Metabolic tumor volume predicts outcome in patients with advanced stage follicular lymphoma from the RELEVANCE trial.

BACKGROUND: We investigated the prognostic value of baseline positron emission tomography (PET) parameters for patients with treatment-naïve follicular lymphoma (FL) in the phase III RELEVANCE trial, comparing the immunomodulatory combination of lenalidomide and rituximab (R2) versus R-chemotherapy (R-chemo), with both regimens followed by R maintenance therapy. PATIENTS AND METHODS: Baseline characteristics of the entire PET-evaluable population (n = 406/1032) were well balanced between treatment arms. The maximal standard uptake value (SUVmax) and the standardized maximal distance between tow lesions (SDmax) were extracted, the standardized distance between two lesions the furthest apart, were extracted. The total metabolic tumor volume (TMTV) was computed using the 41% SUVmax method. RESULTS: With a median follow-up of 6.5 years, the 6-year progression-free survival (PFS) was 57.8%, the median TMTV was 284 cm3, SUVmax was 11.3 and SDmax was 0.32 m-1, with no significant difference between arms. High TMTV (>510 cm3) and FLIPI were associated with an inferior PFS (P = 0.013 and P = 0.006, respectively), whereas SUVmax and SDmax were not (P = 0.08 and P = 0.12, respectively). In multivariable analysis, follicular lymphoma international prognostic index (FLIPI) and TMTV remained significantly associated with PFS (P = 0.0119 and P = 0.0379, respectively). These two adverse factors combined stratified the overall population into three risk groups: patients with no risk factors (40%), with one factor (44%), or with both (16%), with a 6-year PFS of 67.7%, 54.5%, and 41.0%, respectively. No significant interaction between treatment arms and TMTV or FLIPI (P = 0.31 or P = 0.59, respectively) was observed. The high-risk group (high TMTV and FLIPI 3-5) had a similar PFS in both arms (P = 0.45) with a median PFS of 68.4% in the R-chemo arm versus 71.4% in the R2 arm. CONCLUSIONS: Baseline TMTV is predictive of PFS, independently of FLIPI, in patients with advanced FL even in the context of antibody maintenance.

Rituximab: a benchmark in the development of chemotherapy-free treatment strategies for follicular lymphomas.

Background: With the introduction of the anti-CD20 antibody rituximab, the outcome of patients with follicular lymphoma (FL) has greatly improved over the last two decades. First-line prolonged rituximab monotherapy is effective, achieving long-term remission and prolonged failure-free survival in some patients. Additionally, rituximab has been shown to synergize with chemotherapeutic and novel targeted agents alike with measurable gains in duration of response. As such, rituximab has made its mark in the treatment of FL and remains a valid agent despite the availability of newer monoclonal antibodies. This review summarizes the evolving role of rituximab as the first available anti-CD20 monoclonal antibody, emphasizing its clear activity as a single agent and in combination with chemotherapy or molecular targeted agents, and setting the standard for the development of new anti-CD20 monoclonal antibodies. Conclusion: We provide data that support the ongoing use of rituximab as a therapeutic partner for novel agents in future clinical trials exploring chemotherapy-free alternatives.

Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial.

In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) study, nilotinib resulted in earlier and higher response rates and a lower risk of progression to accelerated phase/blast crisis (AP/BC) than imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Here, patients' long-term outcomes in ENESTnd are evaluated after a minimum follow-up of 5 years. By 5 years, more than half of all patients in each nilotinib arm (300 mg twice daily, 54%; 400 mg twice daily, 52%) achieved a molecular response 4.5 (MR(4.5); BCR-ABL⩽0.0032% on the International Scale) compared with 31% of patients in the imatinib arm. A benefit of nilotinib was observed across all Sokal risk groups. Overall, safety results remained consistent with those from previous reports. Numerically more cardiovascular events (CVEs) occurred in patients receiving nilotinib vs imatinib, and elevations in blood cholesterol and glucose levels were also more frequent with nilotinib. In contrast to the high mortality rate associated with CML progression, few deaths in any arm were associated with CVEs, infections or pulmonary diseases. These long-term results support the positive benefit-risk profile of frontline nilotinib 300 mg twice daily in patients with CML-CP.

Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up.

Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Patients compares nilotinib and imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). With a minimum follow-up of 3 years, major molecular response, molecular response of BCR-ABL≤ 0.01% expressed on the international scale (BCR-ABL(IS); MR(4)) and BCR-ABL(IS)≤ 0.0032% (MR(4.5)) rates were significantly higher with nilotinib compared with imatinib, and differences in the depth of molecular response between nilotinib and imatinib have increased over time. No new progressions occurred on treatment since the 2-year analysis. Nilotinib was associated with a significantly lower probability of progression to accelerated phase/blast crisis vs imatinib (two (0.7%) progressions on nilotinib 300 mg twice daily, three (1.1%) on nilotinib 400 mg twice daily and 12 (4.2%) on imatinib). When considering progressions occurring after study treatment discontinuation, the advantage of nilotinib over imatinib in preventing progression remained significant (nine (3.2%) progressions on nilotinib 300 mg twice daily, six (2.1%) on nilotinib 400 mg twice daily and 19 (6.7%) on imatinib). Both nilotinib and imatinib were well tolerated, with minimal changes in safety over time. Nilotinib continues to demonstrate superior efficacy in all key response and outcome parameters compared with imatinib for the treatment of patients with newly diagnosed CML-CP.

Bortezomib, dexamethasone, cyclophosphamide and lenalidomide combination for newly diagnosed multiple myeloma: phase 1 results from the multicenter EVOLUTION study.

This phase 1 study (Clinicaltrials.gov: NCT00507442) was conducted to determine the maximum tolerated dose (MTD) of cyclophosphamide in combination with bortezomib, dexamethasone and lenalidomide (VDCR) and to assess the safety and efficacy of this combination in untreated multiple myeloma patients. Cohorts of three to six patients received a cyclophosphamide dosage of 100, 200, 300, 400 or 500 mg/m(2) (on days 1 and 8) plus bortezomib 1.3 mg/m(2) (on days 1, 4, 8 and 11), dexamethasone 40 mg (on days 1, 8 and 15) and lenalidomide 15 mg (on days 1-14), for eight 21-day induction cycles, followed by four 42-day maintenance cycles (bortezomib 1.3 mg/m(2), on days 1, 8, 15 and 22). The MTD was the cyclophosphamide dose below which more than one of six patients experienced a dose-limiting toxicity (DLT). Twenty-five patients were treated. Two DLTs were seen, of grade 4 febrile neutropenia (cyclophosphamide 400 mg/m(2)) and grade 4 herpes zoster despite anti-viral prophylaxis (cyclophosphamide 500 mg/m(2)). No cumulative hematological toxicity or thromboembolic episodes were reported. The overall response rate was 96%, including 20% stringent complete response (CR), 40% CR/near-complete response and 68% >or=very good partial response. VDCR is well tolerated and highly active in this population. No MTD was reached; the recommended phase 2 cyclophosphamide dose in VDCR is 500 mg/m(2), which was the highest dose tested.

Immunologic recovery following autologous stem-cell transplantation with pre- and posttransplantation rituximab for low-grade or mantle cell lymphoma.

BACKGROUND: Rituximab may improve transplant outcomes but may delay immunologic recovery. PATIENTS AND METHODS: Seventy-seven patients with low-grade or mantle cell lymphoma received autologous stem-cell transplantation (ASCT) on a phase II study. Rituximab 375 mg/m(2) was administered 3 days before mobilization-dose cyclophosphamide, then weekly for four doses after count recovery from ASCT. Immune reconstitution was assessed. RESULTS: Sixty percent of transplants occurred in first remission. Actuarial event-free survival (EFS) and overall survival (OS) were 60% and 73%, respectively, at 5 years, with 7.2-year median follow-up for OS in surviving patients. Median EFS was 8.3 years. Older age and transformed lymphomas were independently associated with inferior EFS, whereas day 60 lymphocyte counts did not predict EFS or late infections. Early and late transplant-related mortality was 1% and 8%, with secondary leukemia in two patients. B-cell counts recovered by 1-2 years; however, the median IgG level remained low at 2 years. Late-onset idiopathic neutropenia, generally inconsequential, was noted in 43%. CONCLUSION: ASCT with rituximab can produce durable remissions on follow-up out to 10 years. Major infections do not appear to be significantly increased or to be predicted by immune monitoring.

Comparison of residence time estimation methods for radioimmunotherapy dosimetry and treatment planning--Monte Carlo simulation studies.

Estimating the residence times in tumor and normal organs is an essential part of treatment planning for radioimmunotherapy (RIT). This estimation is usually done using a conjugate view whole body scan time series and planar processing. This method has logistical and cost advantages compared to 3-D imaging methods such as Single photon emission computed tomography (SPECT), but, because it does not provide information about the 3-D distribution of activity, it is difficult to fully compensate for effects such as attenuation and background and overlapping activity. Incomplete compensation for these effects reduces the accuracy of the residence time estimates. In this work we compare residence times estimates obtained using planar methods to those from methods based on quantitative SPECT (QSPECT) reconstructions. We have previously developed QSPECT methods that provide compensation for attenuation, scatter, collimator-detector response, and partial volume effects. In this study we compared the use of residence time estimation methods using QSPECT to planar methods. The evaluation was done using the realistic NCAT phantom with organ time activities that model (111)In ibritumomab tiuxetan. Projection data were obtained using Monte Carlo simulations (MCS) that realistically model the image formation process including penetration and scatter in the collimator-detector system. These projection data were used to evaluate the accuracy of residence time estimation using a time series of QSPECT studies, a single QSPECT study combined with planar scans and the planar scans alone. The errors in the residence time estimates were 3.8%, 15%, and 2%-107% for the QSPECT, hybrid planar/QSPECT, and planar methods, respectively. The quantitative accuracy was worst for pure planar processing and best for pure QSPECT processing. Hybrid planar/QSPECT methods, where a single QSPECT study was combined with a series of planar scans, provided a large and statistically significant improvement in quantitative accuracy for most organs compared to the planar scans alone, even without sophisticated attention to background subtraction or thickness corrections in planar processing. These results indicate that hybrid planar/QSPECT methods are generally superior to pure planar methods and may be an acceptable alternative to performing a time series of QSPECT studies.

Filgrastim and alemtuzumab (Campath-1H) for refractory chronic lymphocytic leukemia.

Alemtuzumab (anti-CD52; Campath-1H) is effective in fludarabine-refractory chronic lymphocytic leukemia (CLL), but is associated with infection and early onset neutropenia. To reduce toxicity, filgrastim (G-CSF) was administered concurrently with alemtuzumab. In total, 14 CLL patients (median age 59) with a median of 3.5 prior regimens (range 1--12) received i.v. alemtuzumab, stepped up from 3 to 30 mg the first week, then 30 mg thrice weekly for 12 weeks. Filgrastim 5 microg/kg was administered daily 5 days before and throughout alemtuzumab therapy. Six patients developed cytomegalovirus (CMV) reactivation 3--6 weeks into treatment; six patients developed fever, three neutropenia, and one pneumonia. The patient with CMV pneumonia died; ganciclovir cleared CMV in the other patients. Five patients developed early neutropenia (weeks 2--5). Four patients developed delayed neutropenia (weeks 10--13) unassociated with CMV reactivation. Nine patients ceased therapy because of infectious and hematologic toxicity. Five partial responses were noted, all in patients with lymph nodes>cm, lasting a median of 6.5 months (range 5--13). Filgrastim and alemtuzumab were given concurrently with manageable infusion toxicity and clinical activity, but the efficacy of this regimen was limited by delayed neutropenia of unclear etiology and CMV reactivation. Filgrastrim should not be administered prophylactically during alemtuzumab therapy outside clinical trials.

Randomized, multicenter, open-label study of pegfilgrastim compared with daily filgrastim after chemotherapy for lymphoma.

PURPOSE: The primary objective was to assess the duration of grade 4 neutropenia (neutrophil count < 0.5 x 10(9)/L) after one cycle of chemotherapy with etoposide, methylprednisolone, cisplatin, and cytarabine in patients randomly assigned to receive one dose of pegfilgrastim or daily filgrastim after chemotherapy. Febrile neutropenia, neutrophil profiles, time to neutrophil recovery, pharmacokinetics, and safety were also assessed. PATIENTS AND METHODS: An open-label, randomized, phase II study was designed to compare the effects of a single subcutaneous injection of pegfilgrastim (sustained-duration filgrastim) 100 micro g/kg per chemotherapy cycle (n = 33) with daily subcutaneous injections of filgrastim 5 micro g/kg (n = 33) in patients receiving salvage chemotherapy for relapsed or refractory Hodgkin's or non-Hodgkin's lymphoma. RESULTS: The incidence of grade 4 neutropenia in the pegfilgrastim and filgrastim groups was 69% and 68%, respectively. In addition, the mean duration of grade 4 neutropenia was similar in both groups (2.8 and 2.4 days, respectively). The results for the two groups were also not significantly different for febrile neutropenia, neutrophil profile, time to neutrophil recovery, or toxicity profile. A single subcutaneous injection of pegfilgrastim 100 micro g/kg produced a sustained serum concentration relative to daily subcutaneous injections of filgrastim. Filgrastim-treated patients received a median of 11 injections per cycle. CONCLUSION: Pegfilgrastim was safe and well tolerated in this patient population. A single injection of pegfilgrastim per chemotherapy cycle provided neutrophil support with safety and efficacy similar to that provided by daily injections of filgrastim. Once-per-cycle administration of pegfilgrastim simplifies the management of neutropenia and may have important clinical benefits for patients and healthcare providers.

Long-term results of blood and marrow transplantation for Hodgkin's lymphoma.

PURPOSE: To evaluate the long-term outcome after allogeneic (allo) and autologous (auto) blood or marrow transplantation (BMT) in patients with relapsed or refractory Hodgkin's lymphoma (HL). PATIENTS AND METHODS: We analyzed the outcome of 157 consecutive patients with relapsed or refractory HL, who underwent BMT between March 1985 and April 1998. Patients

Carboxyamido-triazole (CAI)--a novel "static" signal transduction inhibitor induces apoptosis in human B-cell chronic lymphocytic leukemia cells.

Signal transduction is a key mechanism by which both proliferative and apoptotic processes of B-cell chronic lymphocytic leukemia (CLL) cells are mediated. Carboxyamido-triazole (CAI) is a cytostatic signal transduction inhibitor currently being tested in phase II clinical trials. Based on this, we investigated the in vitro activity of CAI in mononuclear cell isolates from patients with B-CLL (n=11). Viability, utilizing the MTT assay, was assessed at varying concentrations (0.01-100 microM) of CAI for 4 days. The CAI concentration required for 50% inhibition of cell viability (LC50), determined by the tetrazolium dye (MTT) assay, at 4 days was 53.5 microM (range 29-74.6; 95% CI+/-14.8). Cells from 6 of 11 patients (3 of whom were clinically fludarabine refractory) had a 27 percent (range 11-43) mean decline in viability at 10 microM after a 4 day drug exposure, a concentration readily attainable in humans. To assess if loss of viability was due to apoptosis, we incubated cells from 4 additional CLL patients with media or CAI (10 microM) for 4 days. Annexin-V/propidium iodine labeling subsequently demonstrated CAI significantly (p=0.049) induces apoptosis (40.1%; 95% CI+/-18.1) as compared to media matched control cells (18.3%; 95% CI+/-11.2). These data provide evidence that CAI can induce apoptosis in human CLL cells in vitro at drug concentrations attainable in vivo. These findings justify phase II studies of CAI in patients with B-CLL.

New approaches to blood and marrow transplantation for patients with low-grade lymphomas.

Low-grade lymphomas are generally considered incurable diseases with current standard therapies. Blood or marrow transplantation may be the exception. Nevertheless, the role of bone marrow transplantation in low-grade lymphomas has been limited by the usual indolent course of this heterogeneous group of diseases and the historically high rates of transplant-related mortality associated with most transplant procedures. This review discusses the current issues pertaining to bone marrow transplantation and comments on investigational approaches such as the use of monoclonal antibodies as in vivo purging mechanisms and nonmyeloablative and radioimmunoconjugated antibodies as alternate preparative regimens.

Gemcitabine demonstrates in vitro activity against human B-cell chronic lymphocytic leukemia.

B-cell chronic lymphocytic leukemia (CLL) is the most common type of leukemia diagnosed in the Western Hemisphere and remains incurable with currently available therapy. In an attempt to identify new potential therapy for CLL, we explored the pre-clinical activity of gemcitabine in human B-CLL cells (n =11). Mononuclear cell isolates were exposed to varying concentrations of gemcitabine (0.01-100 microM) for 4, 24, and 96 h. Viability, as determined by the tetrazolium salt (MTT) assay, after a 4 h incubation with gemcitabine declined in 6 of 8 (75%) evaluable patients at a concentration < 30 microM (a physiologically attainable level), and 3 of 8 of the B-CLL cells had an LC50 (concentration where 50% loss of viability is observed) < 30 microM. At 4 days of drug exposure, 82% (9/11) of patients had an LC50 < 30 microM. Annexin-V/propidium iodine staining demonstrated apoptosis in CLL cells exposed to 30 microM of gemcitabine. Examination of changes in apoptosis related proteins demonstrated no significant change in bcl-2, bax or p53 protein expression with gemcitabine (23 microM) at 4, 24, or 48 h. These data demonstrate that gemcitabine has pre-clinical activity in B-CLL and supports its exploration as a single agent and in combination with other active agents in this disease.

UCN-01 induces cytotoxicity toward human CLL cells through a p53-independent mechanism.

OBJECTIVES: UCN-01, a novel protein kinase C inhibitor, is currently being tested in phase I clinical trials after being noted to induce apoptosis in lymphoid cell lines. We sought to study the in vitro activity of UCN-01 against human chronic lymphocytic leukemia (CLL) cells and potential mechanisms of action for inducing this cytotoxicity. METHODS: Detailed in vitro studies were performed from tumor cells derived from patients with CLL cells following attainment of written informed consent. RESULTS: The 50% loss of viability (LC(50)) in mononuclear cells from CLL patients (n = 10) following exposure to UCN-01 for 4 days was 0.4 microM (95% CI +/- 0.21; range 0.09-1.16). Loss of viability in human CLL cells correlated with early induction of apoptosis. Exposure of CLL cells to 0.4 and 5.0 microM of UCN-01 resulted in decreased expression of p53 protein. We therefore investigated the dependence of UCN-01 on intact p53 by exposing splenocytes from wild-type (p53(+/+)) and p53 null (p53(-/-)) mice, which demonstrated no preferential cytotoxicity when compared to the marked differential induced by F-Ara-A and radiation. CONCLUSIONS: UCN-01 has significant in vitro activity against human CLL cells that appears to occur independent of p53 status. While demonstration of in vitro cytotoxicity does not establish in vivo efficacy, the findings described support the early introduction of UCN-01 into clinical trials for patients with B-CLL.

Monoclonal antibodies and autologous stem cell transplantation for lymphoma.

The introduction of monoclonal antibodies into the clinic has paved the way for new approaches to stem cell transplantation for patients with lymphoma. These approaches include the development of new high-dose regimens with radiolabeled antibodies, in vivo purging techniques with the unlabeled antibodies, and post-transplant adjuvant immunotherapy. Numerous trials have demonstrated the feasibility of these approaches. However, questions remain regarding the application of these antibodies including the ultimate efficacy. The recent results of the incorporation of monoclonal antibodies into stem cell transplantation and current research directions are reviewed.

Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity.

PURPOSE: Rituximab has been reported to have little activity in small lymphocytic lymphoma (SLL)/chronic lymphocytic leukemia (CLL) and to be associated with significant infusion-related toxicity. This study sought to decrease the initial toxicity and optimize the pharmacokinetics with an alternative treatment schedule. PATIENTS AND METHODS: Thirty three patients with SLL/CLL received dose 1 of rituximab (100 mg) over 4 hours. In cohort I (n = 3; 250 mg/m(2)) and cohort II (n = 7; 375 mg/m(2)) rituximab was administered on day 3 and thereafter three times weekly for 4 weeks using a standard administration schedule. Cohort III (n = 23; 375 mg/m(2)) administered rituximab similar to cohort II for the first two treatments and then over 1 hour thereafter. RESULTS: A total of 33 CLL/SLL patients were enrolled; only one patient discontinued therapy because of infusion-related toxicity. Thirteen patients developed transient hypoxemia, hypotension, or dyspnea that were associated with significant changes in baseline interleukin-6, interleukin-8, tumor necrosis factor alpha, and interferon gamma compared with those not experiencing such reactions. Infusion-related toxicity occurred more commonly in older (median age 73 v 62 years; P =.02) patients with no other pretreatment clinical or laboratory features predicting occurrence of these events. The overall response rate was 45% (3% CR, 42% PR; 95% CI 28% to 64%). Median response duration for these 15 patients was 10 months (95% CI, 6.8-13.2; range, 3 to 17+). CONCLUSION: Rituximab administered thrice weekly for 4 weeks demonstrates clinical efficacy and acceptable toxicity. Initial infusion-related events seem to be cytokine mediated and resolve by the third infusion making rapid administration possible. Future combination studies of rituximab with other therapies in CLL seem warranted.

Using point-of-care CD34 enumeration to optimize PBSC collection conditions.

BACKGROUND: A PBSC graft containing 4-5 x 10(6) CD34(+) cells/kg is considered optimal in terms of durable engraftment. Tracking CD34 kinetics via point-of-care testing during PBSC mobilization could determine which (and when) patients will yield an optimal product. We evaluated whether microvolume fluorimetry (MVF) would be useful in optimizing PBSC mobilization/harvest and if it will shorten our standard 6 h collection. METHODS: Absolute CD34 values were obtained using the IMAGN 2000 and STELLer CD34 assay (50 microL sample volume). Peripheral blood (PB) CD34 values from 30 patients undergoing PBSC mobilization were used to generate a PB CD34-based algorithm that would predict collection day/duration of apheresis. The algorithm was then used prospectively to collect PBSC products on 50 hematologic malignancy (HM) patients. RESULTS: Using the algorithm, patients were assigned to either a 6 (11-20 CD34/microL), 4 (21-49 CD34/microL) or 2 (> or = 50 CD34/microL) h collection. Patients with a CD34 value < or = 10/microL were re-tested. All patients (n = 43) predicted to mobilize reached the optimal CD34 (4-5 x 10(6)/kg) value with 1.0 apheresis procedure; seven patients had < or = 10/microL (nonmobilizers). The majority (75%) had apheresis charges decreased by 33-66%; 47% only required a 2 h procedure and 28% required 4 h. All patients demonstrated rapid trilineage engraftment. DISCUSSION: Absolute PB CD34 measurement using MVF offers a rapid and reliable approach to obtaining optimal PBSC products with minimal technical expertise. Although not a replacement for conventional flow cytometry, it meets the requirements for a point-of-care procedure.

Allogeneic bone marrow transplantation in patients with sensitive low-grade lymphoma or mantle cell lymphoma.

PURPOSE: To report survival outcomes of allogeneic BMT in patients with low-grade lymphoma or mantle cell lymphoma (MCL). PATIENTS AND METHODS: Thirty-five patients with low-grade lymphoma (48%), chronic lymphocytic leukemia (26%), or MCL (26%) underwent myeloablative allogeneic BMT from HLA-identical siblings at the Johns Hopkins Oncology Center. Patients had a median age of 46 years, a median of 2 prior treatments, and 31% were in complete remission at the time of transplantation. The preparative regimen was cyclophosphamide/total body irradiation for most patients. All grafts were T-cell depleted by counter flow centrifugal elutriation with CD34+ augmentation. RESULTS: The incidence of acute GVHD grade >2 was 6% and of grades 1 to 2 was 37%. The incidence of chronic GVHD was 6%. The median follow-up time was 25 months. The rate of event-free survival (EFS) was 50% (95% confidence interval [CI], 33%-66%). Only 1 patient relapsed. The transplantation-related mortality (TRM) was 46% for all patients. The TRM was 86% for patients with resistant disease and 14% for patients with sensitive disease and <2 prior treatments; rates of EFS were 0% (95% CI, 0%-0%) and 79% (95% CI, 47%-93%), respectively. CONCLUSION: These data show that, with T-cell depletion, the TRM and relapse rates are modest for patients with sensitive disease and <2 prior treatment courses. Thus, if there is a role for allogeneic BMT in the management of patients with these tumors, it is early in the course of the disease.

Characterization of Epstein-Barr virus-infected B cells in patients with posttransplantation lymphoproliferative disease: disappearance after rituximab therapy does not predict clinical response.

Post-transplantation lymphoproliferative disease (PTLD) is associated with Epstein-Barr virus (EBV). Quantitative and qualitative differences in EBV in peripheral blood mononuclear cells (PBMCs) of PTLD patients and healthy controls were characterized. A quantitative competitive polymerase chain reaction (QC-PCR) technique confirmed previous reports that EBV load in PBMCs is increased in patients with PTLD in comparison with healthy seropositive controls (18 539 vs 335 per 10(6) PBMCs, P =.0002). The average frequency of EBV-infected cells was also increased (271 vs 9 per 10(6) PBMCs, P =.008). The distribution in numbers of viral genome copies per cell was assessed by means of QC-PCR at dilutions of PBMCs. There was no difference between PTLD patients and healthy controls. Similarly, no differences in the patterns of viral gene expression were detected between patients and controls. Finally, the impact of therapy on viral load was analyzed. Patients with a past history of PTLD who were disease-free (after chemotherapy or withdrawal of immunosuppression) at the time of testing showed viral loads that overlapped with those of healthy seropositive controls. Patients treated with rituximab showed an almost immediate and dramatic decline in viral loads. This decline occurred even in patients whose PTLD progressed during therapy. These results suggest that the increased EBV load in PBMCs of PTLD patients can be accounted for by an increase in the number of infected B cells in the blood. However, in terms of viral copy number per cell and pattern of viral gene expression, these B cells are similar to those found in healthy controls. Disappearance of viral load with rituximab therapy confirms the localization of viral genomes in PBMCs to B cells. However, the lack of relationship between the change in viral load and clinical response highlights the difference between EBV-infected PBMCs and neoplastic cells in PTLD.