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Waldenström macroglobulinemia is a B-cell malignancy with lymphoplasmacytic infiltration in the bone marrow or lymphatic tissue and a monoclonal immunoglobulin M protein (IgM) in the serum. It is incurable with current therapy, and the decision to treat patients as well as the choice of treatment can be complex. Using a risk-adapted approach, we provide recommendations on timing and choice of therapy. Patients with smoldering or asymptomatic Waldenström macroglobulinemia and preserved hematologic function should be observed without therapy. Symptomatic patients with modest hematologic compromise, IgM-related neuropathy that requires therapy, or hemolytic anemia unresponsive to corticosteroids should receive standard doses of rituximab alone without maintenance therapy. Patients who have severe constitutional symptoms, profound hematologic compromise, symptomatic bulky disease, or hyperviscosity should be treated with the DRC (dexamethasone, rituximab, cyclophosphamide) regimen. Any patient with symptoms of hyperviscosity should first be treated with plasmapheresis. For patients who experience relapse after a response to initial therapy of more than 2 years' duration, the original therapy should be repeated. For patients who had an inadequate response to initial therapy or a response of less than 2 years' duration, an alternative agent or combination should be used. Autologous stem cell transplant should be considered in all eligible patients with relapsed disease. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To determine the long-term outcome of patients presenting with synchronous lymphoma and severe liver dysfunction and to describe the outcome of patients treated with initial mechlorethamine-based therapy used as a bridge to more conventional chemotherapy. PATIENTS AND METHODS: We reviewed the clinical course of all patients diagnosed as having lymphoma who presented with severe liver dysfunction and received intravenous mechlorethamine between September 1988 and February 2003 at the Mayo Clinic in Rochester, Minn. RESULTS: Forty-one patients were identified, 33 (80%) of whom had newly diagnosed, previously untreated lymphoma. Thirty-seven (90%) had non-Hodgkin lymphoma, and 4 (10%) had Hodgkin disease. Thirty-four patients (83%) had stage IV disease, and 31 (84%) of 37 had an intermediate-high International Prognostic Index. The median total bilirubin level before therapy was 10.7 mg/dL (range, 2.5-30.2 mg/dL), and the median alkaline phosphatase level was 982 U/L (range, 233-3415 U/L). In addition to mechlorethamine, 34 patients (83%) received concomitant corticosteroids, and 12 (29%) received concomitant rituximab. Twenty-two patients (54%) had sufficient improvement in liver function to receive subsequent standard chemotherapy. Nine patients (22%) are alive and disease-free at a median of 31 months (range, 4 to > or = 87 months) after mechlorethamine treatment. Factors associated with improved overall survival included improvement in bilirubin levels (P < .001) and receiving subsequent standard chemotherapy (P = .001). CONCLUSION: Mechlorethamine, high-dose corticosteroids, and rituximab are useful therapeutic interventions for this unique group of patients with lymphoma and severe liver dysfunction. Substantial clinical improvement and long-term survival are possible. [ABSTRACT FROM AUTHOR]

The authors report a case of a 69-year-old woman with multiple sclerosis treated with fingolimod for duration of over one year who subsequently developed cutaneous large B cell lymphoma. There are few reported cases of lymphoma associated with fingolimod treatment for multiple sclerosis, but rates are higher than expected in the general population. The authors hope to promote awareness of the potential risk of this medication so that more diligent disease surveillance can be performed by both prescribing practitioners of fingolimod and their patients who receive it., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Importance: Waldenström macroglobulinemia (WM), an IgM-associated lymphoplasmacytic lymphoma, has witnessed several practice-altering advances in recent years. With availability of a wider array of therapies, the management strategies have become increasingly complex. Our multidisciplinary team appraised studies published or presented up to December 2015 to provide consensus recommendations for a risk-adapted approach to WM, using a grading system., Observations: Waldenström macroglobulinemia remains a rare, incurable cancer, with a heterogeneous disease course. The major classes of effective agents in WM include monoclonal antibodies, alkylating agents, purine analogs, proteasome inhibitors, immunomodulatory drugs, and mammalian target of rapamycin inhibitors. However, the highest-quality evidence from rigorously conducted randomized clinical trials remains scant., Conclusions and Relevance: Recognizing the paucity of data, we advocate participation in clinical trials, if available, at every stage of WM. Specific indications exist for initiation of therapy. Outside clinical trials, based on the synthesis of available evidence, we recommend bendamustine-rituximab as primary therapy for bulky disease, profound hematologic compromise, or constitutional symptoms attributable to WM. Dexamethasone-rituximab-cyclophosphamide is an alternative, particularly for nonbulky WM. Routine rituximab maintenance should be avoided. Plasma exchange should be promptly initiated before cytoreduction for hyperviscosity-related symptoms. Stem cell harvest for future use may be considered in first remission for patients 70 years or younger who are potential candidates for autologous stem cell transplantation. At relapse, retreatment with the original therapy is reasonable in patients with prior durable responses (time to next therapy ≥3 years) and good tolerability to previous regimen. Ibrutinib is efficacious in patients with relapsed or refractory disease harboring MYD88 L265P mutation. In the absence of neuropathy, a bortezomib-rituximab-based option is reasonable for relapsed or refractory disease. In select patients with chemosensitive disease, autologous stem cell transplantation should be considered at first or second relapse. Everolimus and purine analogs are suitable options for refractory or multiply relapsed WM. Our recommendations are periodically updated as new, clinically relevant information emerges.

Histological transformation (HT) of follicular lymphoma (FL) to an aggressive lymphoma after chemotherapy remains a key issue. The incidence of HT after radioimmunotherapy (RIT) is unknown. This single institution study analysed the risk of HT in FL after treatment with yttrium-90 ibritumomab tiuxetan in 115 consecutive patients treated during 1987-2012. RIT was administered for progressive FL in 111 (97%) patients and as first-line therapy in the remaining 4. 28% (n = 32) had HT, occurring at a median of 60 months from diagnosis and 20 months after RIT. 48% (12/25) of patients who received fludarabine developed HT. The estimated 10-year risk of HT in the fludarabine and non-fludarabine groups was 67% and 26% respectively (P = 0·015). Only prior fludarabine was significantly associated with predicting the risk of HT after RIT. 8% (9/115) of patients developed therapy-related myelodysplastic syndrome/acute myeloid leukaemia (tMDS/AML) at a median of 41·4 months (range, 5-89). The estimated 10-year risk of tMDS/AML in non-fludarabine treated patients (n = 90) versus fludarabine treated (n = 25) was 13% and 29%, respectively. The estimated overall risk of FL undergoing HT at 10 years without fludarabine exposure appears similar to patients reported in the literature that have not received RIT. Patients with prior purine-analogue therapy are at significantly higher risk of HT., (© 2017 John Wiley & Sons Ltd.)

Relapsed indolent lymphoma often becomes refractory to standard chemoimmunotherapy and requires new therapeutic strategies. Targeting the PI3K/mTOR pathway in several types of lymphoma has shown preclinical and clinical efficacy providing the rationale to test this strategy in the treatment of relapsed/refractory indolent lymphomas. We investigated in a phase II open label clinical trial the efficacy and safety of single agent everolimus, an inhibitor of mTORC1, in patients with relapsed/refractory indolent lymphomas. Eligible patients received oral everolimus 10 mg daily on a 28 day-cycle schedule. The primary endpoint was to evaluate the overall response rate (ORR) and safety of single-agent everolimus in this patient population. Fifty-five patients with indolent lymphoma were accrued. The median age was 67 years (range: 33-85) with a median of five prior therapies (range: 1-10). The ORR was 35% (19/55; 95% CI: 24-48%), with complete response unconfirmed in 4% (2/55), and partial response in 31% (17/55). The ORR was 61% (14/23) in the patients with FL. The median time to response was 2.3 months (range: 1.4-14.1), median duration of response of 11.5 months (95%-CI: 5.7-30.4), and a median progression-free survival of 7.2 months (95%-CI: 5.5-12.5). The most common toxicity was hematologic with grades 3-4 anemia, neutropenia, and thrombocytopenia documented in 15% (8/55), 22% (12/55), and 33% (18/55), respectively. There were no cases of febrile neutropenia, and eight patients discontinued therapy because of adverse events. Everolimus monotherapy is a valid therapeutic option in the relapsed and/or refractory indolent non-Hodgkin lymphoma patients and is well tolerated., (© 2017 Wiley Periodicals, Inc.)

Background: The PI3K-mTORC pathway is upregulated in diffuse large B-cell lymphoma (DLBCL) and can be targeted with the mTOR complex 1 (mTORC1) inhibitor everolimus. Everolimus has activity in relapsed DLBCL. These data provide the rationale to combine everolimus with standard treatment for DLBCL of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone delivered in a 21-day cycle (R-CHOP-21) for six cycles., Methods: We did a phase 1 and feasibility study (NCCTG 1085) of oral everolimus 10 mg/day plus R-CHOP-21 in patients aged at least 18 years with new, untreated, CD20-positive DLBCL (stages II-IV) in the NCCTG (Alliance) National Cancer Institute Cooperative Group (USA). Patients received standard R-CHOP-21 (intravenous rituximab 375 mg/m(2), intravenous cyclophosphamide 750 mg/m(2), intravenous doxorubicin 50 mg/m(2), and intravenous vincristine 1·4 mg/m(2) [maximum 2·0 mg] all on day 1 of the 21-day cycle; and oral prednisone 100 mg/m(2) each day on days 1-5 of the cycle) for six cycles with scheduled subcutaneous pegfilgrastim 6 mg on day 2 of each cycle. We tested two schedules: everolimus given in the fasting state either on days 1-10 or days 1-14 of the R-CHOP cycle. The primary endpoint of the phase 1 portion of this study was to establish the maximum tolerated dose of everolimus that could be combined with R-CHOP-21. The primary endpoint of the feasibility portion of the study was to determine the feasibility of the regimen, which was assessed by determining the rate of significant toxicity. Secondary endpoints were the proportion of patients who achieved an overall response, a complete response, event-free survival at 12 months and 24 months from enrolment, progression-free survival, and overall survival; relapse of DLBCL; and duration of response. We deemed patients as assessable for the primary endpoint in the phase 1 portion if they completed the first cycle as planned. In the feasibility portion, all patients who received at least one dose of everolimus were included. This trial is registered with ClinicalTrials.gov, number NCT01334502., Findings: Between March 21, 2012, and Sept 15, 2014, we enrolled 26 patients into the study. Two were ineligible, therefore results are presented for 24 eligible patients. Nine patients were enrolled into the phase 1 portion of the trial (three given everolimus on days 1-10, and six given everolimus on days 1-14) without any dose-limiting toxicities; therefore, everolimus 10 mg/day given on days 1-14 with R-CHOP-21 was tested in 15 additional patients for a total of 24. One (5%, 95% CI 0-24%) of 21 patients had a toxicity during the feasibility phase-a treatment delay of 12 days due to grade 3 hypokalaemia possibly related to everolimus. The median follow-up was 21·5 months (IQR 17-29). 23 (96%, 95% CI 79-100%) of 24 patients achieved an overall response, and all 23 (96%, 79-100%) also attained a complete metabolic response by PET. The remaining patient withdrew consent after in cycle 1 and attained a complete response with R-CHOP alone. All 24 (100%) patients met 12-month event-free survival, and nine had sufficient follow-up data to be event-free at 24 months. None of the 24 patients had died by the last follow-up (March 30, 2016), and none had had a relapse with DLBCL. Because no events occurred during the study or follow-up, we were unable to assess the duration of response or progression-free survival. The most common grade 3-4 adverse events were haematological; the most common of these was grade 4 neutropenia in 18 (75%) of 24 patients. Five (21%) of 24 had grade 3 febrile neutropenia., Interpretation: The mTORC1 inhibitor everolimus given for 14 days in combination with R-CHOP-21 for patients with DLBCL is safe. These findings suggest that drugs that target the PI3K-mTORC pathway add benefit when combined with standard R-CHOP. The everolimus with R-CHOP regimen should be tested against standard R-CHOP alone in a randomised trial, to support the benefits of this novel combination noted in this study., Funding: National Cancer Institute of the US National Institutes of Health., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A number of reports have shown a propensity of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) to transform into diffuse large B-cell lymphoma (DLBCL). Long-term data on the incidence and outcomes of transformed NLPHL are lacking. A comprehensive analysis of the actively maintained Mayo Clinic Lymphoma Database was performed. Between 1970 and 2011, 222 consecutive adult patients with new untreated NLPHL were identified. Median age at diagnosis was 40 years, and 146 (66%) were males. The median follow-up was 16 years. Seventeen patients (7.6%) developed a transformation to DLBCL. The median time to transformation was 35 months (range, 6-268 months). Based on the observed 17 transformations during 2304 patient-years of follow-up, the rate of transformation was 0.74 per 100 patient-years. In a multivariate analysis, use of any prior chemotherapy ( ITALIC! P= .04) and splenic involvement ( ITALIC! P= .03) were significantly associated with increased risk of transformation. The 5-year overall survival (OS) in those with transformed disease was 76.4%, and transformation did not adversely affect OS when compared with patients who did not experience transformation. In this large single-institution cohort with long-term follow-up, the risk of transformation was lower than that observed in other low-grade lymphomas., (© 2016 by The American Society of Hematology.)

Everolimus is an oral agent that targets the mammalian target of rapamycin (mTOR) pathway. This study investigated mTOR pathway activation in T-cell lymphoma (TCL) cell lines and assessed antitumor activity in patients with relapsed/refractory TCL in a phase 2 trial. The mTOR pathway was activated in all 6 TCL cell lines tested and everolimus strongly inhibited malignant T-cell proliferation with minimal cytotoxic effects. Everolimus completely inhibited phosphorylation of ribosomal S6, a raptor/mTOR complex 1 (mTORC1) target, without a compensatory activation of the rictor/mTORC2 target Akt (S475). In the clinical trial, 16 patients with relapsed TCL were enrolled and received everolimus 10 mg by mouth daily. Seven patients (44%) had cutaneous (all mycosis fungoides); 4 (25%) had peripheral T cell not otherwise specified; 2 (13%) had anaplastic large cell; and 1 each had extranodal natural killer/T cell, angioimmunoblastic, and precursor T-lymphoblastic leukemia/lymphoma types. The overall response rate was 44% (7/16; 95% confidence interval [CI]: 20% to 70%). The median progression-free survival was 4.1 months (95% CI, 1.5-6.5) and the median overall survival was 10.2 months (95% CI, 2.6-44.3). The median duration of response for the 7 responders was 8.5 months (95% CI, 1.0 to not reached). These studies indicate that everolimus has antitumor activity and provide proof-of-concept that targeting the mTORC1 pathway in TCL is clinically relevant. This trial was registered at www.clinicaltrials.gov as #NCT00436618., (© 2015 by The American Society of Hematology.)

The natural history of limited-stage peripheral T-cell lymphoma (PTCL) remains poorly defined. Therefore, we examined outcomes in patients with the most common PTCL subtypes (PTCL, not otherwise specified [PTCL, NOS], angioimmunoblastic T-cell lymphoma [AITL], anaplastic large cell lymphoma [ALCL]) and limited-stage disease. In this retrospective, multicenter study, 75 patients with limited-stage disease were identified. The median event-free survival (EFS) and overall survival (OS) observed were 2.1 and 6.5 years, respectively. In a landmark analysis excluding patients with primary refractory disease, no significant benefit was observed for patients undergoing consolidative radiation therapy. With the exception of patients undergoing salvage hematopoietic stem cell transplant, survival following disease relapse or progression was poor, thus highlighting the need for improved therapeutic strategies.

The serum immunoglobulin free light chain (FLC) assay quantitates free kappa (κ) and lambda (λ) light chains. FLC elevations in patients with diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma (HL), and chronic lymphocytic leukemia (CLL) are associated with an inferior survival. These increases in FLC can be monoclonal (as in myeloma) or polyclonal. The goal was to estimate the frequency of these elevations within distinct types of B-cell and T-cell non-Hodgkin lymphoma (NHL) and whether the FLC measurements are associated with event-free survival (EFS). We studied serum for FLC abnormalities using normal laboratory reference ranges to define an elevated κ or λ FLC. Elevations were further classified as polyclonal or monoclonal. Four hundred ninety-two patients were studied: 453 B-cell and 34 T-cell NHL patients. Twenty-nine % (142/453) of patients had an elevated FLC of which 10% were monoclonal elevations. Within B-cell NHL, FLC abnormalities were most common in lymphoplasmacytic (79%), mantle cell (68%), and lymphomas of mucosa associated lymphoid tissue (31%); they were least common in follicular (15%). The hazard ratio (HR) for EFS in all patients was 1.41 (95% CI; 1.11-1.81); in all B-cell NHL the HR was 1.44 (95% CI 1.11-1.96); in all T-cell NHL the HR was 1.17 (95% CI 0.55-2.49). FLC abnormalities predicted an inferior OS (HR = 2.75, 95% CI: 1.93-3.90, P < 0.0001). The serum FLC assay is useful for prognosis in both B-cell and T-cell types of NHL. In B-cell NHL further discrimination between a monoclonal and polyclonal elevation may be helpful and should be analyzed in prospective clinical trials., (© 2014 Wiley Periodicals, Inc.)

A limitation of the prognostic factor peripheral blood absolute lymphocyte/monocyte ratio (ALC/AMC) at diagnosis in diffuse large B-cell lymphoma (DLBCL) is its inability to sequentially assess the host/tumor microenvironment interaction and clinical outcomes during treatment. Therefore, we studied the ALC/AMC ratio at each rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) cycle as a predictor for survival. We studied 107 consecutive patients with DLBCL diagnosed, treated only with R-CHOP and followed at the Mayo Clinic. Unsupervised hierarchical clustering identified four clusters based on the patterns of ALC/AMC ratio recovery during cycles. The most inferior survival was seen in the cluster with ALC/AMC ratio < 1.1 in all cycles. By multivariate analysis, ALC/AMC ratio < 1.1 during all cycles was an independent predictor for inferior overall survival and progression-free survival. The ALC/AMC ratio during R-CHOP cycles predicts survival and provides a platform to develop therapeutic modalities to manipulate the ALC/AMC ratio during R-CHOP cycles to improve DLBCL clinical outcomes.

Peripheral T-cell lymphomas (PTCLs) are a heterogenous group of aggressive non-Hodgkin's lymphomas that are incurable in the majority of patients with current therapies. Outcomes associated with anthracycline-based therapies are suboptimal, but remain the standard of care for most patients, even though the benefits of this approach remain uncertain. This study retrospectively examined outcomes in a cohort of North American PTCL patients treated with both anthracycline- and nonanthracycline-containing regimens. The incorporation of anthracycline-containing regimens was associated with improved progression-free survival (PFS) and overall survival (OS). Patients treated with nonanthracycline-containing regimens were more likely to have high-risk features and were less likely to undergo high-dose therapy and stem cell transplantation. However, anthracycline use remained an independent predictor of improved PFS and OS when adjusting for these confounding variables. Anthracycline-based regimens and consolidation with high-dose therapy and autologous stem cell transplantation in appropriately selected patients remains a viable option for patients unable to participate in a clinical trial. Long-term disease-free survival is not optimal, highlighting the need for an improved understanding of disease pathogenesis, and the development of novel therapeutic strategies.

Purpose: This study sought to characterize transformation incidence and outcome for patients with follicular lymphoma (FL) in a prospective observational series begun after diffusion of rituximab use., Patients and Methods: Patients with newly diagnosed FL were prospectively enrolled onto the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource from 2002 to 2009. Patients were actively followed for re-treatment, clinical or pathologic transformation, and death. Risk of transformation was analyzed via time to transformation by using death as a competing risk., Results: In all, there were 631 patients with newly diagnosed grade 1 to 3a FL who had a median age at enrollment of 60 years. At a median follow-up of 60 months (range, 11 to 110 months), 79 patients had died, and 60 patients developed transformed lymphoma, of which 51 were biopsy proven. The overall transformation rate at 5 years was 10.7%, with an estimated rate of 2% per year. Increased lactate dehydrogenase was associated with increased risk of transformation. Transformation rate at 5 years was highest in patients who were initially observed and lowest in patients who initially received rituximab monotherapy (14.4% v 3.2%; P = .021). Median overall survival following transformation was 50 months and was superior in patients with transformation greater than 18 months after FL diagnosis compared with patients with earlier transformation (5-year overall survival, 66% v 22%; P < .001)., Conclusion: Follicular transformation rates in the immunochemotherapy era are similar to risk of death without transformation and may be lower than reported in older series. Post-transformation prognosis is substantially better than described in older series. Initial management strategies may influence the risk of transformation.

Background: Perforation is a serious life-threatening complication of lymphomas involving the gastrointestinal (GI) tract. Although some perforations occur as the initial presentation of GI lymphoma, others occur after initiation of chemotherapy. To define the location and timing of perforation, a single-center study was carried out of all patients with GI lymphoma., Patients and Methods: Between 1975 and 2012, 1062 patients were identified with biopsy-proven GI involvement with lymphoma. A retrospective chart review was undertaken to identify patients with gut perforation and to determine their clinicopathologic features., Results: Nine percent (92 of 1062) of patients developed a perforation, of which 55% (51 of 92) occurred after chemotherapy. The median day of perforation after initiation of chemotherapy was 46 days (mean, 83 days; range, 2-298) and 44% of perforations occurred within the first 4 weeks of treatment. Diffuse large B-cell lymphoma (DLBCL) was the most common lymphoma associated with perforation (59%, 55 of 92). Compared with indolent B-cell lymphomas, the risk of perforation was higher with aggressive B-cell lymphomas (hazard ratio, HR = 6.31, P < 0.0001) or T-cell/other types (HR = 12.40, P < 0.0001). The small intestine was the most common site of perforation (59%)., Conclusion: Perforation remains a significant complication of GI lymphomas and is more frequently associated with aggressive than indolent lymphomas. Supported in part by University of Iowa/Mayo Clinic SPORE CA97274 and the Predolin Foundation.

Radioimmunotherapy (RIT) for relapsed indolent non-Hodgkin lymphoma produces overall response rates (ORR) of 80% with mostly partial remissions. Synthetic CpG oligonucleotides change the phenotype of malignant B-cells, are immunostimulatory, and can produce responses when injected intratumorally and combined with conventional radiation. In this phase I trial, we tested systemic administration of both CpG and RIT. Eligible patients had biopsy-proven previously treated CD20+ B-cell NHL and met criteria for RIT. Patients received rituximab 250 mg/m(2) days 1,8, and 15; (111) In-ibritumomab tiuxetan days 1, 8; CpG 7909 days 6, 13, 20, 27; and 0.4 mCi/kg of (90) Y-ibritumomab tiuxetan day 15. The doses of CpG 7909 tested were 0.08, 0.16, 0.32 (six patients each) and 0.48 mg/kg (12 patients) IV over 2 hr without dose limiting toxicity. The ORR was 93% (28/30) with 63% (19/30) complete remission (CR); median progression free survival of 42.7 months (95% CI 18-NR); and median duration of response (DR) of 35 months (4.6-76+). Correlative studies demonstrated a decrease in IL10 and TNFα, and an increase in IL1β, in response to therapy. CpG 7909 at a dose of 0.48 mg/kg is safe with standard RIT and produces a high CR rate and long DR; these results warrant confirmation., (Copyright © 2013 Wiley Periodicals, Inc.)

The peripheral blood absolute lymphocyte/monocyte count ratio at diagnosis (ALC/AMC-DX) predicts survival in classical Hodgkin lymphoma (cHL). However, a limitation of the ALC/AMC-DX is the inability to assess sequentially the host/tumor interaction during treatment. Therefore, we retrospectively examined the ALC/AMC ratio, as a surrogate marker of host immunity (ALC) and tumor microenvironment (AMC), at each adriamycin, bleomycin, vinblastine and dacarbazine treatment cycle as a predictor for clinical outcomes. From 1990 until 2008, 190 cHL patients were diagnosed, treated and followed at Mayo Clinic Rochester and qualified for the study. The ALC/AMC ratio at each treatment cycle was a predictor for overall survival (OS) and progression-free survival (PFS). An ALC/AMC ratio 1.1 versus ALC/AMC <1.1 during treatment cycles was an independent predictor for OS (hazard ratio (HR)=0.14; 95% confidence interval (CI): 0.04-0.40; P<0.0002) and for PFS (HR=0.19; 95% CI: 0.05-0.82; P<0.03). The ALC/AMC ratio during treatment cycles is a predictor for survival and provides a platform to develop therapeutic modalities to manipulate the ALC/AMC ratio during chemotherapy to improve clinical outcomes in cHL.

The absolute monocyte/lymphocyte count prognostic score (AMC/ALC score) has not been directly compared with the cell of origin (COO) to predict overall survival (OS) and progression-free survival (PFS) in diffuse large B-cell lymphoma (DLBCL). Thus, we retrospectively examined a new cohort of 99 patients with DLBCL treated from 2008 to 2010, (1) to validate whether AMC/ALC score affects survival, (2) to investigate whether AMC/ALC score is independent of COO to predict survival and (3) to assess whether AMC/ALC score can further stratify clinical outcomes by COO. By univariate analysis, the AMC/ALC score was a predictor for OS and PFS. On multivariate analysis performed including the COO and the International Prognostic Index, AMC/ALC score remained an independent predictor for OS and PFS. The AMC/ALC score was able to further stratify DLBCL clinical outcomes by COO. The AMC/ALC score was independent of COO and added to its ability to identify patients with high-risk disease.

The pathological background in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) consists of lymphocytes and histocytes. This study analysed the peripheral blood absolute lymphocyte count/absolute monocyte count ratio at diagnosis (ALC/AMC-DX) on the impact of survival in NLPHL. One hundred and three consecutive NLPHL patients that were followed at Mayo Clinic from 1974 to 2010 were included in the study. Receiver operating characteristic and area under the curve were used for ALC/AMC-DX cut-off value analysis and proportional-hazards models were used to compare survival based on the ALC/AMC-DX ratio. With a median follow-up of 8·9 years (range: 0·3-31 years), an ALC/AMC-DX ≥2·1 was the best cut-off value for survival with an area under the curve of 0·82, a sensitivity of 70% and specificity of 84%. After adjusting for the International Prognostic Score (IPS), ALC/AMC-DX remained an independent prognostic factor for overall survival [Hazard Ratio (HR), 0·33, 95% confidence interval (CI), 0·15-0·71%, P < 0·004]; lymphoma-specific survival (HR, 0·05; 95%CI, 0·01-0·68%, P < 0·002); progression-free survival (HR, 0·30; 95%CI, 0·14-0·60%, P < 0·006), and time to progression (HR, 0·06, 95%CI, 0·04-0·30%, P < 0·004). ALC/AMC-DX is a low cost, already standarized, biomarker to predict clinical outcomes in NLPHL., (© 2012 Blackwell Publishing Ltd.)

Follicular lymphoma is characterized by a highly variable clinical course ranging from early transformation and disease-related mortality to prolonged periods of disease stability or even spontaneous remissions. This clinical heterogeneity is likely explained by differences in the tumor microenvironment, including variable infiltration by monocyte-derived cells. Therefore, we examined the absolute monocyte count obtained from a standard complete blood count with differential at the time of diagnosis as a prognostic factor in a cohort of patients with follicular lymphoma (n = 355) treated at a single institution between 1998 and 2007. We found that the absolute monocyte count at diagnosis is associated with overall survival, independent of the Follicular Lymphoma International Prognostic Index (FLIPI). Furthermore, the absolute monocyte count improved the ability to identify high-risk patients when used in conjunction with the FLIPI. These results further support the central role of non-neoplastic myeloid-lineage cells in follicular lymphoma biology.

Background: Lymphopenia and tumor-associated macrophages are negative prognostic factors for survival in classical Hodgkin's lymphoma. We, therefore, studied whether the peripheral blood absolute lymphocyte count/absolute monocyte count ratio at diagnosis affects survival in classical Hodgkin's lymphoma., Design and Methods: We studied 476 consecutive patients with classical Hodgkin's lymphoma followed at the Mayo Clinic from 1974 to 2010. Receiver operating characteristic curves and area under the curve were used to determine cut-off values for the absolute lymphocyte count/absolute monocyte count ratio at diagnosis, while proportional hazards models were used to compare survival based on the absolute lymphocyte count/absolute monocyte count ratio at diagnosis., Results: The median follow-up period was 5.6 years (range, 0.1-33.7 years). An absolute lymphocyte count/absolute monocyte count ratio at diagnosis of 1.1 or more was the best cut-off value for survival with an area under the curve of 0.91 (95% confidence interval, 0.86 to 0.96), a sensitivity of 90% (95% confidence interval, 85% to 96%) and specificity of 79% (95% confidence interval, 73% to 88%). Absolute lymphocyte count/absolute monocyte count ratio at diagnosis was an independent prognostic factor for overall survival (hazard ratio, 0.18; 95% confidence interval, 0.08 to 0.38, P<0.0001); lymphoma-specific survival (hazard ratio, 0.10; 95% confidence interval, 0.04 to 0.25, P<0.0001); progression-free survival (hazard ratio, 0.35; 95% confidence interval, 0.18 to 0.66, P<0.002) and time to progression (hazard ratio, 0.27; 95% confidence interval, 0.17 to 0.57, P<0.0006)., Conclusions: The ratio of absolute lymphocyte count/absolute monocyte count at diagnosis is an independent prognostic factor for survival and provides a single biomarker to predict clinical outcomes in patients with classical Hodgkin's lymphoma.

A phase 2 study of the oral farnesyltransferase inhibitor tipifarnib was conducted in 93 adult patients with relapsed or refractory lymphoma. Patients received tipifarnib 300 mg twice daily on days 1-21 of each 28-day cycle. The median number of prior therapies was 5 (range, 1-17). For the aggressive B-cell, indolent B-cell, and T-cell and Hodgkin lymphoma (HL/T) groups, the response rates were 17% (7/42), 7% (1/15), and 31% (11/36), respectively. Of the 19 responders, 7 were diffuse large B-cell non-Hodgkin lymphoma (NHL), 7 T-cell NHL, 1 follicular grade 2, and 4 HL. The median response duration for the 19 responders was 7.2 months (mean, 15.8 months; range, 1.8-62), and 5 patients in the HL/T group are still receiving treatment at 29-64+ months. The grade 3/4 toxicities observed were fatigue and reversible myelosuppression. Correlative studies suggest that Bim and Bcl-2 should be examined as potential predictors of response in future studies. These results indicate that tipifarnib has activity in lymphoma, particularly in heavily pretreated HL/T types, with little activity in follicular NHL. In view of its excellent toxicity profile and novel mechanism of action, further studies in combination with other agents appear warranted. This trial is registered at www.clinicaltrials.gov as #NCT00082888.

Purpose: To assess the efficacy and toxicity of chemotherapy consisting of cyclophosphamide, doxorubicin (Adriamycin), vincristine, and dexamethasone (CHOD) plus bis-chloronitrosourea (BCNU), cytosine arabinoside, and methotrexate (BVAM) followed by whole-brain irradiation (WBRT) for patients with primary central nervous system lymphoma (PCNSL)., Methods and Materials: Patients 70 years old and younger with newly diagnosed, biopsy-proven PCNSL received one cycle of CHOD followed by two cycles of BVAM. Patients then received WBRT, 30.6 Gy, if a complete response was evoked, or 50.4 Gy if the response was less than complete; both doses were given in 1.8-Gy daily fractions. The primary efficacy endpoint was 1-year survival., Results: Thirty-six patients (19 men, 17 women) enrolled between 1995 and 2000. Median age was 60.5 years (range, 34 to 69 years). Thirty (83%) patients had baseline Eastern Cooperative Oncology Group performance scores of 0 to 1. All 36 patients were eligible for survival and response evaluations. Median time to progression was 12.3 months, and median survival was 18.5 months. The percentages of patients alive at 1, 2, and 3 years were 64%, 36%, and 33%, respectively. The best response was complete response in 10 patients and immediate progression in 7 patients. Ten (28%) patients had at least one grade 3 or higher neurologic toxicity., Conclusions: This regimen did improve the survival of PCNSL patients but also caused substantial toxicity. The improvement in survival is less than that reported with high-dose methotrexate-based therapies., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Despite the use of modern immunochemotherapy regimens, almost 50% of patients with diffuse large-B-cell lymphoma will relapse. Current prognostic models, including the International Prognostic Index, incorporate patient and tumor characteristics. In contrast, recent observations show that variables related to host adaptive immunity and the tumor microenvironment are significant prognostic variables in non-Hodgkin lymphoma. Therefore, we retrospectively examined the absolute monocyte and lymphocyte counts as prognostic variables in a cohort of 366 diffuse large-B-cell lymphoma patients who were treated between 1993 and 2007 and followed at a single institution. The absolute monocyte and lymphocyte counts in univariate analysis predicted progression-free and overall survival when analyzed as continuous and dichotomized variables. On multivariate analysis performed with factors included in the IPI, the absolute monocyte and lymphocyte counts remained independent predictors of progression-free and overall survival. Therefore, the absolute monocyte and lymphocyte counts were combined to generate a prognostic score that identified patients with an especially poor overall survival. This prognostic score was independent of the IPI and added to its ability to identify high-risk patients.

CCND1-IGH@ translocation is considered pathognomonic of mantle cell lymphoma (MCL), as this distinct chromosomal abnormality has not been reported in any other subtypes of mature B-cell lymphoma. Despite this unifying cytogenetic feature, MCL encompasses 2 distinct groups: the usual MCLs with an overall survival of 3 to 5 years and the so-called "indolent non-nodal mantle cell lymphomas (INNMCLs)." The latter group of MCLs has quite distinctive clinical features, including frequent neoplastic lymphocytosis, absent peripheral lymphadenopathy, and indolent clinical courses. The clinical, biological, and molecular characteristics of INNMCL are still not well understood. Herein, we report a patient with clinical and cytogenetic features of INNMCL with overlapping morphologic and immunophenotypic features resembling hairy cell leukemia (HCL). After failing the chemotherapeutic regimen for MCL, he received a HCL-directed therapy and achieved durable response. This case suggests that CCND1-IGH@ may rarely occur in other mature B-cell neoplasms such as HCL. Further clinicopathologic studies of the so-called "INNMCL" are warranted.

Purpose: The serum free light chain (FLC) assay quantitates free kappa (κ) and free lambda (λ) immunoglobulin light chains. This assay has prognostic value in plasma cell proliferative disorders. There are limited data on serum FLC in B-cell malignancies., Patients and Methods: The association of pretreatment FLC with event-free survival (EFS) and overall survival (OS) in diffuse large B-cell lymphoma (DLBCL) was evaluated in 76 patients from the North Central Cancer Treatment Group trial N0489 (NCT00301821) and 219 patients from the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource (MER). Published reference ranges were used to define an elevated FLC or an abnormal κ:λ FLC ratio., Results: Elevated FLC or abnormal κ:λ FLC ratio was present in 32% and 14% of patients, respectively. Patients with elevated FLC had an inferior OS and EFS in both cohorts compared with patients with normal FLC (N0489: EFS hazard ratio [HR], 3.06; OS HR, 3.16; both P < .02; MER: EFS HR, 2.42; OS HR, 3.40; both P < .001; combined EFS HR, 2.57; OS HR, 3.74; both P < .001). All associations remained significant for EFS and OS after adjusting for the International Prognostic Index (IPI). Abnormal κ:λ FLC ratio was modestly associated with outcome in the combined group (EFS HR, 1.61; OS HR, 1.67; both P = .07), but not in patients without corresponding elevated κ or λ. Elevated FLC was the strongest predictor of outcome in multivariable models with the IPI components., Conclusion: Increased serum FLC is an independent, adverse prognostic factor for EFS and OS in DLBCL and warrants further evaluation as a biomarker in DLBCL.

The phosphatidylinositol 3-kinase signal transduction pathway members are often activated in tumor samples from patients with non-Hodgkin's lymphoma (NHL). Everolimus is an oral agent that targets the raptor mammalian target of rapamycin (mTORC1). The goal of this trial was to learn the antitumor activity and toxicity of single-agent everolimus in patients with relapsed/refractory aggressive NHL. Patients received everolimus 10 mg PO daily. Response was assessed after two and six cycles, and then every three cycles until progression. A total of 77 patients with a median age of 70 years were enrolled. Patients had received a median of three previous therapies and 32% had undergone previous transplant. The overall response rate (ORR) was 30% (95% confidence interval: 20-41%), with 20 patients achieving a partial remission and 3 a complete remission unconfirmed. The ORR in diffuse large B cell was 30% (14/47), 32% (6/19) in mantle cell and 38% (3/8) in follicular grade 3. The median duration of response was 5.7 months. Grade 3 or 4 anemia, neutropenia and thrombocytopenia occurred in 14, 18 and 38% of patients, respectively. Everolimus has single-agent activity in relapsed/refractory aggressive NHL and provides proof-of-concept that targeting the mTOR pathway is clinically relevant.

A specific predictor during routine follow-up to ascertain risk for relapse after standard chemotherapy in non-Hodgkin's lymphoma (NHL) has not been identified. Thus, we studied absolute lymphocyte count (ALC) as a marker of poststandard chemotherapy (rituximab, cyclophosphamide, adriamycin, vincristine and prednisone (R-CHOP)) NHL relapse in patients with diffuse large B-cell lymphoma (DLBCL). ALC was obtained at the time of confirmed relapse and at last follow-up. From 2000 until 2006, 149 consecutive DLBCL patients, originally diagnosed, treated with R-CHOP and followed up at Mayo Clinic, Rochester, were included in this study. Patients at last follow-up without relapse (N=112) had a higher ALC compared with those with relapsed lymphoma ((N=37) median ALC x 10(9)/l of 1.43 (range: 0.33-4.0) versus 0.67 (range: 0.18-1.98), P<0.0001, respectively). ALC at the time of confirmed relapse was a strong predictor for relapse with an area under the curve =0.91 (P<0.0001). An ALC <0.96 x 10(9)/l at the time of confirmed relapse had a positive predictive value of 72% and a positive likelihood ratio of 7.4 to predict relapse after R-CHOP in DLBCL. Patients with an ALC>or=0.96 x 10(9)/l (N=103) had a cumulative incidence of relapse of 6 versus 79% with an ALC <0.96 x 10(9)/l (N=46) (P<0.0001). This study suggests that lymphopenia measured by ALC can be used as a marker to assess risk of DLBCL relapse during routine follow-up after standard chemotherapy.

Everolimus is an oral antineoplastic agent that targets the raptor mammalian target of rapamycin (mTORC1). The phosphatidylinositol 3-kinase/mTOR signal transduction pathway has been demonstrated to be activated in tumor samples from patients with Hodgkin lymphoma (HL). The goal of this trial was to learn the antitumor activity and toxicity of everolimus in patients with relapsed/refractory HL. Patients were eligible if they had measurable disease, a platelet count >75,000, and an absolute neutrophil count >1,000. Patients received everolimus 10 mg PO daily. Dose reductions were allowed. Response was assessed after two and six cycles and then every three cycles until progression. Patients could remain on drug until progression or toxicity. Nineteen patients were enrolled. Median age was 37 years (range, 27-68). Patients had received a median of six prior therapies (range, 3-14) and 84% had undergone prior autologous stem cell transplant. The ORR was 47% (95% CI: 24-71%) with eight patients achieving a PR and one patient achieving a CR. The median TTP was 7.2 months. Four responders remained progression free at 12 months. Patients received a median of seven cycles of therapy. Of the 19 patients, one remains on therapy at 36 months; the others went off study because of progressive disease (16), toxicity (1), and death from infection (1). Four patients experienced a Grade 3 or higher pulmonary toxicity. Everolimus has single-agent activity in relapsed/refractory HL and provides proof-of-concept that targeting the mTOR pathway in HL is clinically relevant., ((c) 2010 Wiley-Liss, Inc.)

Background: B-cell chronic lymphocytic leukemia (B-CLL) is a low-grade lymphoproliferative disorder with characteristic histomorphologic features and an identifiable immunophenotype. The skin can be involved in the context of known disease, but cutaneous signs are rarely the presenting findings., Objective: Evaluation of unusual clinical cutaneous presentations of B-CLL., Methods: We conducted a retrospective case series analysis of 3 patients with unusual cutaneous clinicopathologic presentations of B-cell chronic lymphocytic leukemia, including erythematous plaques, angiomatosis/telangiectasia, and erosive skin changes, respectively, without a previous clinical history of chronic lymphocytic lymphoma. Main outcome measures were clinical cutaneous presentations and histopathologic results in the diagnosis of underlying disease., Results: In the 3 cases, lesion locations were the lower cheek, lower extremity, and penis (groin region). Histomorphologic testing showed mild to dense perivascular and periadnexal lymphoid aggregates throughout the dermis and extending into the panniculus, consistent with B-CLL. The diagnosis was confirmed with immunohistochemical studies that showed coexpression of CD5 and CD20 in the neoplastic lymphocytic infiltrate., Limitations: None., Conclusion: Cutaneous manifestations are an uncommon presentation of subclinical B-CLL. Cutaneous changes were the presenting features of underlying lymphoma in all 3 cases, highlighting the importance of maintaining a high index of suspicion for a lymphoproliferative process in cases with unusual or atypical clinicopathologic features. Additional investigations into the behavior of B-CLL in the skin may elucidate further the evolution of cutaneous lesions in this disease.

The aim of this study was to learn the toxicity and efficacy of adding 4 doses of rituximab to a standard platinum-based salvage regimen for relapsed CD20+ B-cell non-Hodgkin lymphoma. Patients were treated with rituximab 375 mg/m(2) days 1,8,15, 22 (cycle 1 only); cisplatin 100 mg/m(2) over 24 h on day 3, cytosine arabinoside 2 g/m(2) IV every 12 h x two doses on day 4, dexamethasone 40 mg PO/IV days 3-6, and G-CSF days 5-14. The ORR was 82% (47/57) with 33% (19/57) complete remissions and 49% (28/57) partial remissions. The duration of response (DR) for the 47 responders was 10.5 months (95% CI: 5.3-16.8). The median time to progression (TTP) was 10.3 months (95% CI: 5.3-14.0), the median event-free survival (EFS) was 5.3 months (95% CI: 3.9-11.0), and the median overall survival was 30.5 months (95% CI: 17.8-60.6). We conclude that rituximab can be safely added to standard DHAP.

DHAP (dexamethasone, cytosine arabinoside and cis-platinum) is a commonly used regimen for relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The optimal treatment for patients who do not respond to DHAP, but are still potential candidates for autologous stem cell transplantation, is unclear. One option is to proceed with an alternative chemotherapy regimen such as ifosfamide, carboplatin, and etoposide (ICE). The overall response rate (ORR) and overall survival (OS) associated with this chemotherapy sequence is unknown. Patients with DLBCL receiving DHAP as the first salvage therapy without response followed by ICE as second salvage were studied to learn the ORR to ICE and OS. The ORR to ICE in these DHAP-failures was 52% (11/21) with 14% (3/21) complete responses and 38% (8/21) partial responses. Nine patients (43%) were able to proceed to transplant and 29% (6/21) are long-term survivors. In patients with stable disease after DHAP the ORR was 67% (8/12) with 42% (5/12) becoming long-term survivors. In contrast, only 33% (3/9) of patients who had progressive disease on DHAP responded to ICE with only one patient achieving a durable response. Patients with stable disease after DHAP can be salvaged with ICE-based chemotherapy regimens whereas patients who progress on DHAP have a poor outcome. Patients with progressive disease on DHAP should be considered for alternative salvage regimens or experimental therapy.

The immunologic mechanisms of action of rituximab include complement mediated lysis and antibody-dependent cellular cytotoxicity. We hypothesised that a stronger host immune system prior to rituximab therapy for follicular (grades 1and 2) lymphomas (FL) would result in better response rates and longer time to progression (TTP). Thus, we studied the role of absolute lymphocyte count (ALC) prior to rituximab therapy on treatment efficacy and TTP in FL patients. Between 1996 and 2002, 79 FL patients were treated with single agent rituximab during their lymphoma treatment at the Mayo Clinic. The median age of the cohort was 56.6 years (range: 25-98 years). The median TTP was 12.5 months (range: 1-76 months). Superior TTP was observed with an ALC > or =0.89 x 10(9)/l (n = 40) compared with an ALC <0.89 x 10(9)/l (n = 39) at the time of rituximab therapy (median: 36.5 vs. 8.1 months, respectively, P < 0.0009). Higher complete response rates were observed in the ALC > or =0.89 x 10(9)/l (23/40, 58%) compared with the ALC <0.89 x 10(9)/l (5/39, 13%) (P < 0.0001). Multivariate analysis showed ALC to be an independent predictor for TTP. This study supports our hypothesis that a higher ALC predicts longer TTP following rituximab therapy.

Background: In this pilot study, the authors assessed the feasibility of combination epratuzumab and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (ER-CHOP) in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL)., Methods: Patients received chemotherapy on the following schedule: epratuzumab 360 mg/m2, rituximab 375 mg/m2, and standard-dose CHOP every 3 weeks for 6 to 8 cycles. The primary endpoint was the incidence of grade 4 neutropenia and grade 3 or 4 antibody infusional toxicity. Secondary endpoints were the complete response (CR) rate, the overall response rate (ORR), and progression-free survival (PFS). Weekly blood counts were obtained to monitor hematologic toxicity. Fifteen patients were enrolled and treated. Baseline patient characteristics included a median age of 63 years (range, 42-78 years), 60% of patients had stage III or IV disease, 7 patients had a low-risk International Prognostic Index (IPI) score (0 or 1), 7 patients had an intermediate-risk IPI score (2 or 3), and 1 patient was high risk., Results: Grade 3 or 4 neutropenia was observed in 14 patients (93%) or in 28 of 92 treatment cycles (30%). Three patients developed grade > or =3 infection or fever. Eleven patients (73%) required dose reductions. No grade 3 antibody infusion-related toxicity was reported. Thirteen of 15 patients responded (ORR, 87%,), including 10 CRs (67%), 3 partial responses (20%), 1 patient with stable disease, and 1 patient with disease progression. At a median follow-up of 30 months, 13 of 15 patients remained alive. The 1-year PFS and OS rates were 93% and 100%, respectively; and the 2-year PFS and OS rates were 86% and 86%, respectively., Conclusions: ER-CHOP every 21 days was feasible as treatment for newly diagnosed patients with DLBCL. A Phase II multicenter study is underway., (Copyright 2006 American Cancer Society.)

The peripheral blood absolute lymphocyte count (ALC) recovery after autologous stem cell transplantation has been shown to be an independent prognostic factor for survival for different haematologic malignancies. The role of ALC at diagnosis for follicular (grades 1 and 2) lymphomas (FL) on survival is not well described. The primary objective of this study was to assess the role of ALC on overall survival (OS) in FL patients. Of 1104 FL patients, 228 patients were originally diagnosed, followed, and had all treatment at the Mayo Clinic from 1984 and 1999, were evaluated. The median follow-up was 89 months (range: 8.35-248). ALC as a continuous variable was identified as a predictor for OS [Hazard ratio (HR) = 0.74, P < 0.04]. ALC >/= 1.0 x 10(9)/l (n = 164) predicted a longer OS versus ALC < 1.0 x 10(9)/l (n = 64; 175 vs. 73 months respectively, P < 0.0001). When compared with the Follicular Lymphoma International Prognostic Index (FLIPI), ALC was an independent prognostic factor for OS by multivariate analysis (HR = 0.677, P < 0.0001). These data suggest a critical role of FL patients' immune status at diagnosis on survival.

Histological transformation of low-grade non-Hodgkin lymphoma (NHL) to diffuse large cell NHL is well recognized and is associated with a poor prognosis. We sought to determine the overall outcome and the factors that affect survival in patients with histological transformation of low-grade NHL. Between November 1979 and September 2000, 93 patients who developed transformed lymphoma were identified. The median time to transformation was 4.2 years from the original diagnosis. The median age at transformation was 63 years. Seventy-eight percent had stage III or IV disease. Fifty-seven percent had extranodal involvement, including bone marrow; 33% had an elevated lactate dehydrogenase. The International Prognostic Index (IPI) at transformation was termed the transformation IPI (tIPI); 29% had a tIPI of 0-1, 59% had a tIPI of 2-3 and 8% had a tIPI of 4-5. At a median follow-up of 15 months from histological transformation, 20 of 93 patients (22%) were alive. The median survival from transformation was 15 months (4 months to 19.7 years). On univariate analysis, the following factors at the time of histological transformation were associated with an improved survival: low tIPI (P = 0.009), time to transformation > 4 years (P = 0.02), age < or = 60 years (P = 0.02) and stage I or II disease (P = 0.04). On multivariate analysis, factors that remained significant included a low tIPI (P = 0.0001) and a time to transformation > 4 years (P = 0.004). tIPI correlated with overall survival (OS); IPI 0-1, median OS 38 months; IPI 2-3, median OS 12 months; IPI 4-5, median OS 4 months. In conclusion, tIPI at the time of histological transformation is an important predictor of OS. A time to transformation > 4 years from diagnosis is associated with better OS.

Purpose: To review the clinical, radiological, and histopathologic features in 8 patients with natural killer/T-cell lymphoma (NKTL) involving the orbit and/or ocular adnexa, and to describe the responses of these patients to various treatment regimens., Design: Retrospective observational case series., Participants: Eight patients (5 male, 3 female) with NKTL involving the orbit and/or ocular adnexa were identified from 1999 through 2005. The mean age at presentation was 45 years (range, 26-65)., Methods: We retrospectively identified patients with NKTL of the ocular adnexa treated in the authors' medical centers from 1999 through 2004 using computerized diagnostic index retrieval. The clinical records and radiologic studies were analyzed to define modes of presentation and progression, response to therapy, and areas of anatomic involvement. Histopathologic findings, including the presence of CD3, CD56, and Epstein-Barr virus-encoded mRNA in each patient, were reviewed., Main Outcome Measurements: Time of survival from presentation to last known follow-up and tumor-related death., Results: Four of the 8 patients (50%) with NKTL involving the orbit or ocular adnexa had systemic involvement at presentation. Five of the 8 patients (62.5%) had concurrent sinonasal involvement, whereas 3 (37.5%) had orbital involvement alone. All lesions demonstrated CD3, CD56, and/or Epstein-Barr virus positivity on immunopathology studies. Therapy consisted of various chemotherapeutic regimens typically employed in the treatment of non-Hodgkins lymphoma, steroids, surgical intervention, and radiation. Seven (87.5%) patients died 5 weeks to 13 months after presentation, and 1 (12.5%) is alive without disease (5-year follow-up)., Conclusions: Natural killer/T-cell orbital lymphoma is a rare Epstein-Barr virus-associated neoplasm that may occur with or without associated sinonasal involvement. Our series, the largest cohort reported to date, demonstrates the high lethality of this condition despite aggressive conventional therapy, suggesting that new treatment options should be considered early in the course of treatment of patients with this disorder.

Purpose: Bleomycin pulmonary toxicity (BPT) has been well described in Hodgkin's lymphoma (HL) patients treated with bleomycin-containing chemotherapy regimens. The influence of this pulmonary complication, along with the omission of bleomycin from further chemotherapy, on overall survival (OS) and progression-free survival (PFS) in HL remains unclear. We reviewed our experience with BPT in HL to better delineate outcome and appropriate treatment in these patients., Patients and Methods: One hundred forty-one patients who were treated with bleomycin-containing chemotherapy for newly diagnosed HL between January 1986 and February 2003 were eligible for this retrospective review. BPT was defined by the presence of pulmonary symptoms, bilateral interstitial infiltrates, and no evidence of an infectious etiology., Results: BPT was observed in 18% of patients. Increasing age, doxorubicin, bleomycin, vinblastine, and dacarbazine as initial therapy, and granulocyte colony-stimulating factor use were associated with the development of BPT. Patients with BPT had a median 5-year OS rate of 63% v 90% (P = .001) in unaffected patients. The mortality rate from BPT was 4.2% in all patients and 24% in patients who developed the pulmonary syndrome. BPT incidence and mortality were highest in patients older than 40 years. The omission of bleomycin had no impact on obtaining a complete remission, PFS, or OS., Conclusion: BPT results in a significant decrease in 5-year OS in patients who are treated for HL. Age > or = 40 years seems to add substantially to the risk. In patients who do not die from acute pulmonary toxicity, both OS and PFS seem equal, despite the omission of bleomycin.

Background: Neurolymphomatosis (NL) is a rare neurologic manifestation of systemic lymphoma characterized by lymphomatous infiltration of the peripheral nervous system. The diagnosis of NL is difficult and requires a multidisciplinary approach for obtaining an adequate biopsy specimen of the suspected nerve. The prognosis of patients with NL has been poor because adequate penetration of chemotherapy into the nervous system is difficult., Methods: The authors presented the case of a 37-year-old man who was treated for Ann Arbor Stage IVB diffuse large B-cell lymphoma. The patient developed disease recurrence in the sciatic nerve without systemic involvement., Results: The patient achieved a clinical response after receipt of high-dose intravenous methotrexate followed by high-dose chemotherapy and autologous stem cell transplant., Conclusions: The authors reported this case to highlight the effectiveness of this regimen in a rare and fatal disorder. In the current study they also reviewed the literature regarding the diagnosis, prognosis, and treatment of NL., (Copyright 2004 American Cancer Society.)

Background: Testicular lymphoma is a rare extranodal presentation of non-Hodgkin lymphoma. The authors report long term follow-up information regarding a group of patients with testicular lymphoma evaluated at the Mayo Clinic and describe the outcome with special attention to patterns of recurrence., Methods: The medical records of patients with testicular lymphoma seen at the Mayo Clinic between January 1970 and March 1993 were reviewed. Patients were included if they had evidence of testicular involvement at the time of diagnosis of lymphoma. Pathology specimens were reviewed for confirmation of diagnosis., Results: Sixty-two patients with a diagnosis of testicular lymphoma were identified. Their median age was 68 years, and 60 patients underwent orchiectomy as the initial therapeutic and diagnostic procedure. Most of patients (79%) had localized or regional disease at the time of presentation. Other treatment modalities after diagnosis included radiotherapy (37%), combination chemotherapy (37%), and combination chemotherapy and radiotherapy (16%). Although 88% of patients had no residual disease after primary treatment, 80% subsequently experienced disease recurrence. There was no significant difference in the rate of recurrence, including Ann Arbor Stage I disease. Treatment did not appear to affect the recurrence rate. At a median follow-up of 2.7 years, 60% of patients had died of disease. Late recurrences were observed, and there appeared to be no plateau in the disease free survival curve. In half (51%) of the patients with disease recurrence, only extranodal locations were involved. Thirteen patients experienced recurrence in the central nervous system, 11 of whom had parenchymal lesions. In 8 of these 13 patients, the central nervous system was an isolated site of disease recurrence., Conclusions: Testicular lymphoma is a unique and aggressive extranodal non-Hodgkin lymphoma. Better treatment strategies are needed to prevent recurrences. The risk of extranodal recurrence is high, especially in the central nervous system., (Copyright 2000 American Cancer Society.)

Per protocol, patients with primary CNS non-Hodgkin's lymphoma in an intergroup phase II trial conducted by the North Central Cancer Treatment Group and the Eastern Cooperative Oncology Group had their cognitive functions measured using the Folstein and Folstein Mini-Mental Status Examination (MMSE) and their physical functions measured using the Eastern Cooperative Oncology Group Performance Score (PS) at study entry, at each treatment evaluation, and at quarterly intervals thereafter until disease progression or death. Of the 53 eligible participants who began therapy, 46 (87%) had baseline MMSE scores recorded, 36 (68%) had at least one follow-up MMSE, and 32 (60%) had both, while 52 (98%) had baseline PS, 49 (92%) had at least one follow-up PS, and 48 (91%) had both. Patterns of MMSE and PS values over time were studied in each individual, in the group as a whole, in the 20 patients who completed the study regimen, in the 23 who survived more than a year, and in patients who were classified as nonprogressors at each key evaluation. For each patient, all recorded values were plotted versus time, with dates of disease progression and death included, to look for signs of decline in cognitive or physical function preceding adverse events. Long-term declines in scores of both cognitive and physical function were observed in many treated patients with primary CNS non-Hodgkin's lymphoma. Nearly all patients who were alive more than 52 weeks after study entry had a demonstrable decline in cognitive and physical functionality. Such declines may occur before disease progression is documented; they may also occur in some patients who have long-term follow-up without evidence of disease progression. Declining MMSE and PS was a poor predictor of disease progression. There was no association of PS and toxicity. The data from this study demonstrated the considerable difficulties we encountered conducting an ancillary study such as this within a multicenter clinical trial. Firstly, the test instruments written into the protocol were unable to tell if the declines seen were due to disease, treatment, co-morbidity, or other factors. Secondly, the missing data created difficulties in interpreting outcome.

Purpose: The International Prognostic Factor Index has been shown to predict the outcome of patients with predominantly B-cell lymphomas classified using traditional classifications, including the Working Formulation, but its prognostic importance has not been tested in a cohort of patients with exclusively T-cell lymphomas. This study was conducted to evaluate the prognostic significance of the International Prognostic Factor Index in patients with peripheral T-cell lymphoma (PTCL)., Patients and Methods: Seventy-eight patients (48 men and 30 women) with PTCL seen at a single institution between 1985 and 1995 were included in the analysis. The morphology and immunocytochemistry of all the original biopsy specimens were reviewed by a single pathologist and classified using the Revised European-American Lymphoma (REAL) classification. The International Prognostic Factor Index, as well as clinical and biochemical parameters, were evaluated by univariate and multivariate analyses to determine their association with patient outcome., Results: The International Prognostic Factor Index strongly predicted survival when all patients were included in the analysis (P < .001). For patients < or = 60 years, the age-adjusted International Index significantly predicted long-term survival (P = .0218). For patients older than 60 years, the age-adjusted International Index also significantly predicted survival (P = .002). Liver involvement (P = .006) and bone marrow involvement (P = .014) were also significant prognostic factors in the univariate analysis, but only the International Index remained significant in the multivariate analysis (P = .001)., Conclusion: The International Prognostic Factor Index, which significantly predicts outcome in patients with aggressive/intermediate-grade B-cell lymphomas, has similar prognostic importance in patients with PTCL.

Purpose: Results of multiple radiation, chemotherapy, and combined treatment trials have shown that the fate of primary central nervous system lymphoma (PCNSL) patients is very different from that of patients with similarly treated systemic IE non-Hodgkin's lymphoma. This study was designed to improve the survival of PCNSL patients by the use of combined initial therapy., Methods and Materials: Forty-six eligible primary PCNSL patients were treated with whole brain irradiation and adjuvant chemotherapy consisting of preirradiation cyclophosphamide-adriamycin-vincristine-prednisone (CHOP) and postirradiation high-dose cytosine arabinoside (HDAC) as part of an ongoing Phase II Mayo/North Central Cancer Treatment Group/Eastern Cooperative Oncology Group (M/NCCTG/ECOG) intergroup effort, which opened in April 1986., Results: This cohort consisted of 23 men and 23 women with median age 63.5 years (range 24 to 75 years). Only 5% were under age 40; 36% were age 40 to 59, 37% were age 60 to 69, and 22% were age 70 and over. Forty-six percent had good performance scores of ECOG 0-1 at time of study entry. Forty-six patients were evaluable for treatment outcome as of October 6, 1993. Of these, 10 were still alive. Estimated median survival and 21-month survival were 45.3 weeks and 29%, respectively. There were four early deaths ranging from Day 9 to Day 15 (three drug-related, one from other complications), and two CHOP responders died at 32 and 35 days, soon after Cycle 2 of CHOP (one probably drug-related, one from other complications). There was no significant difference in survival according to baseline performance status. However, survival was consistently worse for patients > 60 years old than for the younger patients (< or = 60 years). With deaths recorded for 21 of 21 older patients, but only 9 of the 14 younger patients, 21-month survival for older vs. younger was 14 vs. 50% based on the 35 patients who entered the study at least 21 months ago (p = 0.0365). Of the 46 patients evaluable for response, 63% had objective remissions on CHOP and another 20% remained stable., Conclusion: Combined modality therapy in this study did not produce an overall survival advantage in treating PCNSL. The 50% 21-month survival of younger patients may be a reflection of age only.

The Eastern Cooperative Oncology Group (ECOG) conducted a phase II trial in adult patients with lymphoblastic non-Hodgkin's lymphoma. Thirty-nine patients with no central nervous system (CNS) involvement were treated with an induction cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)/L-asparaginase regimen and CNS prophylaxis that included intrathecally administered methotrexate given 6 times and 24 Gy midplane cranial radiation in 12 fractions. Thirty-one patients (79%) achieved a complete remission (CR). Of the 31 patients with CRs, 12 relapsed (39%). CNS relapse occurred in three patients. All patients who entered a CR were treated with maintenance CHOP, cytosine arabinoside (AraC), and methotrexate and subsequently with Ara-C and methotrexate. Life-threatening leukopenia or thrombocytopenia was experienced in 69% of patients in the induction phase and in 70% in the maintenance phase. Nineteen of 39 patients (49%) remain in CR with a followup to 9 years. Bone marrow involvement was associated with a significantly worse survival (P = 0.03).

To summarize recent information about acute porphyrias and to provide clinicians with a practical diagnostic and management approach, we reviewed the pertinent literature and our clinical experience. The acute porphyrias are characterized by recurrent attacks of abdominal pain with or without additional manifestations of autonomic dysfunction or neuropsychiatric symptoms. On the basis of the potential of these disorders to affect the skin, they are further subdivided into neuroporphyrias and neurocutaneous porphyrias. During acute attacks, acute porphyria is always associated with increased levels of urinary porphyrin precursors. Between attacks, patients with neurocutaneous porphyrias may have normal urinary porphyrins; therefore, stool porphyrins, which are invariably increased, are the most helpful. Latent disease can be detected by the measurement of either urinary and stool porphyrins or cellular enzyme activity. Specific intravenous therapy with hematin has resulted in biochemical remissions, but its clinical benefit remains controversial. Measurement of urinary and stool porphyrins or porphyrin precursors is critical for the diagnosis of clinically overt acute porphyria. Enzyme assays are helpful in supporting the diagnosis but are best used to identify family members with latent disease. Preventive measures and supportive therapy are the mainstays of current management of patients with porphyria.