Rafael Cabrera

EPIDEMIOLOGY AND RISK FACTORS FOR URINARY TRACT INFECTION IN PATIENTS WITH SPINAL CORD INJURY

Purpose: To our knowledge risk factors for urinary tract infection associated with various drainage methods in patients with spinal cord injury have never been evaluated overall in the acute period. We identified the incidence and risk factors associated with urinary tract infection in spinal cord injured patients.Materials and Methods: We prospectively followed 128 patients at our spinal cord injury reference hospital for 38 months and obtained certain data, including demographic characteristics, associated factors, methods of urinary drainage, bladder type, urological complications and predisposing factors of each infection episode. Logistic regression modeling was done to analyze variables and identify risk factors that predicted urinary tract infection.Results: Of 128 patients 100 (78%) were male with a mean age plus or minus standard deviation of 32 ± 14.52 years. All patients had a nonfatal condition by McCabe and Jackson guidelines, and 47% presented with associated factors. The incidence of urinar...

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 Ósea 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 Hodgkins 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.

Long-term prognostic significance of response in multiple myeloma after stem cell transplantation

For establishing the true effect of different response categories in patients with multiple myeloma (MM) treated with autologous stem cell transplantation, we evaluated, after a median follow-up of 153 months, 344 patients with MM who received a transplant between 1989 and 1998. Overall survival (OS) at 12 years was 35% in complete response (CR) patients, 22% in near complete response (nCR), 16% in very good partial response (VGPR), and 16% in partial response (PR) groups. Significant differences in OS and progression-free survival were found between CR and nCR groups (P = .01 and P = .002, respectively), between CR and VGPR groups (P = .0001 and P = .003), or between CR and PR groups (P = .003 and P = < 10(-5)); no differences were observed between the nCR and VGPR groups (P = .2 and P = .9) or between these groups and the PR group (P = .1 and P = .8). A landmark study found a plateau phase in OS after 11 years; 35% patients in the CR group and 11% in the nCR+VGPR+PR group are alive at 17 years; 2 cases had relapsed in the nCR+VGPR+PR group. In conclusion, MM achieving CR after autologous stem cell transplantation is a central prognostic factor. The relapse rate is low in patients with > 11 years of follow-up, possibly signifying a cure for patients in CR.

Allogeneic Transplant with Reduced Intensity Conditioning Regimens may Overcome the Poor Prognosis of B-Cell Chronic Lymphocytic Leukemia with Unmutated Immunoglobulin Variable Heavy-Chain Gene and Chromosomal Abnormalities (11q− and 17p−)

Purpose: To evaluate the efficacy of reduced intensity conditioning (RIC) allogeneic transplant in 30 patients with poor-prognosis chronic lymphocytic leukemia (CLL) and/or high-risk molecular/cytogenetic characteristics. Experimental Design: Eighty-three percent of patients had active disease at the moment of transplant. That is, 14 of the 23 patients analyzed (60%) had unmutated immunoglobulin variable heavy-chain gene (IgVH) status; 8 of 25 patients (32%) had 11q−, with four of them also displaying unmutated IgVH; and six (24%) had 17p− (five were also unmutated). Results: After a median follow-up of 47.3 months, all 22 patients alive are disease free; overall survival and event-free survival (EFS) at 6 years were 70% and 72%, respectively. According to molecular/cytogenetic characteristics, overall survival and EFS for unmutated CLL and/or with 11q− aberration (n = 13) were 90% and 92%, respectively, not significantly different to those with normal in situ hybridization, 13q− and +12, or mutated CLL (n = 7). All six patients with 17p deletion were transplanted with active disease, including three with refractory disease; all except one reached complete remission after the transplant and two are alive and disease free. Nonrelapse mortality (NRM) was 20%; more than two lines before transplant is an independent prognostic factor for NRM (P = 0,02), EFS (P = 0.02), and overall survival (P = 0.01). Patients older than 55 years have a higher risk of NRM (hazard ratio, 12.8; 95% confidence interval, 1.5-111). Minimal residual disease was monitored by multiparametric flow cytometry in 21 patients. Clearance of CD79/CD5/CD19/CD23 cells in bone marrow was achieved in 68% and 94% of the patients at days 100 and 360, respectively. Conclusion: According to these results, RIC allogeneic transplant could overcome the adverse prognosis of patients with unmutated CLL as well as those with 11q− or 17p−.

Unrelated umbilical cord blood transplants in adults: Early recoveryof neutrophils by supportive co-transplantation of a low number of highlypurified peripheral blood CD34+ cells from an HLA-haploidentical donor

UNLABELLED OBJECTIVE, METHODS, AND RESULTS: To reduce the period of posttransplant neutropenia and related early morbidity and mortality of cord blood (CB) transplants, we assessed the feasibility of co-infusion of a low number of highly purified peripheral blood CD34+ cells from a related haploidentical donor with a CB graft. Between March 1999 and May 2002, 11 patients with high-risk hematologic malignancies were transplanted using this strategy. The seven patients who received a haploidentical peripheral blood graft and a CB graft from a sibling (6) or the father (1) had prompt recovery (9-17 days, median 10) of the absolute neutrophil count (ANC) to greater than 0.5 x 10(9)/L. Analysis of DNA polymorphisms showed initial predominance of the haploidentical genotype both in granulocytes and in mononuclear cells, and subsequent progressive replacement by cells of CB genotype until final complete CB chimerism was achieved by patients who survived for sufficient periods of time. The four patients who received maternal haploidentical cells had no significant contribution of these to blood leukocytes, although complete CB chimerism was achieved by three of them and two reached engraftment of the CB on days +20 and +36. Morbidity due to early bacterial or fungal infections was remarkably low in patients with prompt ANC recovery. CONCLUSION Our data show that co-infusion of a CB unit and a low number of haploidentical CD34+ cells may result in a shortened period of posttransplant neutropenia. This is likely the result of prompt and transient engraftment of the haploidentical hematopoietic stem cells that may provide the patient antimicrobial protection until the later engraftment of the CB hematopoietic stem cells.

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.

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.

Cord blood transplants: early recovery of neutrophils from co-transplanted sibling haploidentical progenitor cells and lack of engraftment of cultured cord blood cells, as ascertained by analysis of DNA polymorphisms

The number of infused cells is a very important factor in cord blood transplant (CBT) engraftment. Prior ex vivo expansion of aliquots of transplanted cord blood (CB) units is being investigated as a procedure to increase engraftment potential, but results are difficult to evaluate due to a lack of markers for assessing the contribution of expanded cells. We transplanted five patients, infusing the best available CB unit and cells from a second donor simultaneously. In two patients, these cells were obtained from another frozen CB unit by CD34+positive selection and culture expansion; the other three patients received uncultured highly purified haploidentical CD34+ cells. The first two patients had DNA from the culture expanded CB cells detected only for a few days around day +11 when the absolute neutrophil count (ANC) was >200/μl; thereafter and when the ANC was <500/μl, only donor DNA from the uncultured CB was detected. For the other three patients, DNA analysis showed early and transient granulocyte engraftment of haploidentical cells, progressively replaced by the CB-derived granulocytes. We concluded that: (1) simultaneous infusion of lymphocyte-depleted HLA highly mismatched haematopoietic progenitor cells has not produced unfavourable effects for CBT; (2) the double transplant model is suitable for evaluating the engraftment potential of ex vivocultured CB cells in the clinical setting; (3) the culture conditions used did not result in early recovery of ANC; and (4) co-transplantation of purified uncultured HLA haploidentical CD34+ cells may reduce the time of neutropenia following CBT.Bone Marrow Transplantation (2001) 28, 355–363.

Myeloablative Treatments for Multiple Myeloma: Update of a Comparative Study of Different Regimens Used in Patients from the Spanish Registry for Transplantation in Multiple Myeloma

After a previous analysis that did not detect clear differences in the results of three conditioning regimens used for autologous stem cell transplantation (ASCT) in patients from the Spanish Registry for Transplant in Multiple Myeloma (MM), we have updated the registry, including a larger number of cases and a fourth conditioning regimen with a longer follow-up. We evaluate 472 MM patients treated with 200   mg/m 2 melphalan (MEL200), 135 patients treated with 140   mg/m 2 melphalan plus total body irradiation [(MEL140   +   TBI)], 186 patients treated with 12   mg/kg busulphan plus 140   mg/m 2 melphalan (BUMEL) and 28 patients treated with 14   mg/kg busulphan followed by cyclophosphamide 120   mg/kg (BUCY). There were no significant differences in respect to either transplant related death or haematological recovery, regardless of growth factor use, between the four conditioning programs. Nevertheless, hospitalization time with MEL200 was less than with BUMEL when growth factors were used (19 ± 9 vs. 25 ± 9 days, P =0.009) and less than with MEL140   +   TBI without growth factors (20 ± 8 days vs. 27 ± 9 days, P =0.002). In patients with measurable disease at ASCT (non-complete remission [CR]), BUMEL achieved a 51% CR vs. 43%-31% in the other groups (P =0.007). The response rate for patients in partial remission (PR) at ASCT was 100% with BUMEL vs. 93%-86% in the other groups (P between 0.02 and 0.0007). The median overall survival (OS) for the BUMEL group was 57 months (95% confidence interval [CI]: 51-78) as compared to 45 (CI: 36-64) months for the MEL200 group and 39 (CI: 28-72) months for the MEL140   +   TBI and BUCY groups. The median event free survival (EFS) was longer in the BUMEL group [30 (CI: 22-44) mo] than in the MEL200 [22 (CI: 18-26) mo], BUCY [23 (CI: 11-50) mo] or MEL140   +   TBI groups [20 (CI: 15-29) mo]. Nevertheless, the differences in OS and EFS did not reach statistical significance in either the univariate analysis or the multivariate analysis adjusted with other high prognostic weight factors. As in the initial study, differences in regards to the anti-myeloma effect of the conditioning regimens are not conclusive. However, the better response rates associated with the favorable tendency in outcome achieved with BUMEL, continue to justify further prospective studies.

Tandem transplants with different high‐dose regimens improve the complete remission rates in multiple myeloma. Results of a Grupo Español de Síndromes Linfoproliferativos/Trasplante Autólogo de Médula Ósea phase II trial

Summary. Between 1994 and 1999, 88 multiple myeloma (MM) patients were included in a phase II study to evaluate a tandem autologous stem cell transplantation (ASCT) programme. The first was conditioned with melphalan 200 mg/m2 (MEL200‐ASCT1), and the second with cyclophosphamide, etoposide and BCNU (CBV‐ASCT2). All patients were in response after MEL200‐ASCT1. A control group of MM patients with response to a single ASCT was selected to compare outcomes. After MEL200‐ASCT1, 26 patients (30%) achieved complete remission (CR). Of the remaining 48 evaluable patients, 16 (33%) achieved CR with CBV‐ASCT2. The final CR rate was 48%. The 5‐year survival (OS) was 55%[95% confidence interval (CI) 43–67%] while the event‐free survival (EFS) was 28% (95% CI 15–39%). CR status after CBV‐ASCT2 was the most important prognostic factor for OS and EFS (P = 0·00001), although no differences in outcomes were detected when the patients in CR after MEL200‐ASCT1 were compared with those who obtained CR after CBV‐ASCT2. Univariate and multivariate analyses showed improved OS and EFS for the tandem series as compared with the control series treated with a single MEL200‐ASCT. However, in a stratified comparison by response, there were no prognostic differences between tandem patients and control patients treated with a single ASCT. In summary, our study suggests that the benefit of a second high‐dose therapy course depends on its capacity to result in CR for MM patients who have not attained CR after ASCT1.