A. Younes

Hyper-CVAD and high-dose methotrexate/cytarabine followed by stem-cell transplantation: an active regimen for aggressive mantle-cell lymphoma.

PURPOSEnDiffuse and nodular forms of mantle-cell lymphoma (MCL) are consistently associated with poor prognosis. In an effort to improve the outcome, we adopted a treatment plan that consisted of four courses of fractionated cyclophosphamide (CY) 1,800 mg/m2 administered with doxorubicin (DOX), vincristine (VCR), and dexamethasone (Hyper-CVAD) that alternated with high-dose methotrexate (MTX) and cytarabine (Ara-C). After four courses, patients were consolidated with high-dose CY, total-body irradiation, and autologous or allogeneic blood or marrow stem-cell transplantation.nnnPATIENTS AND METHODSnForty-five patients were enrolled; 25 patients were previously untreated, 43 patients had Ann Arbor stage IV disease, and 42 patients had marrow involvement. Forty-one patients had diffuse histology, two patients had nodular, and two patients had blastic variants.nnnRESULTSnHyper-CVAD/MTX-Ara-C induced a response rate of 93.5% (complete response [CR], 38%; partial response [PR], 55.5%) after four cycles of pretransplantation induction chemotherapy. All patients who went on to undergo transplantation achieved CRs. For the 25 previously untreated patients, the overall survival (OS) and event-free survival (EFS) rates at 3 years were 92% (95% confidence interval [CI], 80 to 100) and 72% (95% CI, 45 to 98) compared with 25% (95% CI, 12 to 62; P = .005) and 17% (95% CI, 10 to 43; P = .007), respectively, for the previously treated patients. When compared with a historic control group who received a CY, DOX, VCR, and prednisone (CHOP)-like regimen, untreated patients in the study had a 3-year EFS rate of 72% versus 28% (P = .0001) and a better OS rate (92% v 56%; P = .05). Treatment-related death occurred in five patients: all were previously treated and two received allogeneic transplants.nnnCONCLUSIONnThe Hyper-CVAD/MTX-Ara-C program followed by stem-cell transplantation is a promising new therapy for previously untreated patients with MCL.

Impact of High-Dose Chemotherapy on Peripheral T-Cell Lymphomas

PURPOSEnTo evaluate the outcome of high-dose chemotherapy (HDCT) and autologous or allogeneic hematopoietic transplantation in patients with peripheral T-cell lymphoma (PTCL) who experienced disease recurrence after prior conventional chemotherapy.nnnPATIENTS AND METHODSnWe performed a retrospective analysis of 36 PTCL patients from the University of Texas M.D. Anderson Cancer Center treated between 1989 and 1998 with HDCT and autologous or allogeneic hematopoietic transplantation.nnnRESULTSnA total of 36 patients were studied (29 received autologous transplantation, and seven received allogeneic transplantation). The overall survival rate at 3 years was 36% (95% confidence interval [CI], 23% to 59%), and the progression-free survival (PFS) rate was 28% (95% CI, 16% to 49%). The pretransplant serum lactate dehydrogenase level was the most important prognostic factor for both survival and PFS rates (P < .001). A Pretransplant International Prognostic Index score of < or = 1 indicated a superior survival rate (P = .036) but not an improved PFS rate. A median follow-up of 43 months (range, 13 to 126 months) showed 13 patients (36%) were still alive with no evidence of disease.nnnCONCLUSIONnOur results are comparable to the published data on HDCT in B-cell non-Hodgkins lymphoma (NHL) patients despite the fact that patients with PTCL are known to have a worse outcome compared with B-cell NHL patients. Considering the dismal outcome of conventional chemotherapy in PTCL patients, these data suggest the hypothesis that the poor prognostic implication of T-cell phenotyping in NHL might be overcome by frontline HDCT and transplantation.

Reduced-intensity allogeneic stem cell transplantation in relapsed and refractory Hodgkin's disease: low transplant-related mortality and impact of intensity of conditioning regimen

Summary:A total of 40 patients with relapsed/refractory Hodgkins disease (HD) underwent reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT) from an HLA-identical sibling (n=20) or a matched unrelated donor (n=20). The median age was 31 years (range 18–58). Disease status at allo-SCT was refractory relapse (n=14) or sensitive relapse (n=26). The conditioning regimens were fludarabine-cyclophosphamide±antithymocyte globulin (n=14), a less intensive regimen, and fludarabine-melphalan (FM) (n=26), a more intensive one. The two groups had similar prognostic factors. The median time to neutrophil recovery (ie absolute neutrophil count ⩾500/μl) was 12 days (range 10–24). The median time to platelet recovery (ie platelet count ⩾20u2009000/μl) was 17 days (range 7–132). Day 100 and cumulative (18-month) transplant-related mortalities (TRMs) were 5 and 22%. Twenty-four patients (60%) are alive (14 in complete remission or complete remission, unconfirmed/uncertain) with a median follow-up of 13 months (4–78). In all, 16 patients expired (TRM n=8, disease progression n=8). FM patients had better overall survival (73 vs 39% at 18 months; P=0.03), and a trend towards better progression-free survival (37 vs 21% at 18 months; P=0.2). RIC allo-SCT is feasible in relapsed/refractory HD patients with a low TRM. The intensity of the preparative regimen affects survival.

Untreated Aggressive Mantle Cell Lymphoma: Results with Intensive Chemotherapy without Stem Cell Transplant in Elderly Patients

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

CD30 ligand in lymphoma patients with CD30+ tumors.

PURPOSEnCD30 ligand (CD30L), which is expressed on resting B and activated T lymphocytes, can induce cell death in several CD30+ cell lines. Patients with CD30+ tumors (Hodgkins disease and Ki-1+ non-Hodgkins lymphoma) frequently have elevated soluble CD30 (sCD30) levels in their serum, which correlates with a poor prognosis. The role of sCD30 in protecting tumor cells from CD30L-mediated cell death and the pattern of CD30L expression on human peripheral-blood lymphocytes (PBLs) of normal donors and patients with CD30+ tumors are investigated.nnnMATERIALS AND METHODSnCD30L surface protein expression was determined by two-color flow cytometry on PBLs of patients with CD30+ tumors and normal individuals. CD30L levels were determined on subsets of PBLs before and after stimulation with phytohemagglutinin (PHA), anti-CD3 antibody, or CD40L. sCD30 was measured by enzyme-linked immunosorbent assay (ELISA). The apoptotic activity of membrane-bound CD30L was tested in a CD30+ cell line by the annexin V-binding method.nnnRESULTSnUnstimulated T lymphocytes of normal donors and patients with lymphoma rarely expressed CD30L surface protein, but were able to express it after stimulation with PHA or anti-CD3 antibody. Resting B cells of patients with CD30+ tumors had lower levels of detectable surface CD30L compared with normal donors (mean, 55% and 80.6%, respectively; P = .0008). Patients with high levels of serum sCD30 had lower detectable levels of CD30L on their PBLs (R2 = .72, P = .0008) and exogenous sCD30 blocked membrane-bound CD30L-mediated apoptosis in a CD30+ cell line.nnnCONCLUSIONnIn patients with CD30+ tumors, sCD30 can decrease the availability of CD30L on PBLs. Blocking the apoptosis-inducing activity of CD30L by its soluble receptor may explain how CD30+ tumors escape immunosurveillance and may be related to the reported poor prognosis of patients who have elevated sCD30 levels.

Three-hour paclitaxel infusion in patients with refractory and relapsed non-Hodgkin's lymphoma.

PURPOSEnPaclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ) is a novel antimicrotubule agent with anti-tumor activity against ovarian and breast carcinomas. Its activity when administered as a 3-hour intravenous infusion in patients with relapsed non-Hodgkins lymphoma (NHL) has not been studied.nnnPATIENTS AND METHODSnPatients with relapsed NHL were treated with a 3-hour infusion of 200 mg/m2 of Taxol every 3 weeks in an outpatient setting. All patients received premedication (dexamethasone, diphenhydramine, and cimetidine) to prevent allergic reactions. Responses were assessed after two courses of therapy, and patients who achieved at least partial remission (PR) continued to receive Taxol for a maximum of eight courses.nnnRESULTSnOf 60 eligible patients, 54 (90%) were assessable for treatment toxicity and 53 (88%) were for treatment response (22 with primary refractory and 31 with relapsed disease). Twelve patients (23%) achieved a PR (n = 6) or complete remission (CR; n = 6) (95% confidence interval, 12% to 36%). Responses were observed in intermediate-grade (31%), low-grade (14%), and mantle-cell (17%) lymphomas. In the intermediate-grade lymphomas, there was a trend for a higher response rate in relapsed versus primary refractory disease (54% v 13%; P = .08). Treatment-related toxicity included alopecia (100%), peripheral neuropathy (37%), myalgia or arthralgia (25%), and neutropenic fever (11%). None of the patients had allergic reactions or cardiac toxicity.nnnCONCLUSIONnAt this dose and schedule, Taxol is an active agent in patients with relapsed NHL and can be safely administered in an outpatient setting. Combination programs with Taxol should be investigated for treatment of NHL.

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

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

No effect of 96-hour paclitaxel infusion in patients with relapsed non-Hodgkin's lymphoma refractory to a 3-hour infusion schedule.

PURPOSEnPreclinical data suggest that the efficacy of paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ) is schedule-dependent. Schedule dependency is currently under investigation in ongoing randomized trials.nnnPATIENTS AND METHODSnTwelve patients with relapsed non-Hodgkins lymphoma (NHL) refractory to a 3-hour infusion of 200 mg/m2 Taxol were crossed over to receive a 96-hour infusion of 140 mg/m2 Taxol every 3 weeks in an outpatient setting. Premedication with corticosteroids and antihistamines was not used. Patients who did not achieve at least a partial remission (PR) after two courses or whose disease progressed after one course were removed from the study.nnnRESULTSnAll 12 patients were assessable for response. Eleven patients received at least two courses and one patient received one course of 96-hour Taxol infusion. None of the 12 patients crossed over to receive 96-hour Taxol infusion achieved a PR or complete response (CR). Eight patients (67%) developed progressive lymphoma, three (25%) had stable disease, and only one (8%) had a minor response. No major hypersensitivity reactions or life-threatening toxicities were observed.nnnCONCLUSIONnNinety-six-hour Taxol infusion does not produce significant responses in patients with NHL refractory to 3-hour Taxol infusion. Until the results of an ongoing multicenter trial comparing a 3- with a 96-hour infusion are published, the use of 96-hour Taxol infusion in NHL patients should be restricted to investigational programs. Because 48- to 72-hour infusions can produce higher plasma concentrations of Taxol than a 96-hour infusion, these schedules should be investigated to determine if they can induce better clinical responses.

Infusional Vinorelbine in Relapsed or Refractory Lymphomas

Vinorelbine (Navelbine™) is i. semisynthetic vinca alkaloid devoid ot serious neurotoxicity. When given weekly vinorelbine has documented activity against many tumors, including lymphomas. Since weekly schedules cannot be easily incorporated in combination regimens, we tested an infusional schedule of vinorelbine given every 21 days in adults with relapsed or refractory lymphoma. Patients with inadequate organ or bone marrow reserve. HIV or other serious infection. central nervous system disease, or prior stem cell or bone marrow transplantation were ineligible. In the phase I part, patients received a constant intravenous bolus of 8 mg/m2, followed by intravenous continuous infusion over 24 hours daily for four days increasing from 10, 12, to 14 mg/m2/d in successive three-patient cohorts. Cycles were repeated every 21 days, and the daily continuous infusion dose was adjusted for toxicity. Dose-limiting mucositis and neutropenia were reached at the continuous dose of 14 mg/m2/d. Consequently, for the Phase II trial the starting continuous infusion dose was 12 mg/m2/d. After the first 19 patients were entered in the phase II study, the starling infusion dose was reduced to 10 mg/m2/d because of frequent grade 3/4 myelosuppression and mucositis. Forty-four patients were entered in the phase II study, of whom 41 are evaluable. Median age was 61 years, 23 were males. with clinically aggressive non-Hodgkins lymphoma (NHL) in 22, indolent NHL in 18, and Hodgkins Disease in lone patient. The median number of prior regimens was 3 (range 1-11). The lymphoma was refractory to the initial regimen in nine patients, and to the regimen immediately before vinorelbine in 20 patients. Serum LDH was high in 21/41, and serum β2-microglobulin > 3.0 mg / L in 16/31 patients. Responses were observed in four of 22 patients with aggressive NHL (18%, 95% confidence interval 5%-40%). and in six of 18 with indolent NHL (33%, 95% confidence interval 13%-59%). Median progression-free survival was 6 months for responders. During the Phase II trial 114 vinorelbine courses were administered. Neutrophil nadir was < 1000/μml1 in 65% and < 100/μml1 in 35% of courses, respectively. Platelet nadir was < :100,000/μml1 in 30% and < 20,000/μml1 in 8% of courses, respectively, Grade 3/4 mucositis was seen in 18% of courses, and neutropenic fever in 13%, and was complicated by death in one patient. We conclude that this dosage and schedule of vinorelbine has modest activity in patients with relapsed or refractory NHL. Myelosuppression is frequent but reversible, but there is, no significant neurotoxicity. The role of

Experience with 90Y-ibritumomab tiuxetan for relapsed classical Hodgkin lymphoma

Both non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) are radiosensitive tumors. The efficacy of radioimmunotherapy (RIT) targeting tumor-associated CD20 antigen has been established in several types of B-cell NHL. Although the malignant Hodgkin and Reed–Sternberg (HRS) cells of classical HL are of B-cell origin, they infrequently express CD20 antigen and therefore cannot be effectively targeted by anti-CD20 mAbs [1–6]. However, because the microenvironment surrounding HRS cells frequently contains reactive B lymphocytes that express CD20, we hypothesized that targeting these reactive B cells by anti-CD20 RIT could deliver an effective radiation dose to HRS cells by a crossfire effect [7]. To test this hypothesis, patients with relapsed classical HL were treated with Y-ibritumomab tiuxetan (Zevalin) using an Institutional Review Board (IRB)-approved pilot clinical trial. Patients were considered eligible for the study if they had histologically confirmed, relapsed or refractory classical HL requiring treatment; relapsed from, refused, or were ineligible for stem-cell transplantation; and an absolute neutrophil count of >1500/ll and a platelet count of >100 000/ll. Patients who had prior autologous stem-cell transplantation were required to have backup stored stem cells of at least 2 · 10 CD34 cells/kg. Patients were excluded from the study if they had HL involving extranodal sites, including the bone marrow, nodular lymphocyte-predominant HL, prior allogeneic stem-cell transplantation, central nervous system lymphoma, pleural effusion, human immunodeficiency virus infection, total bilirubin >2.0 mg/dl, serum creatinine >2.0 mg/dl, or if they received prior external beam radiotherapy to >25% of bones. Four patients were treated on an IRB-approved study and all signed a consent form. Two patients received prior autologous stem-cell transplant. Biopsy materials from three cases were available for review and showed that CD20 was expressed by HRS cells in one case (Table 1). Reactive B cells comprised 5%, 10%, and 20% of the reactive cells surrounding HRS cells. All patients received 0.4 mCi/kg up to a maximum dose of 32 mCi. Favorable biodistribution of ibritumomab tiuxetan was confirmed in all four patients during the imaging phase. Tumor visualization was as follows: absent in one patient, faint visualization of some of the known lesions in two patients, and intense visualization of known disease sites in the supraclavicular, infraclavicular, mediastinal, hepatic, and abdominal lymphatic chains in one patient (Table 1). Following ibritumomab tiuxetan therapy, two patients had stable disease (less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions) and two had progression of disease. Treatment was well tolerated with hematologic toxicity similar to that observed in NHL patients treated with ibritumomab tiuxetan [8]. This is the first report using reactive B cells in the tumor microenvironment to indirectly deliver radiation to malignant HRS cells by crossfire effect. The theoretical advantages of this approach are (i) eliminate benign reactive B cells to deprive HRS cells from survival signals, (ii) directly kill CD20 HRS cells by RIT, and (iii) indirectly kill CD20 HRS cells by crossfire radiation from ibritumomab tiuxetan bound to normal infiltrating CD20 B cells. Although the number of patients in this report is small, our data indicate that this novel approach is feasible and safe. Tumor visualization was either absent or faint in three of the four patients, perhaps due to the small fraction of reactive B cells in the microenvironment (Table 1). A biopsy from the patient who had intense tumor imaging contained 20% reactive B cells. Future studies should examine whether there is a minimal requirement of reactive B cells in the microenvironment that is required for effective tumor imaging and to deliver a lethal dose to HRS cells. This will require carrying out needle biopsy and aspiration to quantify the percentage of CD20-expressing cells in HL lesions immediately before RIT and to correlate these findings with