Aggressive Malignant Lymphoma Research Articles

Development of Late over Early Full Donor Chimerism (FDC) Results in Improved Progression-Free and Overall Survival in Patients with Advanced Malignant Lymphomas Receiving Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation (HSCT).

Mixed chimerism (MC) can be induced in mice after non-myeloablative conditioning and allogeneic HSCT. Full donor hematopoiesis conversion from MC can occur when nontolerant donor lymphocyte infusions (DLI) are given weeks following the transplant as a result of lymphohematopoietic GVH reactions that eradicate leukemia/lymphoma without GVHD. Based on this murine model, we initiated a trial in patients with advanced hematologic malignancies of non-myeloablative therapy with HLA-matched related donor HSCT with intentional induction of MC followed by prophylactic DLI (pDLI) at day +35 post-HSCT in those without clinical GVHD. This analysis examines the influence of the kinetics of sustained donor lymphoid (CD3+ cells) chimerism on transplant outcomes. Fifty-four patients with advanced hematologic malignancies received nonmyeloablative preparative therapy (cyclophosphamide, equine antithymocyte globulin, thymic irradiation and a brief course of cyclosporine) and HLA-matched HSCT (bone marrow, BM, n=42; GCSF-mobilized peripheral blood stem cells, PBSC, n=12). Chimerism analyses were performed weekly until day +100 post-HSCT and then once monthly for a year. Twenty-nine patients with aggressive malignant lymphomas (NHL, n=21; HD, n=8) were selected out of 50 evaluable patients in an effort to analyze a relatively uniform group in terms of their disease and sustained chimerism; patients who lost the allograft were removed from this analysis. Twenty five patients attained stable FDC, defined as > or = 90% donor T cells, and 4 maintained stable MC. Using 42 days post-HSCT as the defining point for chimerism conversion 13 patients achieved early FDC and 16 patients achieved late FDC. Median time to achieve FDC in the early and late groups was 14 days (range, 7–42) and 70 days (range, 49–91) respectively. Separation produced fairly equal distribution by disease characteristics as follows (early to late): NHL, 10 to 11 and HD, 3 to 5. The early group included 10 PBSC recipients who did not receive pDLI because of the spontaneous conversion to FDC; in contrast, the majority of the late group received BMT and 13 of them received DLI (pDLI, n=10, therapeutic DLI, n=3). The incidence of acute GVHD (grades II–IV) was similar between the early and late groups with rates of 77% (n=10 of 13) and 69% (n=11 of 16) respectively; for chronic GVHD, there was a tendency toward an increased rate in the early group of 75% (3/4) compared to the late group rate of 63% (5/8). Overall disease response rates in the early and late groups were 62% and 69%, but there was a trend toward improved complete remission rates in the late group relative to the early group (50% vs 31%). Progression-free survival (PFS) and overall survival (OS) at 1 year were improved in the late compared to the early group [31% (5/16) vs 15% (2/13) and 50% (8/16) vs 38% (5/13), respectively]. At 5 years, there was a statistically significant improved PFS and OS rate in the late group over the early group [31% (5/16) vs 0% (0/13), p =0.037, for both PFS and OS]. In conclusion, these data support the observation from our mouse models that the most potent graft-vs-tumor effect occurs in mixed chimeras with late chimerism conversion, often after delayed pDLI.

Residual Disease After Chemotherapy in Aggressive Malignant Lymphoma: The Role of Radiotherapy

Residual disease in patients with diffuse large B-cell lymphoma after intensive chemotherapy remains a problem. Radiotherapy has been used in some retrospective studies without definitive conclusions. We report the first controlled clinical trial to define the role of radiotherapy in this setting of patients. One hundred and sixty-six patients with diagnosis of diffuse large B-cell lymphoma, high- or high-intermediate clinical risk, with residual disease (defined as tumor mass < 5 cm) were randomly assigned to received radiotherapy at the involved field, with 30 Gy delivered in 20 sessions or no radiation (control group). Median follow-up was 135 mo; patients who received radiotherapy have an better outcome. Actuarial curves at 10 yr showed that progressive-free disease was 86% and overall survival was 89%; those were statistical significant when compared to patients who did no received radiotherapy: 32% and 58% respectively, (p < 0.001). Toxicity was mild and well tolerated. We concluded that presence of residual mass after chemotherapy in patients with aggressive malignant lymphoma has a worse prognosis, and salvage radiotherapy improves outcome with mild toxicity. We feel that radiotherapy will be considered as necessary treatment in this special group of patients.

Emergency Treatment of Life-Threatening Intrathecal Methotrexate Overdose

A male 34-year-old patient with aggressive diffuse malignant lymphoma was hospitalized for treatment. Because of high likelihood of CNS involvement, intrathecal methotrexate (MTX) 15 mg was administered with hydrocortisone 100 mg. Shortly after the intrathecal injection the patient became agitated, and complained of severe low back pain and 2 h later he became confused and developed generalized seizures. At this stage, it was realized that the dose contained 1200 mg of MTX (80-fold overdose). The patient developed ARDS and was comatose; he was intubated and transferred to ICU. The patient was immediately treated with intravenous leucovorin 1200 mg, and 15 mg every 6 h, thereafter, for 72 h. In addition, CSF exchange with warm normal saline was initiated via intrathecal catheter, and a total of 200 ml of CSF were replaced during 48 h. Finally, at the end of the exchange 2 mg of leucovorin with 2 mg of dexamethasone were administered intrathecally. MTX levels in CSF 7 h post-injection were 770 μM, and increased to 1250 μM 2 h later. Thereafter, the levels in CSF declined, and 48 h post-injection were 47 μM. The plasma levels of MTX 7 h post-injection were 10 μM, and declined to 0.7 μM at 68 h. The patient regained consciousness and underwent successful weaning from ventilator after tracheostomy. The highest reported intrathecal dose after which the patient survived was 625 mg. Due to the rarity of reported cases, there are no clear guidelines for treatment of massive intrathecal overdose. There is a controversy regarding the toxicity of intrathecal injection of leucovorin. We propose CSF exchange and intravenous leucovorin as the mainstay of treatment.

Growth regulation by p27Kip1 is abrogated by multiple mechanisms in aggressive malignant lymphomas.

The cyclin-dependent kinase inhibitor p27Kip1 is a key regulator of the G1/S transition, and an inverse relationship between p27Kip1 protein expression and proliferation index has been reported in malignant lymphomas. However, a subset of aggressive B-cell lymphomas demonstrates high p27Kip1 expression despite a high proliferation index. The aim of this study was to determine potential mechanisms by which lymphoma cells abrogate the growth inhibitory effect of high p27Kip1. The effect of transforming growth factor-beta (TGF-beta) and serum stimulation on p27Kip1 expression and cyclin E/cdk2 activity was investigated in four lymphoma cell lines, Jurkat, CEM-6, OCI-Ly1 and Nalm-6. Reactive lymphocytes responded to growth inhibitory TGF-beta by inducing p27Kip1 expression, with subsequent accumulation of cells in G0/G1. In contrast, TGF-beta did not alter the level of p27Kip1 in Jurkat, CEM-6 and OCI-Ly1 cells with no change in cyclin E/cdk2-kinase activity. Serum stimulation also did not result in a significant change in p27Kip1 expression. Western blot analysis of subcellular fractions demonstrated cytoplasmic p27Kip1, corroborated by immunocytochemistry in a subset of the lymphoma cells. Sequestration of p27Kip1 by cyclin D3 was observed in the nuclear and cytoplasmic fractions of Nalm-6, OCI-Ly-1 and NCEB cells. These results indicate that multiple mechanisms contribute to the abrogation of growth regulation by unscheduled high p27Kip1 protein expression including deficient response to TGF-beta and serum, sequestration by cyclin D3 and cytoplasmic displacement.

Radiotherapy Versus Combined Therapy in Early Stages with Bulky Disease Aggressive Malignant Lymphoma

The purpose of this study was to evaluate the use of radiotherapy compared with combined therapy (radiotherapy followed by chemotherapy) in early stages (I and II) in patients with diffuse large cell lymphoma and bulky disease.One hundred and thirty patients were randomly assigned to receive either radiotherapy involved field doses range from 40 to 48 Gy (median 44.5 Gy) or the same radiation therapy following chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone, by six cycles.Complete response (CR) was achieved in 58 out of 61 patients (95%) of the patients whose received radiotherapy, that was no different to 91% (63 out of 69 patients) in the combined therapy arm. However, at 10-years event-free survival (EFS) was 68% (95% confidence interval (CI): 61-73%) in the radiotherapy arm that was statistical different to 90% (95% CI: 86-94%) in the combined therapy group (p<0.01). Overall survival (OS) showed statistical differences: 72% (95% CI 67-76%) in the radiotherapy group compared to 89% (95% CI: 84-93%) in the combined therapy arm (p<0.01). Toxicity was mild in both groups, at this time, no second neoplasm or acute leukemia has been observed.We conclude that combined therapy appear to be superior in patients with early stages and bulky disease in patients with aggressive malignant lymphoma.

Therapy of elderly patients with leukemias and malignant lymphomas

Incidence of most malignant lymphomas and leukaemias is increasing with advanced age. 5-year-survival-rates are worse in elderly patients. Therapeutic decisions have to consider possible changes in the biology of the disease together with the age dependent increase in the prevalence of comorbid conditions and the limitations of functional status. Dose intensive chemotherapy protocols, as they are necessary for therapy of acute leukaemias and aggressive malignant lymphomas, are associated with an increased rate of therapy related morbidity and mortality in elderly patients. Supportive care is an essential part of the therapy. Treatment strategies for elderly patients are reviewed within this article.

Spinal Cord Compression as a Primary Manifestation of Aggressive Malignant Lymphomas: Long-term Analysis of Treatments with Radiotherapy, Chemotherapy or Combined Therapy

A controlled clinical trial evaluated the usefulness of three different therapeutic approaches in the treatment of spinal cord compression (SCC) as primary manifestation of malignant lymphoma with the following end-points: neurological function, event free survival (EFS) and overall survival (OS). Forty-eight patients with SCC as unique manifestation (IE) of malignant lymphoma, were randomly assigned to receive either: radiotherapy (16 patients), chemotherapy (11 patients) or combined therapy (radiotherapy followed by chemotherapy, 21 patients). Although neurological recovery was similar in both groups, EFS and OS were better in the combined therapy arm. Actuarial curves at 10 years showed that EFS was 50% for patients treated with radiotherapy, 46% in the chemotherapy arm and 76% in the combined therapy group. Overall survival was 58, 38 and 76%, respectively, however because of the small number of patients, no statistical differences were observed. Although malignant lymphoma with SCC as primary manifestation could be considered as a localized disease, more patients could have microscopic disseminated disease. The use of combined therapy improves the outcome in this group of patients, and so it should be considered the treatment of choice.

Loss of Rho function in the thymus is accompanied by the development of thymic lymphoma.

In vitro studies in model cell lines have implicated the GTPase Rho in the control of diverse cellular responses including the control of the actin cytoskeleton and the regulation of cell cycle progression. It is also reported that the transformation of fibroblasts via oncogenic Ras requires intact Rho signalling. An invaluable tool used to investigate Rho function is the bacterial toxin C3 transferase derived from Clostridium botulinum. C3 transferase ribosylates Rho in its effector domain thereby abolishing interaction with downstream effectors. We have previously reported the use of C3 transferase under the control of the thymocyte specific lck promoter to explore the role of Rho in T cell biology. Strikingly, lck-C3 mice develop aggressive malignant thymic lymphoblastic lymphomas between 4 and 8 months of age. These studies reveal that loss of Rho function is associated with prediposition to lymphoid cell transformation. Inhibition of Rho function has been suggested as a therapeutic strategy for treatment of Ras-transformed tumours. The development of lymphomas in mice devoid of functional Rho in their T cell compartment shows that such a strategy would need to be used with caution.

Intensive brief chemotherapy with hematopoietic growth factors as hematological support and adjuvant radiotherapy improve the prognosis in aggressive malignant lymphoma.

An intensive brief chemotherapy and radiotherapy regimen including high doses of cyclo-phosphamide (5 g/m2), etoposide (1 g/m2), epirubicin (180 mg/m2), and ifosfamide (5 g/m2) administered in a period of 30 days followed by involved field radiotherapy to sites of initial bulky disease was administered to 46 untreated patients with high-intermedium and high-risk malignant lymphoma. G- or GM-CSF were used as hematological support instead of bone marrow transplantation. All patients had more than 3 adverse prognostic factors at diagnosis. Forty-one patients (89%) achieve complete response (33 after chemotherapy and 8 partial responses were converted to complete response after adjuvant radiotherapy). Acturial failure-free survival at 3 years is 83% and 37 of all patients started on therapy remain alive and in first remission at a median of 24.3 months from completion of treatment. Nearly all patients developed granulocytopenia grade IV; only 13 episodes of bacterial infection were documented. Because hematological recovery was very short (mean 13.6 days) no death related treatment and opportunistic infections were observed. Other non-hematological toxicities were scarce and well tolerated. No decrease > 10% was observed in the left ventricular ejection fraction. None have developed clinically evident congestion heart failure or other late side effects. These results showed that G- or GM-CSF can act as hematological support instead of bone marrow transplantation during intensive and brief chemotherapy. These regimens produce higher complete remission rate, and adjuvant radiotherapy will improve the outcome in patients with bulky disease.

Randomised comparison of CHOEP versus alternating hCHOP/IVEP for high-grade non-Hodgkin's lymphomas: Treatment results and prognostic factor analysis in a multi-centre trial

With CHOP, the standard protocol of recent decades, about 30% of long-term survival has been reported. A number of studies using more aggressive multidrug regimens or alternating chemotherapies have recently suggested higher CR rates and increased survival. In 1989 we reported similar results with a combined-modality treatment administering 6 cycles of CHOP supplemented with etoposide and an involved field irradiation for patients in PR or CR. To confirm the efficacy of this approach, we initiated a prospective randomised trial comparing 4 cycles of CHOP-VP16 (CHOEP) with 4 cycles of two alternating regimens, 'hCHOP and IVEP'. One hundred seventy-five patients with high-grade non-Hodgkin's lymphomas stages II-IV were stratified for age, stage and LDH and randomised to receive either four cycles of cyclophosphamide, doxorubicin, vincristine, etoposide, prednisolone (CHOEP) in arm A or four cycles of chemotherapy with a dose-intensified CHOP (hCHOP) alternating with ifosfamide, etoposide, vindesine, prednisolone (IVEP) in arm B. After four cycles of chemotherapy an involved field irradiation with a total dose of 35 Gy was given to all patients demonstrated to be in complete or partial remission. Of the 185 randomised patients, 175 were eligible and 171 evaluable for response and survival. One hundred forty-six of the 171 patients (85%) achieved complete remission (CR) with 87% and 84% CRs in arms A and B, respectively. With a median follow-up of 36 months the estimated overall survival at 2 years is 66% and 73% for arms A and B, respectively. The percentage of all patients in first CR is estimated to be 59% and 55% at 2 years for arms A and B, respectively. None of the differences in CR rate, survival, or relapse-free survival are statistically significant. Multivariate analysis of subgroups incorporating the factors of sex, age, performance status, stage, B symptoms, bulky disease, LDH and histology revealed that only stage and LDH were factors which independently affected outcome. The estimated 2-year survival rate of patients with stages II, III and IV is predicted to be 84%, 62% and 52%, respectively. Patients with LDH > 250 U/l have an estimated survival of 52% at 2 years versus 84% for patients with LDH < or = 250 U/l. According to the newly proposed international score system, the 2-year survival was 81% for low-risk-, 64% for low intermediate risk-, 50% for high intermediate risk-, and 43% for high-risk patients. The toxicity in both arms was tolerable. Three patients died of treatment-related causes (2 in arm A, 1 in arm B). The main toxicity was haematological with 75% of patients suffering from grades 3 or 4 neutropenia at some point during treatment. We observed no superior benefit for alternating regimens, and conclude that both are effective treatment protocols for aggressive histologic-type malignant lymphomas. The results obtained with four cycles of poly-chemotherapy followed by an involved field irradiation are comparable to programs using more aggressive and/or prolonged chemotherapy.

Long-term outcome and sequelae in aggressive lymphoma patients treated with the LNH-80 regimen.

One hundred patients with aggressive malignant lymphoma treated with the LNH-80 regimen were evaluated for long-term survival, late relapse and long-term sequelae. The LNH-80 regimen consisted of three intensive courses of adriamycin, cyclophosphamide, vindesine and bleomycin, followed by consolidation and final intensification, as previously described. Of the eighty-four patients who achieved CR after induction, fifty-two are alive in continuous complete remission with a median follow-up of 9.2 years. Twenty-nine CR patients (35%) relapsed. Sixty-six percent of the relapses occurred during the first 18 months following the end of treatment but late relapses were observed up to 7 years off-therapy. The fifty-two long-term responders were evaluated for their ability to resume work, sexual function, fertility and presence of long-term sequelae. Of the 41 patients who worked before diagnosis of their disease, 66% had resumed their normal jobs and 24% had retired. Sexual activity was considered to be satisfactory by 66% of the patients. Eleven of the 15 patients (73%) who wanted children had between one and three children. Seven patients (14%) were considered to have mild long-term sequelae but all long-term survivors reported having an acceptable quality of life. Five of the patients who reached CR (6%) had second neoplasias. The LNH-80 regimen allowed 52% of the patients to benefit from long-term disease-free survival with minor long-term toxicity.

Splenic involvement by aggressive malignant lymphomas of B-cell and T-cell types. A morphologic and immunophenotypic study

To determine whether there are any consistent morphologic differences between B-cell and T-cell aggressive non-Hodgkin's lymphomas of the spleen, the authors analyzed 16 spleens involved by mixed cell (1 case) or large cell (15 cases) lymphomas. Immunologic data were derived from cell suspensions or frozen tissue in each case. Five cases had a T-cell phenotype, and 11 were B-cell. Morphologic features favoring a T-cell phenotype included epithelioid histiocytic reactions, confinement of the lymphomas to the splenic T-zones (periarteriolar lymphoid sheath and marginal zone), and clear cell or polymorphous cytologic features. Features favoring a B-cell phenotype included multiple discrete nodules in the white pulp, large coalescent tumor nodules in association with small lymphocytic lymphoma, and large non-cleaved or immunoblastic plasmacytoid cytologic characteristics. Four cases were unusual because most neoplastic large cells were distributed diffusely or formed only small aggregates in the red pulp without definite tumor masses or nodules involving the white pulp. Because of this distribution and the frequently encountered erythrophagocytosis by benign-appearing histiocytes, these cases resembled malignant histiocytosis. A T-cell phenotype was predicted for all four cases; however, only one case, a lymphoma with polymorphous cytologic characteristics, was of T-cell lineage. The other three cases were of B-cell lineage. The authors' results indicate that in most instances the B-cell or T-cell nature of aggressive splenic lymphomas is predictable from the distributional and cytologic features. As in lymph nodes, there are cases for which the morphologic characteristics of B-cell and T-cell lymphomas are indistinguishable.

Prognostic factors in aggressive malignant lymphomas: description and validation of a prognostic index that could identify patients requiring a more intensive therapy. The Groupe d'Etudes des Lymphomes Agressifs.

The objectives of this study were to determine prognostic factors for response to treatment, freedom-from-relapse (FFR) survival, and overall survival of 737 aggressive malignant lymphoma patients treated with the doxorubicin, cyclophosphamide, vindesine, bleomycin, methylprednisolone, methotrexate with leucovorin, ifosfamide, etoposide, asparaginase, and cytarabine (LNH-84) regimen; to construct a prognostic index with factors isolated by multivariate analyses; and to validate this prognostic index with another set of patients. Complete response (CR) was reached in 75% of LNH-84 patients, and 30% of them relapsed. With a median follow-up of 36 months, median FFR survival and median overall survival were not reached. Low serum albumin level, high tumoral mass, weight loss, bone marrow involvement, greater than or equal to 2 extranodal sites, and increased lactic dehydrogenase (LDH) level were associated with a low response rate. Advanced stage, increased LDH level, and nonlarge-cell histologic subtypes (diffuse mixed, lymphoblastic, and small non-cleaved) were statistically associated with a high relapse rate and short FFR survival. Increased LDH level, low serum albumin level, tumoral mass larger than 10 cm, greater than or equal to 2 extranodal sites, advanced stage, and age older than 65 years were statistically associated with short overall survival. Four of these parameters, namely, LDH level, stage, number of extranodal sites, and tumoral mass, were put together to construct a prognostic index. This index partitioned LNH-84 patients into three subgroups of good, intermediate, and poor prognosis (P less than .00001): CR rates of 93%, 83%, and 61%; relapse rates of 12%, 25%, and 45%; 3-year FFR survival of 87%, 73%, and 53%, and 3-year survival of 88%, 71%, and 41%, respectively. This prognostic index was applied to a test set of patients: 155 patients treated on protocols of the Nebraska Lymphoma Study Group. Using this index, these patients had 3-year FFR survival of 70%, 40%, and 22% (P = .0002) and 3-year survival of 79%, 52%, and 31% (P = .005). In patients with aggressive lymphomas, this simple prognostic index could distinguish between patients requiring intensive treatment such as autologous bone marrow transplantation in first complete remission and those who could be treated with standard regimens.

Superiority of ProMACE-CytaBOM over ProMACE-MOPP in the treatment of advanced diffuse aggressive lymphoma: results of a prospective randomized trial.

One hundred ninety-three patients with stage II, III, or IV follicular large-cell, diffuse large-cell, diffuse mixed, immunoblastic, or diffuse small noncleaved-cell (non-Burkitt's) lymphoma were randomized to receive either cyclophosphamide 650 mg/m2 intravenously (IV), doxorubicin 25 mg/m2 IV, etoposide 120 mg/m2 IV on day 1, mechlorethamine 6 mg/m2 IV, vincristine 1.4 mg/m2 (no cap at 2 mg total dose) IV on day 8, prednisone 60 mg/m2 orally daily days 1 through 14, procarbazine 100 mg/m2 orally daily days 8 through 14, and methotrexate 500 mg/m2 IV on day 15 with leucovorin 50 mg/m2 orally every 6 hours for four doses beginning 24 hours after methotrexate with cycles repeated every 28 days (ProMACE-MOPP) or same day-1 treatment as ProMACE-MOPP plus cytarabine 300 mg/m2 IV, bleomycin 5 U/m2 IV, vincristine 1.4 mg/m2 (no cap at 2 mg total dose) IV, and methotrexate 120 mg/m2 IV on day 8, leucovorin 25 mg/m2 orally every 6 hours for four doses beginning 24 hours after methotrexate, and prednisone 60 mg/m2 orally daily days 1 through 14 with cycles repeated every 21 days (ProMACE-CytaBOM). Co-trimoxazole two double-strength tablets orally twice daily throughout the period of treatment was added to the ProMACE-CytaBOM regimen when an increased risk of Pneumocystis carinii pneumonia was found in the first 35 patients receiving this combination. Median follow-up is 5 years. Among the 99 patients treated with ProMACE-MOPP, 73 achieved a complete remission (CR) (74%), 30 complete responders have relapsed (41%), and 45 patients have died (45%), including two (2%) of treatment-related causes. Among the 94 patients treated with ProMACE-CytaBOM, 81 achieved a CR (86%), 22 complete responders have relapsed (27%), and 31 patients have died (33%). The complete response rate (P2 = .048) and survival (P2 = .046) were significantly higher for patients treated with ProMACE-CytaBOM. The mortality of ProMACE-CytaBOM treatment overall was six of 94 patients (6.4%). There was no treatment-related mortality among patients treated with prophylactic co-trimoxazole (n = 59). ProMACE-CytaBOM combination chemotherapy with co-trimoxazole prophylaxis is a safe and effective treatment for patients with aggressive histology malignant lymphoma and is superior to ProMACE-MOPP.

LNH-84 regimen: a multicenter study of intensive chemotherapy in 737 patients with aggressive malignant lymphoma.

From July 1984 to September 1987, 737 patients with aggressive malignant lymphoma (ML) were treated by an intensive regimen (LNH-84) comprising three or four courses of doxorubicin, 75 mg/m2; cyclophosphamide, 1,200 mg/m2; vindesine, 2 mg/m2 x 2; bleomycin, 10 mg x 2; and prednisolone, 60 mg/m2 x 5 (ACVB), consolidation with high-dose methotrexate, ifosfamide, etoposide, asparaginase, and cytarabine, and a randomized late intensification with two courses of cytarabine, cyclophosphamide, teniposide, bleomycin, and prednisone (AraCVmB). Four hundred forty-two patients had intermediate-grade ML, 221 highgrade ML, and 74 unclassified ML. Most of the patients had advanced disease: stage IIE (23%), III (13%), or IV (47%); 38% disseminated nodes; 38% two or more extranodal sites; and 41% a tumoral mass greater than 10 cm. Five hundred fifty-three patients (75%) went into complete remission (CR), 63 (9%) into partial remission, 62 (8%) failed to respond, and 59 (8%) died during ACVB courses, 17 of them from progression of the disease. With a median follow-up of 23 months, the estimated 2-year overall survival time to failure (TTF), and time to relapse (TTR) survival are 67%, 56%, and 67%, respectively. Patients receiving a late intensification had the same relapse rate as the other patients. A persistent fibronecrotic mass was found in 150 patients (20%) and did not influence the relapse rate. Toxicity was mainly neutropenia and infection during the ACVB courses, with 40 patients (5%) dying from septic complications while responding to treatment. Fifty-three percent of the patients had a neutropenia less than 0.500 x 10(9)/L, 58% fever (6% grade 4), and 49% a documented infection (8% grade 4). These results obtained with the LNH-84 regimen demonstrate that this therapeutic scheme is an effective treatment for aggressive ML.

Prognosis of Aggressive Lymphomas: A Study of Five Prognostic Models With Patients Included in the LNH-84 Regimen

Four prognostic models described for aggressive malignant lymphomas and the classical Ann Arbor staging system were used to compare the survival of 737 patients treated with the LNH-84 regimen. The aim of the study was to determine the optimal prognostic system at the time of diagnosis. Three institutions have described these models after multivariate analyses: the Dana Farber Cancer Institute (DFCI1 and DFCI2), the MD Anderson Hospital (MDAH), and the Memorial Sloan-Kettering Cancer Center (MSKCC). The models were constructed with the following variables: performance status, LDH level, and tumor extension. The latter is the most difficult to assess: it was considered as the number of extranodal sites and the diameter of the largest mass in DFCI1, stage and the diameter of the largest mass in DFCI2, the number of extranodal and extensive nodal sites in MDAH, and the number of nodal sites and their localization in MSKCC. Univariate studies with LNH-84 regimen patients showed all these variables to have major prognostic significance (logrank tests: P less than 10(-4)). All five prognostic systems divided patients into three subgroups: good, intermediate, and poor prognosis. Logrank analyses of survival showed highly significant differences (X2 greater than 90 and P less than 10(-6)) between the subgroups. No gross difference was found between the models, and none was better than the others. A new, internationally accepted prognostic system for the expression and comparison of treatment results in aggressive malignant lymphomas should include major univariate prognostic parameters and must be reliable and easy to use in clinical practice. Until such time, stage or LDH level are the best alternatives.

Prognosis of aggressive lymphomas: a study of five prognostic models with patients included in the LNH-84 regimen

Four prognostic models described for aggressive malignant lymphomas and the classical Ann Arbor staging system were used to compare the survival of 737 patients treated with the LNH-84 regimen. The aim of the study was to determine the optimal prognostic system at the time of diagnosis. Three institutions have described these models after multivariate analyses: the Dana Farber Cancer Institute (DFCI1 and DFCI2), the MD Anderson Hospital (MDAH), and the Memorial Sloan- Kettering Cancer Center (MSKCC). The models were constructed with the following variables: performance status, LDH level, and tumor extension. The latter is the most difficult to assess: it was considered as the number of extranodal sites and the diameter of the largest mass in DFCI1, stage and the diameter of the largest mass in DFCI2, the number of extranodal and extensive nodal sites in MDAH, and the number of nodal sites and their localization in MSKCC. Univariate studies with LNH-84 regimen patients showed all these variables to have major prognostic significance (logrank tests: P less than 10(-4)). All five prognostic systems divided patients into three subgroups: good, intermediate, and poor prognosis. Logrank analyses of survival showed highly significant differences (X2 greater than 90 and P less than 10(- 6)) between the subgroups. No gross difference was found between the models, and none was better than the others. A new, internationally accepted prognostic system for the expression and comparison of treatment results in aggressive malignant lymphomas should include major univariate prognostic parameters and must be reliable and easy to use in clinical practice. Until such time, stage or LDH level are the best alternatives.

Intensive Chemotherapy in Aggressive Lymphomas: Updated Results of LNH-80 Protocol and Prognostic Factors Affecting Response and Survival

One hundred patients with aggressive malignant lymphomas treated with the LNH-80 regimen were evaluated for long-term survival and pretreatment characteristics predictive of response and survival. LNH-80 consists of three intensive courses of adriamycin cyclophosphamide vindesine bleomycin (ACVB) followed by sequential consolidation and final intensification. Eighty-four patients went into complete remission (CR), eight had a partial response (PR), three failed to respond, and five died during induction. Twenty-three patients (27%) relapsed, in two of whom a prolonged second remission was obtained. Sixty-three patients are currently alive, two of them with disease. Four patients died in CR. Median survival and median freedom from relapse survival were not reached with a median follow-up of 4 1/2 years. Characteristics negatively associated with response in multivariate analysis were: poor performance status, bone marrow involvement, and two or more extranodal sites of disease. Duration of CR was associated with splenic involvement. Three characteristics were negatively associated with survival in multivariate analysis: age, high grade subtypes, and bone marrow involvement.

Intensive chemotherapy in aggressive lymphomas: updated results of LNH- 80 protocol and prognostic factors affecting response and survival

One hundred patients with aggressive malignant lymphomas treated with the LNH-80 regimen were evaluated for long-term survival and pretreatment characteristics predictive of response and survival. LNH- 80 consists of three intensive courses of adriamycin cyclophosphamide vindesine bleomycin (ACVB) followed by sequential consolidation and final intensification. Eighty-four patients went into complete remission (CR), eight had a partial response (PR), three failed to respond, and five died during induction. Twenty-three patients (27%) relapsed, in two of whom a prolonged second remission was obtained. Sixty-three patients are currently alive, two of them with disease. Four patients died in CR. Median survival and median freedom from relapse survival were not reached with a median follow-up of 4 1/2 years. Characteristics negatively associated with response in multivariate analysis were: poor performance status, bone marrow involvement, and two or more extranodal sites of disease. Duration of CR was associated with splenic involvement. Three characteristics were negatively associated with survival in multivariate analysis: age, high grade subtypes, and bone marrow involvement.

Intensive and sequential combination chemotherapy for aggressive malignant lymphomas (protocol LNH-80).

Ninety-seven patients with aggressive malignant lymphoma (ML) were treated with an intensive and sequential chemotherapy (protocol LNH-80). There were 42 patients with intermediate grade ML, 53 patients with high-grade ML, and two patients with true histiocytic ML. Most of the patients were in advanced stage: 21 stage III and 61 stage IV. The LNH-80 protocol schedule comprised three phases: (1) induction with three courses of an intensified CHOP-Bleo (cyclophosphamide, doxorubicin, vindesine, methylprednisolone, and bleomycin); (2) consolidation with cytarabine, followed by high-dose methotrexate and folinic acid rescue, then asparaginase; and (3) final intensification with two courses of CVAP-Bleo (cyclophosphamide, teniposide, cytarabine, methylprednisolone, and bleomycin). CNS prophylaxis included one injection of methotrexate during each induction course and the drugs of the consolidation phase. In cases of initial CNS localization, cranial radiotherapy was added. Eighty-four patients (87%) went into complete remission (CR), 18 (21%) of whom relapsed, usually during the phase of treatment or within 6 months of completing chemotherapy. Sixty-three patients are alive with an overall median follow-up of 24 months. The median survival time and the median disease-free survival have not been reached, and the survival curve seems to have plateaued at above 60%. There was no statistical difference between intermediate-grade ML (CR 90%, relapse 18%) and high-grade ML (CR 84%, relapse 24%). The toxicity of this treatment is mainly encountered during the induction phase: almost all patients had short-term neutropenia, less than 0.500 g/L in 57, with a documented infection in 25. Overall treatment-related mortality was 6%, with four patients dying during the induction phase.