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.

The role of body mass index in survival outcome for lymphoma patients: US intergroup experience.

BACKGROUND: The role of body mass index (BMI) in survival outcomes is controversial among lymphoma patients. We evaluated the association between BMI at study entry and failure-free survival (FFS) and overall survival (OS) in three phase III clinical trials, among patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Hodgkin's lymphoma (HL). PATIENTS AND METHODS: A total of 537, 730 and 282 patients with DLBCL, HL and FL were included in the analysis. Baseline patient and clinical characteristics, treatment received and clinical outcomes were compared across BMI categories. RESULTS: Among patients with DLBCL, HL and FL, the median age was 70, 33 and 56; 29%, 29% and 37% were obese and 38%, 27% and 37% were overweight, respectively. Age was significantly different among BMI groups in all three studies. Higher BMI groups tended to have more favorable prognosis factors at study entry among DLBCL and HL patients. BMI was not associated with clinical outcome with P-values of 0.89, 0.30 and 0.40 for FFS, and 0.64, 0.67 and 0.09 for OS, for patients with DLBCL, HL and FL, respectively. The association remains non-significant after adjusting for other clinical factors in the Cox model. A subset analysis of males with DLBCL treated on R-CHOP revealed no differences in FFS (P = 0.48) or OS (P = 0.58). CONCLUSION: BMI was not significantly associated with clinical outcomes among patients with DLBCL, HD or FL, in three prospective phase III clinical trials. The findings contradict some previous reports of similar investigations. Further work is required to understand the observed discrepancies.

A multicenter phase II study incorporating high-dose rituximab and liposomal doxorubicin into the CODOX-M/IVAC regimen for untreated Burkitt's lymphoma.

BACKGROUND: Despite improvement with intensive multi-agent chemotherapy, 2-year progression-free survival (PFS) rates for adults with high-risk Burkitt's lymphoma (BL) remains <55%. PATIENTS AND METHODS: We conducted a phase II trial for newly diagnosed classic BL utilizing liposomal doxorubicin (Adriamycin) in lieu of doxorubicin and incorporating intravenous rituximab (at 500 mg/m(2) twice/cycle) into the CODOX-M/IVAC regimen. Correlative analyses included paired serum and cerebrospinal fluid (CSF) rituximab levels and close examination of cardiac function. RESULTS: Among 25 BL patients, the median age was 44 years (23-70) and 4 patients were HIV positive. There were 20 high-risk and 5 low-risk patients. At baseline, 40% of high-risk patients had bone marrow involvement, 35% had bulky disease and 15% had central nervous system involvement. The overall response rate was 100% (complete remission 92%). At 34-month median follow-up, the 2-year PFS and overall survival (OS) rates for all patients were 80% and 84%, respectively (low-risk: both 100%; high-risk: 76% and 81%, respectively). Furthermore, the 2-year PFS, OS, and disease-specific survival (DSS) rates for high-risk, HIV-negative patients were 84%, 89% and 100%, respectively. Adverse events (AEs) appeared to be consistent with prior CODOX-M/IVAC data, although there were several grade 3 cardiac events noted (all declined ejection fraction without clinical symptoms). The mean serum rituximab levels at 24 h after cycles 1 and 3 for patients without relapse were 258 and 306 µg/ml, respectively, versus 131 and 193 µg/ml, respectively, for patients with early progression (P = 0.002 and 0.002, respectively). The mean CSF rituximab levels for all patients were 0.11 and 0.24 µg/ml, respectively, at cycle 1 (24/72 h), which equated to serum:CSF ratios of 0.05% and 0.20%, respectively. CONCLUSIONS: The integration of rituximab into CODOX-M/IVAC for adult BL was feasible and tolerable, while changes in cardiac function warrant continued examination. This regimen was associated with excellent survival rates for HIV-negative BL. Further investigation of the predictive value of serum rituximab is needed. Clinicaltrials.gov NCT00392990.

Primary CNS posttransplant lymphoproliferative disease (PTLD): an international report of 84 cases in the modern era.

We performed a multicenter, International analysis of solid organ transplant (SOT)-related primary central nervous system (PCNS) posttransplant lymphoproliferative disease (PTLD). Among 84 PCNS PTLD patients, median time of SOT-to-PTLD was 54 months, 79% had kidney SOT, histology was monomorphic in 83% and tumor was EBV+ in 94%. Further, 33% had deep brain involvement, 10% had CSF involvement, while none had ocular disease. Immunosuppression was reduced in 93%; additional first-line therapy included high-dose methotrexate (48%), high-dose cytarabine (33%), brain radiation (24%) and/or rituximab (44%). The overall response rate was 60%, while treatment-related mortality was 13%. With 42-month median follow-up, three-year progression-free survival (PFS) and overall survival (OS) were 32% and 43%, respectively. There was a trend on univariable analysis for improved PFS for patients who received rituximab and/or high-dose cytarabine. On multivariable Cox regression, poor performance status predicted inferior PFS (HR 2.61, 95% CI 1.32-5.17, p = 0.006), while increased LDH portended inferior OS (HR 4.16, 95% CI 1.29-13.46, p = 0.02). Moreover, lack of response to first-line therapy was the most dominant prognostic factor on multivariable analysis (HR 8.70, 95% CI 2.56-29.57, p = 0.0005). Altogether, PCNS PTLD appears to represent a distinct clinicopathologic entity within the PTLD spectrum that is associated with renal SOT, occurs late, is monomorphic and retains EBV positivity.

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

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

Phase I/II trial of total lymphoid irradiation and high-dose chemotherapy with autologous stem-cell transplantation for relapsed and refractory Hodgkin's lymphoma.

BACKGROUND: The standard approach to treatment of relapsed/refractory Hodgkin's lymphoma (HL) is high-dose chemotherapy conditioning followed by autologous hematopoietic stem-cell transplantation (aHSCT). We report the results of a prospective phase I/II clinical trial of accelerated hyperfractionated total lymphoid irradiation (TLI) immediately followed by high-dose chemotherapy for relapsed/refractory HL. PATIENTS AND METHODS: Forty-eight patients underwent aHSCT with either sequential TLI/chemotherapy (n = 32) or chemotherapy-alone conditioning (n = 16), based on prior radiation exposure. The first 22 patients enrolled on trial received escalating doses of etoposide (1600-2100 mg/m(2)) with high-dose carboplatin and cyclophosphamide. RESULTS: No dose-limiting toxicity was seen and TLI/chemotherapy was well tolerated. The 5-year event-free survival (EFS) estimate for all patients was 44% with overall survival (OS) of 48%. Five-year EFS and OS for the TLI/chemotherapy group was 63% and 61%, respectively, compared with 6% and 27%, respectively, for the chemotherapy-alone group (P < 0.0001 and P = 0.04, respectively). Patients with primary induction failure HL who received TLI/chemotherapy had 5-year EFS and OS rate of 83%. The 100-day treatment-related mortality was 4.2% and two secondary cancers were seen. Significant factors predicting survival by multivariate analysis included TLI/chemotherapy conditioning and B symptoms at relapse. CONCLUSIONS: Sequential TLI/chemotherapy conditioning for relapsed/refractory HL is safe and associated with excellent long-term survival rates.

Does younger donor age affect the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies beneficially?

Sixty three patients aged 27-66 years (median 52) were allografted from HLA-matched sibling (n=47), 10 of 10 allele-matched unrelated (n=19), or one-antigen/allele-mismatched (n=7) donors aged 24-69 years (median 46) after a conditioning regimen comprising 100 mg/m(2) melphalan. Cyclophosphamide (50 mg/kg) was also administered to patients who had not been autografted previously. Cyclosporine or tacrolimus, and mycophenolate mofetil were administered to prevent graft-versus-host disease (GVHD). The 2-year cumulative incidences of relapse and TRM were 55 and 24% respectively, and 2-year probabilities of overall survival (OS) and disease-free survival (DFS) were 36 and 21%, respectively. Poor performance status, donor age >45 years and elevated lactate dehydrogenase (LDH) increased the risk of treatment-related mortality (TRM), refractory disease and donor age >45 years increased the risk of relapse, and OS and DFS were adversely influenced by refractory disease, poor performance status, increased LDH, and donor age >45 years. Our data suggest that younger donor age is associated with better outcome after sub-myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) for hematologic malignancies due to lower TRM and relapse. This finding raises the question of whether a young 10-allele-matched unrelated donor is superior to an older matched sibling donor in patients where the clinical situation permits a choice between such donors.

Ideal rather than actual body weight should be used to calculate cell dose in allogeneic hematopoietic stem cell transplantation.

Whether the CD34+ and CD3+ cell doses in allogeneic HSCT should be estimated using actual (ABW) or ideal (IBW) body weight has never been definitively determined. We have shown that CD34+ cell doses based upon IBW are better predictive of engraftment after autologous and allogeneic HSCT. Sixty-three patients undergoing reduced-intensity HSCT after a uniform preparative regimen were evaluated to determine the effect of cell dose. ABW and IBW were 45-147 kg (median 79) and 52-85 kg (median 67) respectively. The ABW-IBW difference was -24% to +133% (median +16%); nine patients were >5% underweight and 41 were >5% overweight. The CD34+ cell dose (10(6)/kg) was 1.4-11.8 (median 5) by IBW and 1.2-9.3 (median 4.5) by ABW. The CD3+ cell dose (10(8)/kg) was 0.9-14.9 (median 3) by IBW and 0.7-19.7 (median 2.7) by ABW. While CD34+ and CD3+ cell doses based upon IBW were found to affect transplant-related mortality, and disease-free and overall survival significantly, those based on ABW were either not predictive of outcome or the differences were of borderline significance. We suggest using IBW rather than ABW to calculate cell doses for HSCT; for statistical analyses and for clinical practice if a specific cell dose is being targeted.

Use of total leukocyte and platelet counts to guide stem cell apheresis in healthy allogeneic donors treated with G-CSF.

Healthy stem cell donors start leukapheresis 4-5 days after starting G-CSF based on the peripheral blood CD34+ cell count (PBCD34). Data from 137 harvests (68 donors) were analyzed to determine correlation between pre-apheresis leukocytes (11.0-94.8x10(9)/l; median 38.8) and platelets (49-374x10(9)/l; median 180), and PBCD34 (3-276/microl; median 40). PBCD34 correlated positively with leukocytes (r=0.48; P<0.0001) and platelets (r=0.40; P<0.0001). When pre-apheresis leukocytes were >or=25 and platelets were >or=100, PBCD34 and CD34+ collection were 5-276/microl (median 57) and 0.5-27.6x10(6)/kg (median 4.7), respectively; significantly higher than PBCD34 of 3-74/microl (median 17) and CD34+ collection of 0.2-8.9 x 10(6)/kg (median 2.2) when leukocytes were <25 and/or platelets were <100. With leukocytes >or=25 and platelets >or=100, PBCD34 was low (<20/microl) 8% of the time, compared to 57% of the time with leukocytes <25 and/or platelets <100 (P<0.0001). Our data suggest that it is not always necessary to measure PBCD34 to guide leukapheresis in healthy donors because pre-apheresis leukocytes and platelets >or=25 and >or=100, respectively, are associated with excellent mobilization. When blood counts do not meet these criteria, PBCD34 should be determined prior to initiation of apheresis.

Rust and corrosion in hematopoietic stem cell transplantation: the problem of iron and oxidative stress.

Iron overload is a common acute and long-term event associated with autologous and allogeneic hematopoietic stem cell transplantation (HSCT). In a state of iron excess, free iron becomes available to catalyze the conversion of reactive oxygen species (ROS) intermediates such as superoxide anion (O2*-) and hydrogen peroxide (H2O2) to highly toxic free radicals such as hydroxyl radical (OH*). ROS may help to promote chronic liver disease, sinusoidal obstruction syndrome, idiopathic pneumonia syndrome and bacterial, fungal and other opportunistic infections. Phlebotomy has been effectively and safely used to deplete excess iron stores post-HSCT in thalassemic and other iron-overloaded patients. Intracellular iron levels may also be decreased through pharmacologic chelating agents, while antioxidants such as N-acetylcysteine, glutamine (glutathione precursor) and captopril have been shown to replenish glutathione redox potential and scavenge free radicals. A better understanding of the mechanisms involved in the iron-generated pro-oxidant state associated with HSCT will likely lead to reduced toxicity and improved patient outcomes.

Ideal or actual body weight to calculate CD34+ cell doses for allogeneic hematopoietic stem cell transplantation?

The number of CD34+ cells infused influences hematologic recovery after transplantation. Limited data suggest that cell dose should be based on ideal (IBW) rather than actual (ABW) body weight for autotransplantation, but none in allografts. We compared the correlation between recovery to 0.5 x 10(9)/l neutrophils and the CD34+ cell dose based upon ABW and IBW in 78 allograft recipients. ABW was > or =25% over IBW in 47% of patients. The median CD34+ cell dose was 5.1 x 10(6)/kg IBW and 4.4 x 10(6)/kg ABW. The time to neutrophil recovery was 8-26 days (median 12). There was a stronger inverse correlation between CD34+ cell dose/IBW and neutrophil recovery (r(2)=0.160; P<0.0001) than between CD34+ cell dose/ABW and neutrophil recovery (r(2)=0.138; P=0.001). When neutrophil recovery in patients receiving <3 or <5 x 10(6) CD34+ cells/kg was compared to those receiving > or =3 or > or =5 x 10(6) CD34+ cells/kg, respectively, separately by IBW and ABW, the magnitude and significance of the differences were greater for IBW-based comparisons. These data suggest the CD34+ cell dose based on IBW is a better predictor of neutrophil recovery after allografting. Further work in a larger, more homogeneous group of patients is required to confirm this observation.

Ideal or actual body weight to calculate CD34+ cell doses for autologous hematopoietic stem cell transplantation?

The number of CD34+ cells infused influences the speed of hematologic recovery post-transplant. There are limited data on whether ideal (IBW) or actual (ABW) body weight should be used to calculate CD34+ cell dose. We compared the correlation between recovery to 0.5 x 10(9)/l neutrophils and the CD34+ cell dose based upon ABW as well as IBW in 87 patients autografted for cancer. ABW was >or=25% over IBW in 43% of patients. The median number of CD34+ cells administered was 3.6 x 10(6)/kg ABW and 4.2 x 10(6)/kg IBW. The time to neutrophil recovery was 8-15 days (median 10). There was a stronger inverse correlation between CD34+ cell dose/IBW and neutrophil recovery (r(2)=0.308; P<0.0001) than between CD34+ cell dose/ABW and neutrophil recovery (r(2)=0.267; P<0.0001). The median time to neutrophil recovery was comparable for those receiving >or=2 x 10(6)/kg CD34+ cells/kg IBW as well as ABW (10 days) and those receiving >or=2 x 10(6)/kg CD34+ cells/kg IBW but <2/kg ABW (10 days), but was significantly slower for those receiving <2 x 10(6)/kg CD34+ cells/kg IBW (12 days). These data show that the CD34+ cell dose based on IBW is a better predictor of neutrophil recovery after autotransplantation.

Reassessing the definition of myeloid engraftment after autotransplantation: it is not necessary to see 0.5 x 10(9)/l neutrophils on 3 consecutive days to define myeloid recovery.

The time to myeloid recovery after autologous hematopoietic stem cell transplantation (HSCT) is usually defined as the first of 3 consecutive days with an absolute neutrophil count (ANC) of >or=0.5 x 10(9)/l (ANC500). Universal documentation of ANC500 for 3 consecutive days, historically required to ensure robust myeloid recovery, has become difficult with a trend towards early discharge and outpatient HSCT. We studied 90 autografted patients to see how frequently ANC declined after having reached >or=0.5 x 10(9)/l. ANC500 was documented on 2 and 3 consecutive days in 14 and 63 patients, respectively. ANC increased by a median of 213% from the 1st to the 2nd day (rise in 75 and unchanged in two), and by a median of 142% from the 2nd day to the 3rd (rise in 60, unchanged in one, and decline in two; higher than the 1st day in the latter three). The increase from the 1st to the 3rd day was 13-3433% (median, 557%). Thus, in all 63 patients, no decline below ANC500 was seen, and the first day with ANC500 was also the first of 3 consecutive days with ANC500. The remaining 13 patients had repeat counts 2-7 days after the 1st day with ANC500 documenting further increase in ANC with no evidence of failed engraftment. These data show that the first day with ANC500 is also consistently the first of 3 consecutive days with ANC500 in autografted patients. Therefore, the traditional definition of myeloid engraftment should be changed to consider the first day with ANC500 as the day of engraftment without necessarily documenting ANC500 on the subsequent 1-2 days. This simple change in definition has significant implications for how data are reported to transplant registries and how peer-review organizations such as the Foundation for the Accreditation of Hematopoietic Cell Therapy (FAHCT) define completeness of data.

Secondary acute myelogenous leukemia with MLL gene rearrangement following radioimmunotherapy (RAIT) for non-Hodgkin's lymphoma.

Targeted therapy with conjugated and unconjugated monoclonal antibodies for non-Hodgkin's lymphoma has revolutionized the approach to this disease. The efficacy and low toxicity of these agents have allowed introduction of this strategy in the early stages of therapy. Longer follow-up is needed before validating the safety of these agents. Since monoclonal antibodies are being given as front-line therapy, it is important to identify all potential adverse events. We report a case of secondary acute myelogenous leukemia (AML) with 11q23 cytogenetic abnormality and mixed lymphoid leukemia (MLL) gene expression in a patient treated with Y90 labeled anti-CD20 antibody (Zevalin). The patient was not exposed to topoisomerase II inhibitors. Our observations suggest a relationship between 11q23 leukemia and radioimmunotherapy (RAIT) and further studies are needed.

Thrombotic microangiopathy in the cancer patient.

Thrombotic microangiopathy, manifesting as thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome, is a common complication in cancer patients. It shares the pathogenic microvascular occlusive lesion and many clinical manifestations as the classical TTP, but the spectrum of complications varies widely. Several subsets are seen, including a microangiopathic hemolytic anemia in advanced cancer, chemotherapeutic drug-associated microangiopathy and those with the transplant setting. The prognosis is not as favorable as in classical TTP. Anecdotal reports indicate that responses are seen with plasma exchange and with immunoadsorption.

Phase I study of fludarabine plus cyclophosphamide in patients with previously untreated low-grade lymphoma: results and and long-term follow-up--a report from the Eastern Cooperative Oncology Group.

PURPOSE: To determine the toxicity and recommended phase II doses of the combination of fludarabine plus cyclophosphamide in chemotherapy-naive patients with low-grade lymphoma. PATIENTS AND METHODS: Previously untreated patients with low-grade lymphoma were entered onto dosing cohorts of four patients each. The cyclophosphamide dose, given on day 1, was increased from 600 to 1, 000 mg/m(2). Fludarabine 20 mg/m(2) was administered on days 1 through 5. The first eight patients were treated every 21 days; later patients were treated every 28 days. Prophylactic antibiotics were required. RESULTS: Prolonged cytopenia and pulmonary toxicity each occurred in three of eight patients treated every 3 weeks. The 19 patients treated every 28 days, who were given granulocyte colony-stimulating factor as indicated, did not have undue nonhematologic toxicity. Dose-limiting toxicity was hematologic. At the recommended phase II/III dose (cyclophosphamide 1,000 mg/m(2)), grade 4 neutropenia was observed in 17% of all cycles and 31% of first cycles. Grade 3 or 4 thrombocytopenia was seen in only 1% of all cycles. The median number of cycles per patient was six (range, two to 11) for all patients enrolled. The response rate was 100% of 27 patients entered; 89% achieved a complete and 11% a partial response. Nineteen of 22 patients with bone marrow involvement had clearing of the marrow. Median duration of follow-up was more than 5 years; median overall and disease-free survival times have not been reached. Kaplan-Meier estimated 5-year overall survival and disease-free survival rates were 66% and 53%, respectively. CONCLUSION: The recommended dosing for this combination in patients with previously untreated low-grade lymphoma is cyclophosphamide 1, 000 mg/m(2) day 1 and fludarabine 20 mg/m(2) days 1 through 5. The regimen has a high level of activity, with prolonged complete remissions providing 5-year overall and disease-free survival rates as high as those reported for other therapeutic approaches in untreated patients.