Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: long-term outcome of the LPA 99 multicenter study by the PETHEMA Group.

A previous report of the Programa de Estudio y Tratamiento de las Hemopatías Malignas (PETHEMA) Group showed that a risk-adapted strategy combining all-trans retinoic acid (ATRA) and anthracycline monochemotherapy for induction and consolidation in newly diagnosed acute promyelocytic leukemia results in an improved outcome. Here we analyze treatment outcome of an enlarged series of patients who have been followed up for a median of 65 months. From November 1999 through July 2005 (LPA99 trial), 560 patients received induction therapy with ATRA plus idarubicin. Patients achieving complete remission received 3 courses of consolidation followed by maintenance with ATRA and low-dose chemotherapy. The 5-year cumulative incidence of relapse and disease-free survival were 11% and 84%, respectively. These results compare favorably with those obtained in the previous LPA96 study (P = .019 and P = .04, respectively). This updated analysis confirms the high antileukemic efficacy, low toxicity, and high degree of compliance of a risk-adapted strategy combining ATRA and anthracycline monochemotherapy for consolidation therapy.

Pegylated liposomal doxorubicin, melphalan and prednisone therapy for elderly patients with multiple myeloma.

Melphalan & Prednisone (MP) is considered as the standard therapy for Multiple Myeloma (MM) patients not eligible for high-dose therapy. Here, we report the results of a phase I-II study to evaluate the feasibility and efficacy of the association of PLD to the conventional MP regimen during the first six cycles of the front-line therapy for untreated MM patients older than 70. Thirty patients were included in the study with a median age of 77 years (71-84) and a M/F ratio of 17/13. The phase I of the study demonstrated that the maximum tolerable dose of PLD in this setting was 30 mg/m(2), so it was the final dose evaluated in the study. Twenty-nine patients were valuable for response, which was: complete in 4 (14%) partial in 15 (52%) minor/no changes in 7 (24%) and progressive in 3 (10%). The median progression free survival (PFS) was 24 months. The median overall survival (OS) has not been reached yet, with a 3-year probability for OS and PFS of 52 and 37%, respectively. Haematological toxicity was frequent but usually weak/moderate (grades 1 & 2 of the WHO scale) and it was resolved only with dose delays. Infection was a relatively frequent event (30% of patients), but only in 4 cases it was of grade 3. No cases of palmar-plantar erythrodysesthesia were observed. In conclusion, pegylated liposomal doxorubicin can be safely added to the other chemotherapeutic drugs in the treatment of elderly MM patients, which can be very useful for patients in whom novel agents are not tolerated or inefficient.

Prognostic factors affecting long-term outcome after stem cell transplantation in Hodgkin's lymphoma autografted after a first relapse.

PURPOSE: To analyse outcome and prognostic factors for overall survival (OS) and time to treatment failure (TTF) in 357 patients with Hodgkin's lymphoma (HL) undergoing an autologous stem cell transplantation (ASCT) after a first relapse and reported to the The Grupo Espanol de Linfomas/Trasplante Autologo de Medula Osea (GEL/TAMO) Cooperative Group. METHODS: Two hundred and twenty males and 137 females with a median age of 29 years were autografted in second remission (n=181), first sensitive relapse (n=148) and first resistant relapse (n=28). RESULTS: Five-year actuarial TTF and OS were of 49% +/- 3% and 57% +/- 3%. Advanced stage at diagnosis, complementary radiotherapy before ASCT, a short first complete response (CR) and detectable disease at ASCT adversely influenced TTF. Year of transplant < or =1995, bulky disease at diagnosis, a short first CR, detectable disease at ASCT and > or =1 extranodal areas involved at ASCT were adverse factors for OS. CONCLUSIONS: ASCT constitutes a therapeutic option for HL patients after a first relapse. Promising results are observed in patients with low tumour burden at diagnosis, autografted after a long CR and without detectable disease at ASCT. Innovative approaches should be pursued for patients with risk factors at relapse.

Autologous stem-cell transplantation in diffuse large B-cell non-Hodgkin's lymphoma not achieving complete response after induction chemotherapy: the GEL/TAMO experience.

BACKGROUND: Here we evaluate the results of high-dose chemotherapy and autologous stem-cell transplantation (HDC/ASCT) in 114 patients included in the GEL/TAMO registry between January 1990 and December 1999 with diffuse large B-cell lymphoma who failed to achieve complete remission (CR) with front-line conventional chemotherapy. PATIENTS AND METHODS: Sixty-eight per cent had a partial response (PR) and 32% failed to respond to front-line therapy. At transplant, 35% were chemoresistant and 29% had two to three adjusted International Prognostic Index (a-IPI) risk factors. RESULTS: After HDC/ASCT, 57 (54%) of 105 patients evaluable for response achieved a CR, 16 (15%) a PR and 32 (30%) failed. Nine patients were not assessed for response because of early death due to toxicity. With a median follow-up of 29 months for alive patients, the survival at 5 years is 43%, with a disease-free survival for complete responders of 63%. The lethal toxicity was 8%. Multivariate analysis revealed a-IPI and chemoresistance to be predicting factors. CONCLUSIONS: Our results show that one-third of patients who do not obtain a CR to front-line chemotherapy may be cured of their disease with HDC/ASCT. However, most chemoresistant patients pretransplant failed this therapy. For this population, as well as for those who presented with adverse factors of the a-IPI, pretransplant novel therapeutic modalities need to be tested.

High-dose chemotherapy and autologous stem cell transplantation in peripheral T-cell lymphoma: the GEL-TAMO experience.

BACKGROUND: T-cell immunophenotype constitutes an unfavorable prognostic factor in aggressive non-Hodgkin's lymphomas. High-dose chemotherapy with autologous stem-cell rescue (HDC/ASCT) is the best salvage therapy for patients with aggressive B-cell lymphomas. However, results with this therapy in peripheral T-cell lymphoma (PTCL) are not well defined. PATIENTS AND METHODS: From January 1990 to December 1999, 115 patients with PTCL underwent HDC/ASCT inside the Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea (GEL-TAMO) registry. At diagnosis the median age was 41 years and 60% of patients presented with two or three risk factors from the adjusted International Prognostic Index (a-IPI). Thirty-two per cent of patients were transplanted in first complete response (CR), 62% in chemosensitive disease and 5% in refractory disease. RESULTS: Eighty-six per cent of the patients attained a CR and 5% a partial response (PR). With a median follow-up of 37 months (range 1-133), overall survival (OS), time-to-treatment failure (TTF) and disease-free survival (DFS) at 5 years was 56%, 51% and 60%, respectively; for the 37 patients transplanted in first CR, OS and DFS at 5 years were 80% and 79%, respectively. Lactase dehydrogenase (LDH), a-IPI and disease status pre-transplant were associated with outcome. CONCLUSIONS: More than half of patients with chemosensitive disease who were transplanted are expected to be alive at 5 years. We confirm the utility of the pre-transplant IPI system in predicting outcome. Salvage treatment results with HDC/ASCT in PTCL are similar to those found in corresponding aggressive B-cell lymphomas.

High-dose therapy in diffuse large cell lymphoma: results and prognostic factors in 452 patients from the GEL-TAMO Spanish Cooperative Group.

BACKGROUND: The purpose of this study was to analyse the results and prognostic factors influencing overall survival (OS) and disease-free survival (DFS) in 452 patients diagnosed with diffuse large cell lymphomas (DLCL) treated with high-dose therapy (HDT) included in the Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea (GEL-TAMO) Spanish registry. PATIENTS AND METHODS: At transplantation, median age was 42 years (range 15-73), 146 patients (32%) were transplanted in first complete remission (1st CR), 19% in second CR (2nd CR) and 47% had active disease: sensitive disease in 157 (35%) patients [95 were in first partial remission (1st PR) and 62 in second PR (2nd PR)] and refractory disease in 55 (12%) patients. Age-adjusted International Prognostic Index (IPI) was 2 or 3 in 51 patients (12%). Conditioning regimen consisted of BEAM (carmustine, etoposide, cytarabine and melphalan) in 39% of patients, BEAC (carmustine, etoposide, cytarabine and cyclophosphamide) in 33%, CBV (carmustine, etoposide and cyclophosphamide) in 10% and cyclophosphamide plus total body irradiation (TBI) in 12%. RESULTS: Estimated overall survival (OS) and disease-free survival (DFS) at 5 years were 53% and 43%, respectively. The transplant-related mortality was 11% (53 cases). By multivariate analysis three variables significantly influenced OS and DFS: number of protocols to reach 1st CR, disease status at transplant and TBI in the conditioning regimen. Age-adjusted IPI at transplantation also influenced OS. CONCLUSIONS: Prolonged OS and DFS can be achieved in patients with DLCL after HDT and our results suggest that the best line of chemotherapy should be used up-front in patients considered as candidates for HDT in order to obtain an early CR. Resistant patients are not good candidates for HDT and they should be offered newer strategies. Finally, polichemotherapy conditioning regimens offer better results compared with TBI.

Multiparametric analysis of apoptotic and multi-drug resistance phenotypes according to the blast cell maturation stage in elderly patients with acute myeloid leukemia.

BACKGROUND AND OBJECTIVES: Acute myeloid leukemia (AML) is a heterogeneous group of malignant diseases, often characterized by coexistence of more than one subpopulation of blast cells. Multiparametric flow cytometry immunophenotyping has proven to be a reliable and sensitive approach for the discrimination of myeloid blast cells from residual normal cells present in bone marrow samples from AML patients and, at the same time, allows the identification of different maturation compartments among myeloid blasts. Therefore, it provides a unique tool for assessing apoptotic and multidrug resistance (MDR)-associated phenotypes in individual subsets of leukemic cells. DESIGN AND METHODS: The aim of the present study was to explore the simultaneous expression of proteins related to both apoptosis (APO2.7, bcl-2, bax) and multidrug resistance (MDR1, MRP, LRP) in the different blast cell subpopulations detected at diagnosis in a group of 72 elderly patients with AML. In addition, we included 5 bone marrow samples from healthy adult donors in the analysis. RESULTS: Immature blast cells (CD34+: subset I) showed a significantly higher level of bcl-2 expression (p <0.0001) together with a lower reactivity for APO 2.7 (p=0.02) as compared to the other more mature CD34- cell subsets. The expression of Bax parallelled that of APO 2.7, although the difference between immature CD34+ blast cells and the mature blast cell subsets did not reach statistical significance (p=0.18). These results translated into a significantly (p<0.0001) higher bcl-2/bax ratio for the CD34+ blast cells as compared to that of the two CD34- blast cell subpopulations. Regarding the expression of the multidrug resistance-associated proteins Pgp and MRP, CD34+ blast cells displayed a greater expression of both proteins as compared to the more mature CD34- AML blast cells, but differences according to maturation stage of AML blast cells did not reach statistical significance. In contrast, LRP expression was significantly lower in the more immature CD34+ blast cell subset than in the more mature ones (p=0.01). INTERPRETATIONS AND CONCLUSIONS: As far as normal bone marrow is concerned our results suggest that all blast cell subpopulations are more protected from apoptosis than their normal counterparts. We conclude that in elderly patients with AML the more immature blast cells are more resistant to apoptotic processes, which could explain why, when AML relapses, the blast cells frequently display a more immature phenotype than that observed at diagnosis. Contradictory results in multidrug resistance profile support the hypothesis that failure to respond to chemotherapeutic drugs in AML is a multifactorial phenomenon.

Autologous stem cell transplantation for clinically aggressive non-Hodgkin's lymphoma: the role of preparative regimens.

We investigated the impact of the most commonly used preparative regimens on the outcome of 395 patients with diffuse large cell lymphoma (DLCL), consecutively reported to the registry of the Spanish GEL/TAMO. Among them, 139 (35%) were autografted in 1st CR, 86 (22%) in 2nd/3rd CR, 124 (31%) had chemosensitive disease and 46 (12%) had chemoresistant disease. Conditioning consisted of chemotherapy-only in 348 patients (BEAM, 164; BEAC, 145; and CBV, 39) and radiochemotherapy with CY and TBI in 47. Median times to granulocyte, platelet recovery and to discharge were significantly shorter in the chemotherapy-only group. Early transplant-related mortality was significantly higher when using CY-TBI. After a median follow-up of 28 months, overall survival (OS) at 8 years of patients conditioned with BEAM or BEAC (58% (95% CI 50-66%)) was more favorable than with CBV (40% (95% CI 24-56%)), and significantly better than with CY-TBI (31% (95% CI 18-44%)). Multivariate analysis revealed that patients conditioned with chemotherapy-only regimens had improved OS, disease-free (DFS) and relapse-free survival (RFS) when compared to those conditioned with CY-TBI. Status at transplant was also a powerful prognostic indicator. We conclude that preparative regimens consisting of chemotherapy-only seem more efficacious than CY-TBI as conditioning for DLCL, because of faster engraftment and greater anti-lymphoma effect, as indicated by improved OS, DFS and RFS.

Autologous stem-cell transplantation for Hodgkin's disease: results and prognostic factors in 494 patients from the Grupo Español de Linfomas/Transplante Autólogo de Médula Osea Spanish Cooperative Group.

PURPOSE: To analyze clinical outcome and significant prognostic factors for overall (OS) and time to treatment failure (TTF) in a group of 494 patients with Hodgkin's disease (HD) undergoing autologous stem-cell transplantation (ASCT). PATIENTS AND METHODS: Detailed records from the Grupo Español de Linfomas/Transplante Autólogo de Médula Osea Spanish Cooperative Group Database on 494 HD patients who received an ASCT between January 1984 and May 1998 were reviewed. Two hundred ninety-eight males and 196 females with a median age of 27 years (range, 1 to 63 years) received autografts while in complete remission (n = 203) or when they had sensitive disease (n = 206) or resistant disease (n = 75) at a median time of 26 months (range, 4 to 259 months) after diagnosis. Most patients received high-dose chemotherapy without radiation for conditioning (n = 443). The graft consisted of bone marrow (n = 244) or peripheral blood (n = 250). RESULTS: The 100-day mortality rate was 9%. The 5-year actuarial TTF and OS rates were 45.0% (95% confidence interval [CI], 39.5% to 50.5%) and 54.5% (95% CI, 48.4% to 60.6%), respectively. In multivariate analysis, the presence of active disease at transplantation, transplantation before 1992, and two or more lines of therapy before transplantation were adverse prognostic factors for outcome. Sixteen patients developed a secondary malignancy (5-year cumulative incidence of 4.3%) after transplantation. Adjuvant radiotherapy before transplantation, the use of total-body irradiation (TBI) in the conditioning regimen, and age > or = 40 years were found to be predictive factors for the development of second cancers after ASCT. CONCLUSION: ASCT achieves long-term disease-free survival in HD patients. Disease status before ASCT is the most important prognostic factor for final outcome; thus, transplantation should be considered in early stages of the disease. TBI must be avoided in the conditioning regimen because of a significantly higher rate of late complications, including secondary malignancies.

Conditioning regimens in autologous stem cell transplantation for multiple myeloma: a comparative study of efficacy and toxicity from the Spanish Registry for Transplantation in Multiple Myeloma.

High-dose chemoradiotherapy conditioning regimens for autologous stem cell transplantation (ASCT) are generally held to give similar results in multiple myeloma (MM), but no specific comparative study has been published. We addressed this issue by comparing the main high-dose chemoradiotherapy regimens used in the Spanish Registry. Patient cohorts included 315 cases treated with 200 mg/m2 melphalan (MEL200), 127 patients with 140 mg/m2 melphalan plus total body irradiation (MEL140 + TBI) and 121 cases with 12 mg/kg busulphan plus 140 mg/m2 melphalan (BUMEL). After ASCT, granulocyte and platelet recovery time was similar in all conditioning groups. There were no differences in transplant-related mortality. All regimens yielded a similar response in reference to pre-ASCT MM status, although BUMEL produced a slightly better overall response when compared with the other regimens (97% vs. 89% and 92%, P = 0.003). The 5-year overall survival (OS) with BUMEL was 47% [95% confidence interval (CI) 26-68] compared with 43% (CI 31-54) for MEL140 + TBI and 37% (CI: 18-56) for MEL200. The median survival for the BUMEL group was 64 months compared with 45 and 37 months for the MEL200 and MEL140 + TBI groups respectively. These differences were non-significant (P = 0.2). The median event-free survival (EFS) was better for BUMEL (32 months) than for MEL200 (22 months) or for MEL140 + TBI (20 months). The differences in EFS between BUMEL and the other conditioning regimens reached statistical significance (P = 0.01). Nevertheless, the adjusted multivariate analysis for OS and EFS revealed that the conditioning regimens had no independent prognostic value. We concluded that three different conditioning regimens, commonly used for ASCT in MM, have a similar antimyeloma effect. However, the trend for better results observed in our series with BUMEL requires a prospective trial.

Remission status defined by immunofixation vs. electrophoresis after autologous transplantation has a major impact on the outcome of multiple myeloma patients.

We have retrospectively analysed 344 multiple myeloma (MM) patients (202 de novo patients) treated in a non-uniform way in whom high-dose therapy and autologous stem cell transplantation (ASCT) response was simultaneously measured by both electrophoresis (EP) and immunofixation (IF). Patients in complete remission (CR) by EP were further subclassified as CR1 when IF was negative and CR2 when it remained positive. Partial responders (PR) were also subclassified as PR1 (very good PR, > 90% reduction in M-component) or PR2 (50-90% reduction). CR1 patients showed a significantly better event-free survival (EFS) [35% at 5 years, 95% confidence interval (CI) 17-53, median 46 months] and overall survival (OS) (72% at 5 years, CI 57-86, median not reached) compared with any other response group (univariate comparison P < 0.00000 to P = 0. 004). In contrast, comparison of CR2 with PR1 and with PR2 did not define different prognostic subgroups (median EFS 30, 30 and 26 months respectively, P = 0.6; median survival 56, 44 and 42 months respectively, P = 0.5). The non-responding patients had the worst outcome (5-year OS 8%, median 7 months). Multivariate analysis confirmed both the absence of differences among CR2, PR1 and PR2 and the highly discriminatory prognostic capacity of a three-category classification: (i) CR1 (ii) CR2 + PR1 + PR2, and (iii) non-response (EFS P < 0.00000; OS P < 0.00000; both Cox models P < 0.00000). In the logistic regression analysis, the factors significantly associated with failure to achieve CR1 were the use of two or more up-front chemotherapy lines, status of non-response pre-ASCT and inclusion of total body irradiation (TBI) in the preparative regimen. Tandem transplants or the use of multiple agents (busulphan and melphalan) in the preparative regimen resulted in a higher CR1 level; none of the biological factors explored influenced the possibility of achieving CR1. These results confirm that, in MM patients undergoing ASCT, achieving a negative IF identifies the patient subset with the best prognosis; accordingly, therapeutic strategies should be specifically designed to achieve negative IF.

Are myeloma patients with renal failure candidates for autologous stem cell transplantation?

INTRODUCTION: Renal function is one of the most important prognostic factors in multiple myeloma (MM). Patients with renal failure are generally excluded from high dose therapy even though they display a poor prognosis with conventional chemotherapy schemes. The aim of this study was to analyze the outcome of MM patients with renal insufficiency undergoing autologous stem cell transplantation (ASCT), including the evaluation of the quality of PB stem cell collections, kinetics of engraftment, transplant-related mortality, response to high dose chemotherapy and survival. MATERIALS AND METHODS: From a total of 566 valuable patients included in the MM Spanish ASCT registry, three groups of patients were defined: group BA, patients with abnormal renal function at diagnosis but normal at transplant (73 cases); group BB, patients with abnormal function both at diagnosis and at transplant (14 cases); and group AA (control group, 479 cases), patients who constantly had normal renal function. RESULTS AND CONCLUSION: Patients from groups BA and BB presented with a significantly higher number of adverse prognostic factors, reflecting that we were dealing with high tumor MM cases, as compared with patients from group AA. The number of mononuclear cells, CD34+ cells and CFU-GM cells collected in patients with non-reversible renal insufficiency was similar to those harvested in MM patients with normal renal function. Moreover, neutrophil and platelet engraftments were identical in patients with and without renal failure (days +11 and +12, respectively). By contrast, transplant-related mortality (TRM) was significantly higher in group BB patients (29%) than in groups BA (4.1%) and AA (3.3%). In multivariate analysis only three variables showed independent influence on TRM: poor performance status (ECOG 3), hemoglobin <9.5 g/dl and serum creatinine > or =5 mg/dl. The response to high dose therapy was independent of renal function. Interestingly, 43% of patients from group BB showed an improvement in renal function (creatinine < 2 mg/dl) after transplant. The three-year overall survival from transplantation was 56, 49 and 61% for the BB, BA and AA groups, respectively, with a statistically significant difference favoring group AA (P<0.01). PFS did not differ significantly between the three groups of patients. In multivariate analysis the only unfavorable independent prognostic factors for overall survival were poor performance status either at diagnosis or at transplant, high beta(2)-microglobulin levels, and no response to transplant. According to these results, ASCT is an attractive alternative for MM patients with renal insufficiency, and it should not constitute a criterion for exclusion from transplant unless patients display poor performance status and very high creatinine levels (>5 mg/dl).

Stage, percentage of basophils at diagnosis, hematologic response within six months, cytogenetic response in the first year: the main prognostic variables affecting outcome in patients with chronic myeloid leukemia in chronic phase treated with interferon-alpha. Results of the CML89 trial of the Spanish Collaborative Group on interferon-alpha2a and CML.

BACKGROUND AND OBJECTIVE: Interferon-a (IFN) is increasingly being used as the drug of choice in chronic myeloid leukemia patients. The main objectives of the study were to study the influence of the classic prognostic variables and response to IFN, and to assess the influence of this response on the course of the disease and survival. DESIGN AND METHODS: Single arm, prospective, multicenter study, without a control group. Only Ph1-positive CML patients were included. The treatment scheme was biphasic: the patients first received standard chemotherapy and thereafter IFN-a2a was used as monotherapy, with a target dose of 9 MU/d/s.c. RESULTS: Twenty-one centers in Spain enrolled 132 patients (72 men, 60 women). The median dose of IFN given was 5.8 MU/d, and the median treatment duration was 431 days (range: 18-2,597). Seventy-two percent of patients obtained a hematologic response in the first six months of IFN treatment. Genetic response was obtained in 47% of the patients, and the response was major or complete in 27% and 19%, respectively. The median time to obtain this response was 7, 9, and 18 months for minimal, partial and complete genetic response, respectively. Multivariant analysis showed that only a higher percentage of basophils at diagnosis was associated with a worse hematologic response at six months (p=0.001) (OR: 1.23) and with a worse cytogenetic response in the first year of IFN therapy (p=0.018) (OR: 1.4). Over an observation period of 8 years, 35.6% of the patients died, and 85 (64.4%) remained alive. With a median follow-up of 42 months (3.7-98), the 6-year projected probabilities of survival and transformation-free survival were 0.61+/-0.07 vs. 0.54+/-0.07, respectively. Patients with Kantarjian's stage 3 disease or in a high-risk Sokal group had lower probabilities of survival, but these systems did not adequately discriminate in our series. Obtaining a complete hematologic response in the first six months of IFN therapy was favorable in terms of overall survival (p=0.05; HR=0.33). Cox's analysis demonstrated that obtaining a cytogenetic response in the first year was independently associated with better overall survival (p=0.04; HR=0.19) and better transformation-free survival (p=0.0035; HR=0.11). INTERPRETATION AND CONCLUSIONS: Nearly half of the patients obtained some degree of Philadelphia suppression, which was major in 27%, and complete in 19%. A higher percentage of basophils at diagnosis was the only variable associated with a lower probability of cytogenetic response. Obtaining a cytogenetic response during the first year of IFN treatment was a favorable and independent variable in terms of survival and transformation-free survival. Obtaining a major cytogenetic response during this period decreased the risk of transformation twenty times. Our results suggest that the effect of IFN on survival is independent of the classic prognostic variables.

[Reconstitution of peripheral blood lymphocytes in patients treated with bone marrow transplantation: comparison between allogeneic and autologous transplantation]. / Reconstitución de los linfocitos de sangre periférica en pacientes tratados con trasplante de médula ósea: comparación entre el trasplante alogénico y el autólogo.

BACKGROUND: This study compares the immune reconstitution of total T cells, CD4 and CD8 cell subsets, activated T cells, NK cells and B cells in 66 patients who underwent allogeneic or autologous bone marrow transplantation (BMT). PATIENTS, MATERIAL AND METHODS: The reconstitution of peripheral lymphocytes subsets was studied using two-color flow cytometry. The study group consisted of 39 patients who received allogeneic BMT compared with 27 patients who received autologous BMT. Peripheral blood was examined at different time intervals. As a measure of immune function, the response to the mitogen phytohemaglutinin (PHA) was determined. RESULTS: The pattern of recovery of CD3+, CD4+ and CD8+ T cells, as well as the PHA response, was similar for each type of transplant. CD3+CD5- cells were significantly higher following autologous BMT than after allogeneic BMT and during more time. An overexpression of DR on T cells following autologous or allogeneic BMT demonstrates an increasing degree of T-lymphocyte activation. This activated T-cell subset was more stable in patients transplanted with allogeneic BM than in patients treated with autologous BM. The levels of total B cells and CD19+CD5+ B-cells were increased during 2 to 12 months following autologous MBT, remaining normal afterwards; in contrast, the levels of CD19+ lymphocytes and CD19+CD5+B-cells remained higher than normal ranges until 36 months in patients transplanted with allogeneic BM. The percentage of NK cells was significantly increased following both autologous and allogeneic BMT. The highest percentage of NK cells were detected about 2 and 6 months post-transplant in patients treated with autologous or allogeneic BM, respectively. CONCLUSIONS: Allogeneic BMT appears to induce a slight delay recovery of B and NK cells in comparison to autologous BMT. In contrast, T-cells recovery was similar for each type of transplant, although a higher percentage of CD3+CD5- T cells and a faster recovery of activated CD3+DR+ cells to normal levels were observed in patients transplanted with autologous BM.

Other cancers in patients with gastric MALT lymphoma.

Patients with Hodgkin's disease and nodal non-Hodgkin's lymphomas seem to have an excess risk for other cancers. A high incidence of other cancers has also been found in some series of patients with gastric MALT lymphomas. In a series of 136 patients with gastric MALT lymphomas the occurrence and features of other cancers have been described. In order to evaluate their occurrence statistically (excluding skin cancers) standard incidence ratios (SRI) have been calculated, using the incidence rates of a Cancer Registry in Spain as a reference. A Cox's multivariate proportional hazard model was fitted in order to evaluate the influence of age, sex, histological grade and treatment with chemotherapy or chemotherapy plus radiotherapy in the development of other non-skin cancers occurring after the diagnosis of MALT lymphoma. Other cancers were detected in 16 of the 136 patients (11.7%); the other cancer was detected prior to MALT gastric lymphoma in 6 patients (4.41%), concomitantly in 4 (2.9%) and after diagnosis of the lymphoma in 6 (4.41%). Other cancers occurred in 14.4% of the male and in 8.3% of the female patients; in 12% of the patients with low grade and in 11% of the patients with high grade lymphomas. Of the 6 cancers that occurred after diagnosis of the gastric lymphoma, 3 did in the 80 patients (3.7%) that had been treated with chemotherapy, 1 in the 3 cases (33%) treated with chemotherapy and radiotherapy and 2 in the 53 patients (3.7%) who had not received chemotherapy or radiotherapy. The most frequent other cancers were lymphoid neoplasms and gastric carcinoma. There was not an excess of other cancers in the whole cohort or in the sex or histological grade strata. There was an excess close to significance (SIR =2.59; 95% CI:0.98-6.88) in the patients under 50 years of age. In the Cox's analysis, age, sex, histological grade and treatment did not influence the occurrence of other cancers after the diagnosis of lymphoma. In conclusion, in patients with gastric MALT lymphoma other cancers also occur. An excess incidence was not demonstrated, although it may exist in patients under 50 years. Of special importance is the occurrence of gastric cancer that appears concomitantly or after gastric lymphoma.

Role of interferon alfa-2b in the induction and maintenance treatment of low-grade non-Hodgkin's lymphoma: results from a prospective, multicenter trial with double randomization.

PURPOSE: To evaluate the effectiveness of adding interferon (IFN) alfa-2b to chemotherapy in the induction treatment of low-grade non-Hodgkin's lymphoma (NHL), and to assess the role of maintenance IFN. PATIENTS AND METHODS: A multicenter, two-phase controlled trial with double randomization was conducted in 155 patients with low-grade NHL. In the first randomization, 78 patients received cyclophosphamide, vincristine, and prednisone (CVP) and IFN, 3 MU/m2 three times a week for 3 months, and 77 patients received CVP alone. Responding patients were randomized to receive IFN for 1 year versus observation. RESULTS: Of 144 assessable patients, 73 received CVP + IFN and 71 received CVP. Responses were similar: CVP + IFN 79% versus CVP 76% (P = .62). The number of patients who did not complete the treatment was higher in the CVP + IFN group than in the CVP group (18% v 4%; P = .009), although the received dose-intensity of chemotherapy was comparable. Duration of response and progression-free survival (PFS) were significantly higher in the CVP + IFN group than in the CVP group (P = .0004). However, we observed no differences in overall survival (OS) (P = .30), with a median follow-up for the surviving patients of 3 years. Grade 3/4 granulocytopenia was the most frequent toxicity and was similar in both groups (33% v32%). Eighty-three (74%) of the 112 responding patients were randomized to maintenance IFN or observation. The duration of response was similar between 42 patients that received IFN compared with 41 control patients (P = .83), independently of treatment previously administered. CONCLUSION: Adding IFN alfa-2b to induction CVP in low-grade NHL did not induce a higher response rate, but it significantly increased the duration of the responses. We found significant differences in PFS that favored the patients who received CVP + IFN, but not in OS. To date, no additional benefit has been seen from the administration of IFN for maintenance.

Autologous peripheral blood stem cell transplantation for multiple myeloma: a report of 259 cases from the Spanish Registry. Spanish Registry for Transplant in MM (Grupo Español de Trasplante Hematopoyético-GETH) and PETHEMA.

Between January 1989 and November 1995, 259 patients with multiple myeloma (MM), 22 stage I, 57 stage II and 180 stage III at diagnosis were treated with myeloablative high-dose therapy followed by autologous peripheral blood stem cell (PBSC) transplantation. The median time from diagnosis to transplantation was 17 months (6-112). At the time of transplant, 56 patients were in CR, 153 in PR, 25 were nonresponders and 25 had progressive disease. Mobilization of stem cells was performed with G-CSF alone in 141 cases, chemotherapy plus G-CSF in 65, chemotherapy plus GM-CSF in 36 and chemotherapy alone in 17 patients. The conditioning regimen consisted of high-dose melphalan alone in 96 patients, melphalan plus TBI in 73, busulfan plus melphalan in 56, busulfan plus cyclophosphamide in 27 and cyclophosphamide plus TBI in seven. The median durations of neutropenia (>0.5 x 10(9)/l) and thrombocytopenia (>20 x 10(9)/l) were 12 (5-118) and 13 days (5-360), respectively. Transplant-related mortality occurred in 11 patients (4%). Once a stable graft was achieved, 114 patients (44%) received maintenance treatment with recombinant alpha interferon (IFN-alpha). Among the 248 patients evaluable for response 125 (51%) had a CR and 100 had a PR (40%). The median duration of progression-free survival (PFS) and overall survival (OS) after transplantation was 23 and 35 months, respectively. Univariate analysis showed that response status pretransplant, only one line of primary induction treatment and IFN-alpha maintenance treatment post-transplant significantly influenced OS. Female sex, pretransplant responsive disease, and treatment with IFN-alpha post-transplant were the factors significantly influencing PFS. The conditioning regimen and method of stem cell mobilization had no significant impact on OS and PFS. On multivariate analysis the only independent factors associated with a longer survival were the number of chemotherapy courses prior to autologous PBSC transplantation and the pretransplant response status. The present analysis from the Spanish Registry confirms the feasibility of autologous PBSC transplantation in myeloma patients with a very low toxicity (4% toxic deaths). The high complete response rate after transplantation is encouraging. The best results are obtained when the procedure is performed early after the first line of induction therapy and in patients with chemosensitive disease. Whether early high-dose therapy followed by autotransplantation in responding patients is superior to conventional chemotherapy is currently being investigated in prospective randomized studies.

Autologous stem cell transplantation for poor prognosis Hodgkin's disease in first complete remission: a retrospective study from the Spanish GEL-TAMO cooperative group.

Although more than 50% of Hodgkin's disease patients are cured with conventional chemotherapy, many will relapse and eventually die from their disease. Many efforts have been made to identify poor prognostic factors that could be useful in selecting high-risk patients in 1st CR who may benefit from high-dose chemo/radiotherapy. However, the role of early transplantation in 1st CR remains unclear. We have retrospectively analyzed the results obtained with this procedure in 22 hospitals belonging to the Spanish GEL/TAMO cooperative group. Twenty-seven patients, of whom 19 were males, underwent autologous transplantation for Hodgkin's disease in 1st CR between January 1987 and January 1996. Remission had been achieved after one (n = 22) or two (n = 5) lines of treatment. Twenty-four patients had advanced stage disease, 12 patients bulky mediastinal disease, nine bone marrow involvement and 18 had extranodal disease. Peripheral blood was used as the source of hematopoietic stem cells in 15 patients, BM in nine, and both in three. All but three patients received chemotherapy-based conditioning regimens (16 CBV, four BEAM and four BEAC), while three were conditioned with CY and TBI. There were no transplant-related deaths. Median (range) times to recover >0.5 x 10(9)/l neutrophils and >50 x 10(9)/l platelets were 14 (8-56) days and 16 (8-240) days, respectively. With a median follow-up of 30 (8-66) months, 21 patients are alive and in continuous CR. Four patients who relapsed after transplant at 8, 17.5, 22 and 26 months achieved a second CR with conventional chemotherapy; one patient relapsed 92 months post-transplant and died 5 months afterwards. Another patient died 30.5 months post-transplant from a secondary malignancy. In conclusion, high-dose therapy in poor prognosis Hodgkin's disease in 1st CR was well tolerated with no transplant-related mortalities. Although the follow-up of this series is relatively short, our results seem promising. Nevertheless, late relapses can occur, and the role of this procedure vs conventional treatment in very high-risk patients should be assessed in prospective randomized studies.

High-dose granulocyte-colony stimulating factor (G-CSF) in vitro induces the growth of high proliferative potential colony forming cells (HPP-CFC) in patients undergoing blood stem cell mobilization.

We evaluated the role of high-dose granulocyte colony stimulating factor (G-CSF) in vitro, in inducing the generation of high-proliferative potential colony forming cells (HPP-CFC), from either mononuclear cells or purified CD34+ cells. Both normal controls and patients undergoing peripheral blood stem cell (PBSC) mobilization and transplantation were studied. In serum-driven agar cultures, G-CSF stimulated the proliferation of HPP-CFC in a dose dependent manner (r = 0.92). The number of HPP-CFC was four-fold greater in mobilized patients than in normal controls. Purified CD34+ cells yielded 11-fold more colonies than mononuclear cells. HPP-CFC from mobilized patients showed replating capacity, giving rise to secondary colonies of more mature appearance. In serum-free cultures, the effect of G-CSF appeared to be mediated by synergistic interaction with stem cell factor. Our results suggest that G-CSF stimulates primitive hematopoietic cells that are detectable in increased amounts in patients receiving mobilization therapy. Therefore, determination of G-CSF induced HPP-CFC could be a useful tool in the evaluation of mobilization strategies.