Antibiotic treatment of gastric lymphoma of mucosa-associated lymphoid tissue. An uncontrolled trial.

BACKGROUND: Gastric lymphoma of mucosa-associated lymphoid tissue (MALT) is related to Helicobacter pylori infection and may depend on this infection for growth. OBJECTIVE: To determine the response of gastric MALT lymphoma to antibiotic treatment. DESIGN: Prospective, uncontrolled treatment trial. SETTING: University hospital referral center and three collaborating university and community hospitals. PATIENTS: 34 patients with stage I or stage II N1 gastric MALT lymphoma. INTERVENTION: Two of three oral antibiotic regimens--1) amoxicillin, 750 mg three times daily, and clarithromycin, 500 mg three times daily; 2)tetracycline, 500 mg four times daily, and clarithromycin, 500 mg three times daily; or 3) tetracycline, 500 mg four times daily, and metronidazole, 500 mg three times daily--were administered sequentially (usually in the order written) for 21 days at baseline and at 8 weeks, along with a proton-pump inhibitor (lansoprazole or omeprazole) and bismuth subsalicylate. MEASUREMENTS: Complete remission was defined as the absence of histopathologic evidence of lymphoma on endoscopic biopsy. Partial remission was defined as a reduction in endoscopic tumor stage or 50% reduction in the size of large tumors. RESULTS: 34 patients were followed for a mean (+/-SD) of 41 +/- 16 months (range, 18 to 70 months) after antibiotic treatment. Of 28 H. pylori-positive patients, 14 (50% [95% CI, 31% to 69%]) achieved complete remission, 8 (29%) achieved partial remission (treatment eventually failed in 4 of the 8), and 10 (36% [CI, 19% to 56%]) did not respond to treatment. Treatment failed in all 6 (100% [CI, 54% to 100%]) H. pylori-negative patients. Patients with endoscopic appearance of gastritis (stage I T1 disease) were most likely to achieve complete remission within 18 months. Tumors in the distal stomach were associated with more favorable response than tumors in the proximal stomach. CONCLUSIONS: A subset of H. pylori-positive gastric MALT lymphomas, including infiltrative tumors, may respond to antibiotics. The likelihood of early complete remission seems to be greatest for superficial and distal tumors.

Correlation of bcl-2 rearrangement with clinical characteristics and outcome in indolent follicular lymphoma.

The t(14;18) translocation, which involves the bcl-2 oncogene, occurs in follicular lymphomas (FL) at two common sites: the major breakpoint region (MBR) and the minor cluster region (mcr). The biological and clinical significance of these breakpoints is unknown. The bcl-2 breakpoint site was determined in 247 previously untreated patients (49% men; median age 52 years) with indolent FL (155 grade I, 83 grade II, and 8 grade III) to correlate it with pretreatment characteristics, response, and outcome. The bcl-2 breakpoint site was determined by a polymerase chain reaction method of peripheral blood (all cases), bone marrows (149 cases), and fresh lymph node biopsy specimens (68 cases). The breakpoint site occurred at MBR in 175 cases (71%) and at mcr in 27 (11%). In 45 cases (18%), no breakpoint was detected (germline). No significant relationship was found between the rearrangements and the expression of BLC-2 and BAX proteins. Patients' germline for MBR and mcr tended to present more frequently with stage IV disease and higher beta2-microglobulin (beta2M) levels, whereas mcr-rearranged patients presented more frequently with early stage and normal beta2M. The complete response rate of germline patients was significantly lower than that of MBR and mcr patients. An estimated 3-year failure-free survival (FFS) for mcr, MBR, and germline cases was 95%, 76%, and 57%, respectively (P <.001). The bcl-2 breakpoint site was independent of serum beta2M and lactate dehydrogenase in its correlation with FFS. In conclusion, the bcl-2 rearrangement site is an important prognostic factor in indolent FL, useful to identify patients who may require different treatment.