Detection of extranodal and spleen involvement by FDG-PET imaging predicts adverse survival in untreated follicular lymphoma.

Predicting early clinical failure in patients with untreated follicular lymphoma (FL) is important but difficult. This study aimed to determine the incidence and patterns of extranodal (EN) and spleen disease using PET/CT, and assess their utility in predicting early clinical failure. PET/CT images from 613 cases of untreated FL (2003-2016) were reviewed. The location and number of EN sites, patterns of bone involvement, and splenic involvement were recorded. Outcomes were assessed using event-free survival (EFS), overall survival (OS), and early clinical failure at 24 months (EFS24). So, 49% (301/613) of patients had PET/CT-detected EN involvement, and 28% (171/613) had spleen involvement. The presence of ≥2 EN sites, spleen, bone or soft tissue involvement all predicted failure to achieve EFS24. Presence of ≥2 EN sites and bone involvement pattern were also predictive of OS in a univariate analysis. In a multivariate analysis with FLIPI-2 factors, spleen involvement, pattern of bone involvement, and soft tissue involvement independently predicted a lower EFS (HR 1.49 (1.11-2.00), P = .007; HR 1.71 (1.10-2.65), P = .017; and HR 1.67 (1.06-2.62), P = .026, respectively). When the multivariate analysis was performed using PRIMA-PI factors (marrow and B2M), the number of EN sites was an independent prognostic factor for inferior OS (HR 2.28; P = .05). Baseline PET/CT identifies EN involvement in nearly half of patients with untreated FL. The presence of ≥2 EN sites, bone, soft tissue, or splenic involvement predicts early clinical failure. These results, when combined with other factors, may better identify high-risk patients and guide therapy.

Role of systemic high-dose methotrexate and combined approaches in the management of vitreoretinal lymphoma: A single center experience 1990-2018.

Vitreoretinal lymphoma (VRL) management remains a challenge. We present 72 patients with VRL, diagnosed at Mayo Clinic between 1990-2018. Three nondiffuse large B-cell lymphoma (DLBCL) histology cases were excluded. Among 69 DLBCL, 33 patients had primary VRL (PVRL), 18 concurrent intraocular and central nervous system (CNS) or systemic disease and 18 secondary VRL. Patients received intraocular chemotherapy (intraocular injections of rituximab or metothrexate or steroids or in combination), radiotherapy, systemic or combined systemic plus intraocular treatment in 9, 10, 35, and 15 cases, respectively. Among primary and concurrent VRL, median failure free survival (FFS), CNS relapse-free survival (CNS-RFS) and overall survival (OS) were: 1.8, 4.9, and 4.1 years, respectively; among PVRL, median FFS, CNS-RFS, and OS were: 2.6 year, Not Reached and 9.3 year, respectively. No CNS relapse occurred beyond 4 years in PVRL. Median OS for patients diagnosed between 1990 and 1999 vs between 2000 and 2018 was 1.5 vs 9.4 years, respectively (P = .0002). OS was significantly higher in PVRL, as compared with concurrent VRL (P = .04). Previous immunosuppression and poor performance status were predictive of worse outcome. In PVRL, a combined systemic and intraocular therapy showed higher FFS (P = .002) and CNS-RFS (P = .003), but no differences in OS. Among 18 secondary VRL, at a median follow-up of 1.1 year after vitreoretinal relapse, median FFS and OS were 0.3 and 1.3 years. An improvement in survival of VRL has been observed over the decades. PVRL should undergo combined systemic and intraocular chemotherapy to prevent CNS progression.

Elevated monoclonal and polyclonal serum immunoglobulin free light chain as prognostic factors in B- and T-cell non-Hodgkin lymphoma.

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.

Cost-effectiveness analysis of a risk-adapted algorithm of plerixafor use for autologous peripheral blood stem cell mobilization.

Historically, up to 30% of patients were unable to collect adequate numbers of peripheral blood stem cells (PBSCs) for autologous stem cell transplantation (ASCT). Plerixafor in combination with granulocyte colony-stimulating factor (G-CSF) has shown superior results in mobilizing peripheral blood (PB) CD34+ cells in comparison to G-CSF alone, but its high cost limits general use. We developed and evaluated risk-adapted algorithms for optimal utilization of plerixafor. In plerixafor-1, PBSC mobilization was commenced with G-CSF alone, and if PB CD34 on day 4 or day 5 was <10/µL, plerixafor was administered in the evening, and apheresis commenced the next day. In addition, if on any day, the daily yield was <0.5 × 10(6) CD34/kg, plerixafor was added. Subsequently, the algorithm was revised (plerixafor-2) with lower thresholds. If day-4 PB CD34 <10/µL for single or <20/µL for multiple transplantations, or day-1 yield was <1.5 × 10(6) CD34/kg, or any subsequent daily yield was <0.5 × 10(6) CD34/kg, plerixafor was added. Three time periods were analyzed for results and associated costs: January to December 2008 (baseline cohort; 319 mobilization attempts in 278 patients); February to November 2009 (plerixafor-1; 221 mobilization attempts in 216 patients); and December 2009 to June 2010 (plerixafor-2; 100 mobilization attempts in 98 patients). Plerixafor-2 shows a significant improvement in PB CD34 collection, increased number of patients reaching minimum and optimal goals, fewer days of apheresis, and fewer days of mobilization/collection, albeit at increased costs. In conclusion, although the earlier identification of ineffective PBSC mobilization and initiation of plerixafor (plerixafor-2) increases the per-patient costs of PBSC mobilization, failure rates, days of apheresis, and total days of mobilization/collection are lower.

Epratuzumab with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated diffuse large B-cell lymphoma.

Approximately 60% of patients with diffuse large B-cell non-Hodgkin lymphoma (DLBCL) are curable with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemoimmunotherapy. Epratuzumab (E) is an unlabeled anti-CD22 monoclonal antibody with efficacy in relapsed DLBCL. This phase 2 trial tested the safety and efficacy of combining E with R-CHOP (ER-CHOP) in untreated DLBCL. A secondary aim was to assess the efficacy of interim positron emission tomography (PET) to predict outcome in DLBCL. Standard R-CHOP with the addition of E 360 mg/m(2) intravenously was administered for 6 cycles. A total of 107 patients were enrolled in the study. Toxicity was similar to standard R-CHOP. Overall response rate in the 81 eligible patients was 96% (74% CR/CRu) by computed tomography scan and 88% by PET. By intention to treat analysis, at a median follow-up of 43 months, the event-free survival (EFS) and overall survival (OS) at 3 years in all 107 patients were 70% and 80%, respectively. Interim PET was not associated with EFS or OS. Comparison with a cohort of 215 patients who were treated with R-CHOP showed an improved EFS in the ER-CHOP patients. ER-CHOP is well tolerated and results appear promising as a combination therapy. This study was registered at www.clinicaltrials.gov as #NCT00301821.

Multi-institutional phase 2 study of the farnesyltransferase inhibitor tipifarnib (R115777) in patients with relapsed and refractory lymphomas.

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.

A phase I trial of immunostimulatory CpG 7909 oligodeoxynucleotide and 90 yttrium ibritumomab tiuxetan radioimmunotherapy for relapsed B-cell non-Hodgkin lymphoma.

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 IL1ß, 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.

Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma.

This phase 3, multicenter, randomized (1:1), double-blind, placebo-controlled study evaluated the safety and efficacy of plerixafor with granulocyte colony-stimulating factor (G-CSF) in mobilizing hematopoietic stem cells in patients with multiple myeloma. Patients received G-CSF (10 microg/kg) subcutaneously daily for up to 8 days. Beginning on day 4 and continuing daily for up to 4 days, patients received either plerixafor (240 microg/kg) or placebo subcutaneously. Starting on day 5, patients began daily apheresis for up to 4 days or until more than or equal to 6 x 10(6) CD34(+) cells/kg were collected. The primary endpoint was the percentage of patients who collected more than or equal to 6 x 10(6) CD34(+) cells/kg in less than or equal to 2 aphereses. A total of 106 of 148 (71.6%) patients in the plerixafor group and 53 of 154 (34.4%) patients in the placebo group met the primary endpoint (P < .001). A total of 54% of plerixafor-treated patients reached target after one apheresis, whereas 56% of the placebo-treated patients required 4 aphereses to reach target. The most common adverse events related to plerixafor were gastrointestinal disorders and injection site reactions. Plerixafor and G-CSF were well tolerated, and significantly more patients collected the optimal CD34(+) cell/kg target for transplantation earlier compared with G-CSF alone. This study is registered at www.clinicaltrials.gov as #NCT00103662.

Acute weight gain and diastolic dysfunction as a potent risk complex for post stem cell transplant atrial fibrillation.

The management of atrial fibrillation (AF) following stem cell transplant (SCTX) is often challenging because of the universal presence of profound bone marrow suppression. The incidence of and risk factors for AF/flutter following SCTX are not well known. A total of 395 multiple myeloma (MM) patients consecutively underwent SCTX between 2002 and 2005 at the Mayo Clinic, and 383 of whom, mean age 57 +/- 9 years, had no history of evidence of AF/flutter constituted the study population. During 1,002 person-years of follow up, 39 (10%) patients developed first AF/flutter (incidence of 39 per 1,000 person years), and 28 of these (72%) occurred within 21 days of SCTX. In multivariable-adjusted analyses, weight gain of > or = 7% in the 1st week post-SCTX (HR 3.68; P = 0.0120) and presence of diastolic dysfunction at MM diagnosis (HR 2.294; P = 0.0082) were independent predictors of AF/flutter. The risk of AF/flutter post-SCTX increased by about ninefold when both factors were present. Compared to age and sex-matched MM patients without SCTX, the risk of AF/flutter differed significantly only over the 1st year after MM diagnosis, during which SCTX was performed for the majority. Beyond the 1st year, there was no significant difference in risk of AF/flutter between the two groups. The data suggested that SCTX was associated with significantly increased risk of first AF/flutter, which typically occurred within the first 21 days of the transplant. Weight gain of > or = 7% was strongly predictive of first AF/flutter, and the risk was augmented by the presence of diastolic dysfunction at baseline.

AMD3100 affects autograft lymphocyte collection and progression-free survival after autologous stem cell transplantation in non-Hodgkin lymphoma.

PURPOSE: Autograft absolute lymphocyte count (A-ALC) affects survival after autologous stem cell transplantation (ASCT) in non- Hodgkin lymphoma (NHL). AMD3100, a CXCR4 antagonist, mobilizes CD34+ stem cells in patients with NHL undergoing ASCT. We sought to study the impact of AMD3100 on A-ALC collection in patients with NHL undergoing ASCT. PATIENTS AND METHODS: The primary endpoint of the study was to assess the association between AMD3100 and A-ALC collection. We compared 7 consecutive patients with NHL mobilized with AMD3100 and granulocyte colony-stimulating factor with 29 control patients with NHL mobilized with granulocyte colony-stimulating factor alone. RESULTS: Higher median A-ALCs were observed in the AMD3100 group compared with the control group (4.16 x 10(9) lymphocytes/kg vs. 0.288 x 10(9) lymphocytes/kg; P < 0.0001). With a median follow-up of 20 months (range, 4-24 months), no relapses were reported in the AMD3100 group compared with 15 of 29 in the control group (P < 0.02). CONCLUSION: Our data suggest that AMD3100 affects A-ALC and clinical outcome in patients with NHL undergoing ASCT.

Randomized phase II study of interleukin-12 in combination with rituximab in previously treated non-Hodgkin's lymphoma patients.

PURPOSE: Rituximab is a chimeric antibody that induces B-cell apoptosis and recruits immune effector cells to mediate cell lysis. Interleukin-12 (IL-12) facilitates cytolytic responses by T cells and natural killer cells. This phase II study was done to determine the efficacy and toxicity of IL-12 in combination with rituximab in patients with B-cell non-Hodgkin's lymphoma (NHL). EXPERIMENTAL DESIGN: Fifty-eight patients with histologically confirmed relapsed B-cell NHL were randomized to receive concurrent treatment with rituximab and IL-12 (arm A) or rituximab with subsequent treatment with IL-12 after documented nonresponse or progression after rituximab (arm B). Treatment consisted of 375 mg/m2 rituximab on days 1, 8, 15, and 22 and 300 ng/kg IL-12 given s.c. twice weekly starting on day 2 for arm A or upon progression for arm B. RESULTS: The overall response rate was 37% (11 of 30) in arm A and 52% (13 of 25) in arm B. All of the responses seen in arm B occurred while patients received rituximab, and no responses occurred during treatment with subsequent IL-12. The median duration of response was 16 months for arm A and 12 months for arm B. Biopsy specimens were serially obtained in a subset of patients and showed that changes in gene expression were different when cells from the peripheral blood were compared with cells from lymph node biopsies. CONCLUSIONS: The concomitant use of IL-12 and rituximab had modest disease activity in patients with B-cell NHL, but the sequential administration of IL-12 after rituximab did not result in additional clinical responses.

The International Prognostic Index predicts outcome after histological transformation of low-grade non-Hodgkin lymphoma.

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.

The effect of absolute lymphocyte count recovery kinetics on survival after autologous stem cell transplantation for non-Hodgkin's lymphoma.

Absolute lymphocyte count (ALC) >or=500 cells/microl at day 15 after autologous stem cell transplantation (ASCT) is a powerful independent, prognostic indicator for survival in multiple hematological malignancies. A limitation in these studies was the selection of a single time point (day 15 post-ASCT) as the only discriminator of clinical outcome in relation to ALC recovery. We hypothesized there is a continuous and not discrete relationship between ALC recovery and clinical outcome post-ASCT in NHL. Therefore, we analyzed 274 consecutive patients who underwent ASCT for NHL between 1987 and 2001. The primary end point was to assess the impact of the kinetics of post-ASCT lymphocyte recovery>or=500 cells/microl (K-ALC) on overall survival (OS) and progression-free survival (PFS). K-ALC was a predictor of OS and PFS when the Cox proportional hazards model was used with K-ALC entered as a continuous variable (p<0.0001). Multivariate analysis demonstrated K-ALC recovery post-ASCT to be an independent prognostic indicator for OS and PFS. These data support our hypothesis that the K-ALC post-ASCT is associated with clinical outcome in NHL.

Stem cell transplantation for the management of primary systemic amyloidosis.

PURPOSE: To review the characteristics and outcomes of amyloidosis patients treated with high-dose chemotherapy and stem cell reconstitution. SUBJECTS AND METHODS: Sixty-six patients with biopsy-proven amyloidosis received transplants between March 1996 and January 2001. All patients had evidence of a clonal plasma cell dyscrasia; those with nonimmunoglobulin forms of amyloidosis were excluded, as were those who had no symptoms of amyloidosis, purpura, carpal tunnel syndrome, or symptomatic multiple myeloma. RESULTS: Amyloid was seen clinically in the kidneys (n = 45 patients), heart (n = 32), peripheral nerves (n = 11), and liver (n = 11). A monoclonal protein was found in the serum in 46 patients and in the urine in 57 patients. The median daily urinary protein loss was 4.1 g. Septal thickness, measured by echocardiography, ranged from 7 to 24 mm (median, 12 mm); 8 patients had a septal thickness > or =16 mm. Ten patients received transplants 1 year or more after diagnosis. All patients received melphalan-based chemotherapy; 17 patients were conditioned with total body irradiation. Nine patients required dialysis, 7 of whom died. Treatment-related mortality for stem cell transplantation was 14% (9/66). After a median of 25 months of follow-up after transplantation, the percentage of patients alive with one organ involved was 91% (31 of 34); two organs, 82% (18 of 22); three organs, 33% (3 of 9); and four organs, 0% (0 of 1). Hematologic responses were seen in 33 patients and organ responses in 32 patients. The 2-year actuarial survival of all patients was 70%. CONCLUSION: The number of organs involved before stem cell transplantation for amyloidosis is the most important factor in predicting subsequent survival. Stem cell transplantation should be considered as a treatment option for selected patients with amyloidosis.

Posttransplantation thrombotic thrombocytopenic purpura: a single-center experience and a contemporary review.

OBJECTIVE: To assess the activity of von Willebrand factor-cleaving protease (vWF-CP) in patients with thrombotic thrombocytopenic purpura (TTP) complicating bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT). PATIENTS AND METHODS: From March 1, 1999, to June 30, 2001, allogeneic and autologous hematopoietic stem cell transplantation was performed in 118 and 400 patients, respectively. We reviewed risk factors for development of posttransplantation TTP and measured vWF-CP activity during active TTP in 10 recipients. RESULTS: The incidence of TTP after allogeneic and autologous transplantation was 6.8% (8/118) and 0.25% (1/400), respectively. Among the allogeneic transplant recipients, the incidence of TTP after nonmyeloablative (NMA) PBSCT, matched unrelated donor BMT, and sibling BMT or PBSCT was 15.4% (2/13), 11.8% (2/17), and 4.5% (4/88), respectively. Of the 10 patients with TTP, 9 (90%) had received extensive prior therapy, including autologous transplantation in both NMA recipients. Acute graft-vs-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate in most affected patients. The vWF antigen level was elevated in all patients, and no patients showed evidence of vWF-CP deficiency. During active TTP, 6 patients had grade II-IV acute GVHD, 1 had extensive chronic GVHD, and 4 had cytomegalovirus viremia. Risk factor analysis for development of TTP showed that transplant type (NMA and matched unrelated donor) and source of stem cells (bone marrow vs peripheral blood stem cell) were significant. CONCLUSIONS: Posttransplantation TTP was not found to be associated with severe vWF-CP deficiency. The elevated levels of vWF antigen are consistent with diffuse endothelial injury likely because of multiple interacting factors such as extensive prior therapy, GVHD, cyclosporine, and reactivation of cytomegalovirus. The disorder appears to be more frequent among patients with, or at risk for, acute GVHD, suggesting a possible role in the pathogenesis. Nonmyeloablative transplantation does not appear to confer a lesser risk, possibly for these reasons.

Therapeutic options in patients with lymphoma and severe liver dysfunction.

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.

Ongoing trials with yttrium 90-labeled ibritumomab tiuxetan in patients with non-Hodgkin's lymphoma.

Targeted radiation therapy or radioimmunotherapy has been an important recent advance in the treatment of patients with B-cell non-Hodgkin's lymphoma (NHL). Yttrium 90-labeled ibritumomab tiuxetan (Zevalin) comprises the murine monoclonal antibody ibritumomab, the linker chelator tiuxetan, and the radiolabeled isotope yttrium 90. Yttrium 90 ibritumomab tiuxetan has been shown to be efficacious in the treatment of B-cell NHL. Initial phase I/II trials established the therapeutic dose of ibritumomab tiuxetan for low-grade NHL to be 0.4 mCi/kg, or 0.3 mCi/kg for patients with mild thrombocytopenia. Currently, there are many ongoing trials of ibritumomab tiuxetan with different dose schedules and dose intensities in combination with chemotherapy and autologous or allogeneic stem cell transplantation in an attempt to improve response rate and duration and to study its effectiveness in other B-cell lymphomas including mantle cell lymphoma, and chronic lymphocytic leukemia. This article reviews the ongoing trials with 90Y ibritumomab tiuxetan. Radioimmunotherapy has great promise, and the safe incorporation of 90Y ibritumomab tiuxetan into treatment will hopefully result in improved survival for patients with NHL.

The absolute monocyte count is associated with overall survival in patients newly diagnosed with follicular lymphoma.

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.

Elevated serum free light chains are associated with event-free and overall survival in two independent cohorts of patients with diffuse large B-cell lymphoma.

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.