Biomedical subjects
Publications and source records attributed to A Iriondo.
We report two cases of hyperammonemic encephalopathy in patients with multiple myeloma. This rare complication, whose pathophysiology remains unknown, is associated with disease progression and so with a very bad prognosis. We believe that this complication should be included in the differential diagnosis of encephalopathy occurring in multiple myeloma.
We retrospectively compared the outcome in patients in the EBMT database transplanted for acute leukaemia from January 1987 to January 1994 who received busulphan and cyclophosphamide (BU/CY) as a pretransplant regimen versus those who received cyclophosphamide and total-body irradiation (CY/TBI). The patients were matched for type of transplant (autologous bone marrow transplantation (ABMT) versus allogeneic (BMT)), diagnosis (acute lymphoblastic leukaemia (ALL) or acute myeloid leukaemia (AML)), status (early (first complete remission, CR-1) versus intermediate (second or later remission, first relapse)), age, FAB classification for AML, prevention of graft-versus-host disease and year of transplantation. In ABMT recipients (matched paired 530 x 2) with ALL CR-1, AML CR-1 and AML intermediate disease, transplant-related mortalities (TRM) relapse incidence (RI) and leukaemia-free survival (LFS) did not differ significantly in patients treated with BU/CY or CY/TBI. However, in ABMT recipients with ALL intermediate disease, the probability of relapse was 82 +/- 5% (+/- 95% confidence interval) in the BU/CY group compared to 62 +/- 6% in the CY/TBI group (P = 0.002) and the 2-year leukaemia-free survival 14 +/- 4% and 34 +/- 6%, respectively (P = 0.002). In BMT recipients of bone marrow from HLA-identical siblings (matched paired 391 x 2), the TRM, RI and LFS did not differ significantly between the two treatments in all groups. In particular, the 2-year LFS in patients with AML CR-1 was 64 +/- 3% in those treated with BU/CY (n = 237) compared to 66 +/- 3% in those given CY/TBI (n = 237). In all groups the findings were confirmed in a multivariate analysis of prognostic factors. Veno-occlusive disease (VOD) of the liver (P < 0.05) and haemorrhagic cystitis (P < 0.001) was more common in the BU/CY group compared to the CY/TBI group for ABMT and BMT patients. In conclusion, BU/CY and CY/TBI as pretransplant regimens gave similar results in all situations, except ABMT for ALL intermediate stages with more than 2 years from diagnosis to transplantation, where a lower RI and a higher LFS were associated with CY/TBI.
A total of 229 patients with chronic myeloid leukaemia (CML) in chronic phase were randomized between 1986 and 1990 to receive or not receive additional splenic irradiation as part of their conditioning prior to bone marrow transplantation (BMT). Both groups, 115 patients with and 114 patients without splenic irradiation, were very similar regarding distribution of age, sex, donor/recipient sex combination, conditioning, graft-versus-host disease (GvHD) prevention method and blood counts at diagnosis or prior to transplant. 135 patients (59%) are alive as of October 1995 with a minimum follow-up of 5 years. 52 patients have relapsed (23%), 26 patients in the irradiated, 26 patients in the non-irradiated group (n.s.) with a relapse incidence at 6 years of 28%. The main risk factor for relapse was T-cell depletion as the method for GvHD prevention, and an elevated basophil count in the peripheral blood prior to transplant. Relapse incidence between patients with or without splenic irradiation was no different in patients at high risk for relapse, e.g. patients transplanted with T-cell-depleted marrows (P = n.s.) and in patients with low risk for relapse, e.g. patients transplanted with non-T-cell-depleted transplants and basophil counts < 3% prior to transplant (P = n.s.). However, relapse incidence differed significantly in patients with non-T-cell-depleted transplants and high basophil counts (> 3% basophils in peripheral blood). In this patient group, relapse incidence was 11% at 6 years with splenic irradiation but 32% in the non-irradiated group (P = 0.05). Transplant-related mortality was similar whether patients received splenic irradiation or not. This study suggests an advantage in splenic irradiation prior to transplantation for CML in this subgroup of patients and illustrates the need for tailored therapy.
We analyzed retrospectively data from 1696 patients with AML transplanted in Europe from January 1987 to December 1992 and reported to the acute leukemia EBMT registry. Groups of patients were analyzed according to age (adults and children) and status at transplant (first remission = CR1; second remission = CR2). (1) 1114 adult patients were transplanted in CR1; 516 received an allograft; 598 received an autograft. Following alloBMT, the transplant-related mortality (TRM) was significantly higher (27 vs 13%, P < 10(-4)), the relapse incidence (RI) lower (25 vs 52%, P < 10(-4)) and the leukemia-free survival (LFS) better (55 vs 42%, P = 0.006). Favorable prognostic factors for alloBMT were a FAB type other than M4-M5, a donor-recipient combination excluding a female donor to a male recipient, and a younger age. Favorable prognostic factors for ABMT were a younger age of the patients at time of transplant, the AML3 FAB type, and a longer interval from CR1 to ABMT. (2) 288 adult patients were transplanted in CR2: 98 received an allograft; 190 received an autograft. The TRM was higher following allogeneic BMT (32 vs 20%, P = 0.02) and the RI lower (42 vs 63%, P = 0.001). The LFS was not significantly different (alloBMT: 39%; ABMT: 30%, P = 0.22). (3) 242 children were transplanted in CR1; 129 received an allograft; 113 received an autograft. Following alloBMT, the RI was lower (25 + 5 vs 48 + 6%, P < 10(-4)), and the LFS better (68 vs 47%, P = 0.002). The use of TBI was a favorable prognostic factor in allografted patients with a lower RI and a better LFS. (4) The number of children transplanted in CR2 was too small for a comparative analysis. These results confirm that both allogeneic and autologous BMT are suitable curative approaches for AML. They favor the use of an HLA identical related allogeneic transplant when available, especially in younger patients, over ABMT with unpurged marrow. The role of purging in ABMT could not be addressed in this study.
We report four patients with chronic myeloid leukemia (CML) that showed poor graft function after a non-T-depleted bone marrow transplantation (BMT) from an HLA-compatible sibling donor and who were successfully treated with splenectomy. Conditioning was done with cyclophosphamide (CY) and total body irradiation (TBI) without additional splenic irradiation. Three patients had enlarged spleens before BMT. The nucleated cell dose infused ranged from 2.3-3.2 x 10(8)/kg. Bone marrow (BM) examination prior to splenectomy showed BM aplasia (three cases) or hypocellularity (one case). At splenectomy no patient had evidence of cytomegalovirus (CMV) infection or severe acute GVHD; and three patients had moderately enlarged spleens. All patients were transfusion dependent. Complete hematological recovery was obtained in all patients. BM cellularity was normal 1 month after splenectomy. Complete chimerism of donor origin was documented. The four patients are alive (+16 to +58 months after BMT). Thus, in patients with CML, a poor graft function may be successfully corrected by splenectomy.
A 52-year-old male diagnosed with acute myeloid leukemia (AML) developed an invasive middle-ear mucormycosis during the neutropenic period after consolidation chemotherapy which resolved successfully with surgery and antifungal therapy. The patient underwent autologous peripheral blood stem cell transplantation (APBSCT) in first complete remission with antifungal prophylaxis with liposomal amphotericin B (AmB). There was no clinical, radiological or microbiological data of mycotic reactivation. This is the first reported stem cell transplantation (SCT) in a patient with prior invasive mucormycosis.
BACKGROUND: To carry out a study on the prognostic factors in large cell lymphomas (LCL) treated during the last decade and validate the international prognostic index (IPI). METHODS: One hundred twenty-four cases of newly diagnosed LCL, treated from 1978 to 1990, with a mean follow up of 27 months (1-142) were included in the study. The chemotherapy used was: CHOP (65%), ProMACE-CytaBOM (17%) and others (C-MOPP, MACOP-B). RESULTS: Complete remission (CR) was achieved in 71% of the cases and partial in 11%. Logistic analysis allowed the identification of three adverse factors to CR: Ann Arbor stage III, IV (p = 0.004; odds ratio, OR = 0.19), elevated tumoral load (p = 0.006; OR = 0.22) and age > or = 60 years (p = 0.02; OR = 0.31). Recurrence free survival (RFS) at 3 years was 67% (CI 95%; 55-79) with the median not having been achieved. Cox analysis allowed the identification to the ECOG > or = 2 scale as the only independent adverse factor (p = 0.0006; RR = 4.85) while Ann Arbor staging demonstrated marginal influence (p = 0.08). Global survival (GS) at 5 years was 45% (CI 95%; 35-55) with a median of 38 months. Multivariant analysis of independent adverse factors of GS were ECOG scale > or = 2 (p < 0.00001; RR = 6.07), Ann Arbor stage (p = 0.004; RR = 2.64) and hypoalbuminemia (p = 0.01; RR = 2.28). On inclusion of therapeutic response (TR) in the analysis, the factors chosen were absence of CR (p < 0.00001; RR = 9.58) and ECOG > or = 2 (p = 0.0004; RR = 4.24). CONCLUSIONS: Three variables evaluated at diagnosis, general state (ECOG), Ann Arbor stage and albumin, determined the prognosis in this series of large cell lymphoma. A prognostic model was designed from the same with three risk groups. The application of the international prognostic index to this series separated the patients into 4 groups of differentiated prognosis.
Leukemic relapse is the major complication following autologous bone marrow transplantation (BMT) in acute myeloblastic leukemia (AML). Previously, we have shown that recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) infusion after autologous BMT has the ability to augment endogenous activated killer (AK) cell function which may play a role in the eradication of minimal residual disease. However, the clinical application of rhGM-CSF in patients with AML has been limited by its potential stimulatory effect on the malignant clone. Here we report the effect of rhGM-CSF 5 micrograms/kg/day infusion on AK cell function in 20 patients with AML undergoing autologous BMT. AK cell function was investigated before autologous BMT, during rhGM-CSF therapy and after withdrawal. In addition, its influence on the actuarial risk of relapse is analyzed and compared with a historical control group of 20 patients transplanted immediately before initiation of this study. rhGM-CSF significantly enhanced AK cell function. During rhGM-CSF treatment, median AK cell function rose from 1.8% before autologous BMT (range 0-8%) to 35% (range 3-80%) and remained increased after cessation of rhGM-CSF (median 20%; range 0-36%; P < 0.001). After a median follow-up of 24 months, the actuarial risk of relapse is 37.4% in rhGM-CSF-treated patients compared with 49.5% in controls (P = 0.05). Interestingly, none of the 7 patients with an AK cell activity > or = 20% in the first 2-5 weeks after autologous BMT have relapsed compared with 6 of 9 patients with an AK cell activity < 20% (P < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
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One hundred and four patients with low grade (9 patients), intermediate grade (31 patients) and high grade (64 patients) non-Hodgkin's lymphoma received an autologous bone marrow transplantation (BMT). Disease status at transplant was first complete remission (CR) in 46 patients, second CR in 14 patients, third CR in 7 patients, chemosensitive disease in 16 patients and chemoresistant disease in 21 patients. Estimated 5 year disease-free survival (DFS) for all 104 patients was 49% (95% confidence interval (CI), 36-63%) with a median follow-up of 24 months. Five year relapse rate for 80 evaluable patients was 26% (95% CI, 14-44%). The 8 year DFS and relapse for the 46 patients transplanted in first CR were 75% (95% CI, 63-82%) and 15% (95% CI, 7-33%), respectively, with a median follow-up of 27 months (range 13-104 months) and a median time to relapse of 5 months (range 4-20 months). In the univariate analysis, variables correlated with DFS were performance status at autologous BMT, disease status at autologous BMT, LDH level at autologous BMT, failure to achieve CR at diagnosis, front-line chemotherapy (1 vs 2 or more regimens) and Working Formulation. Variables correlated with relapse were disease status at autologous BMT, preparative regimen and Coiffer's index at diagnosis. Multivariate analysis showed that performance status was the only independent predictor of DFS and that disease status at autologous BMT was the best relapse predicting variable. In patients transplanted in first CR, the variables correlated with DFS were stage at diagnosis and performance status at autologous BMT.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute promyelocytic leukemia (M3) is a distinct subtype of AML considered to have better response to chemotherapy and a higher cure rate than other subtypes. We analyzed the outcome for 362 M3 patients transplanted in Europe from November 1979 to December 1992 and reported to the acute leukemia registry of the European Cooperative Group for Bone Marrow Transplantation (EMBT). Of these 362 patients, 187 received an autograft, 129 in first remission (CR1) and 58 in second remission (CR2), and 175 an allograft, 142 in CR1 and 33 in CR2. Patients autografted in CR1 had at 7 years a leukemia-free survival (LFS) of 48 +/- 5%, a relapse rate (RR) of 41 +/- 5% and a probability of transplant-related mortality (TRM) of 18 +/- 6%. Patients allografted in CR1 had a LFS of 42 +/- 6%, a RR of 28 +/- 5% and a TRM probability of 42 +/- 8%. For patients transplanted in CR2, the respective figures after auto and allotransplantation were: LFS: 31 +/- 7% and 22 +/- 8%, RR: 54 +/- 8% and 64 +/- 11%, TRM: 23 +/- 9% and 40 +/- 9%. These data, which do not permit comparison between autologous and allogeneic BMT, indicate that roughly 45% of M3 patients achieving CR1 may be cured by a marrow transplant. Since the recent use of transretinoic acid-containing induction regimens has increased early control for patients with AML M3, it will be important to find out how these results affect outcome following allogeneic or autologous BMT.
To investigate the impact of frozen and non-frozen bone marrow on engraftment kinetics and disease outcome, 94 patients with non-Hodgkin's lymphoma (NHL) autografted with frozen marrow (F group) were retrospectively compared with 38 who received marrow stored at 4 degrees C or 10 degrees C (NF group). The major end points of this study were time to hematopoietic recovery and early toxicity; disease response, disease-free survival (DFS), and relapse rate were also analyzed. Upon comparison of the NF and F groups, no significant differences were found in the period of time required to achieve a granulocyte count higher than 0.5 x 10(9)/l (20 and 22 days, respectively, p = 0.47) or a platelet count higher than 20 x 10(9)/l (28 and 27 days, respectively, p = 0.54). In addition, both groups behaved similarly in respect to toxic death (NF group 13%, F group 22%, p = 0.36), response rate (complete remission rate 78% in both groups), DFS (NF group 48%, F group 49%, p = 0.66), and relapse rate (NF group 30, F group 19%, p = 0.37). This study confirms that nonfrozen bone marrow is useful to support patients with NHL treated with myeloablative therapies.
Eight patients with acute leukemia (AL) and invasive pulmonary aspergillosis (IPA) developing during previous antileukemic therapy underwent BMT (autologous in 6 cases and allogeneic 2). IPA was treated prior to BMT with full doses of amphotericin B, associated with surgical resection in three cases. One patient was treated with amphotericin B and itraconazole. Prior to BMT, seven patients had minimal residual pulmonary lesions. All patients received amphotericin B (0.5 mg/kg/day) during the aplastic period prior to engraftment. One patient died of Gram-negative septic shock before engraftment. Seven patients achieved complete hematological engraftment without any evidence of IPA reactivation. Amphotericin B was well tolerated with only minimal transient renal dysfunction in three patients. Later pulmonary complications related to IPA were observed in only one patient who developed a self-limited episode of hemoptysis. One patient died of CMV pneumonitis and two of leukemia relapse. Four patients survive disease-free and without complications related to IPA. We conclude that the reactivation of correctly treated IPA can be successfully prevented in BMT patients by use of prophylactic amphotericin B. With this approach, prior IPA is not a contraindication to BMT.
The interactions of GM-CSF with cells of lymphoid lineage are not well understood and their clinical use has been focused on the acceleration of hematopoietic recovery. However, several reports have shown that human GM-CSF can affect certain T lymphocyte in vitro cytotoxic functions. To assess whether recombinant human GM-CSF (rhGM-CSF) has a more broadly based activity in the immune system, we studied its in vivo effects on endogenously-generated killer function in patients undergoing ABMT for hematologic malignancies. Eleven patients received rhGM-CSF after ABMT: eight received rhGM-CSF as a 2-h infusion daily from days +3 to +17 and three received rhGM-CSF until reaching > 500 x 10(6)/l granulocytes. Eight patients not enrolled in the rhGM-CSF therapy protocol served as controls. Natural killer (NK) cell activity and activated killer (AK) cell activity were studied before conditioning, during rhGM-CSF therapy and after withdrawal of GM-CSF. rhGM-CSF therapy does not affect NK activity. Circulating lymphocytes with the ability to kill AK-sensitive targets appear spontaneously in control ABMT patients. AK activity was 1.6 +/- 0.8% before ABMT increasing to 9 +/- 2.5% and 14 +/- 2.1% at 2 and 3 weeks after ABMT, respectively (p = 0.002). In rhGM-CSF-treated patients this phenomenon also occurs. AK activity increased from 2.4 +/- 1.5% before ABMT to 33.6 +/- 8.1% during rhGM-CSF administration (p = 0.001) and 17.5 +/- 3.4% after withdrawal (p = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
BACKGROUND: Initially, the aim of the present study was to evaluate the incidence and implicated organisms in the infections in patients receiving a bone marrow transplants (BMT). METHODS: 194 febrile episodes (FE) were evaluated in 115 patients having received a BMT between 1980 and 1987. The analysis was carried out at three different moments: during the period of most marked neutropenia (period I) to the 100th day after BMT (period II) and beyond the 100th day (period III). RESULTS: The unequivocal confirmation that FE was infective was found in 62% of cases (confirmation was microbiological in 46% and clinical in 16%), while 31% of FE were considered as possible infections and the remaining 7% as doubtful infections. The causative organisms were bacteria (73%), viruses (10%), fungi (8%), and combinations of them (polymicrobial infections) (9%). Gram negative and Gram positive organisms were more common, respectively, in period I and in periods II and III (p = 0.02). Bacteremia was the commonest cause of confirmed infection. The overall mortality rate due to infection was 18%. There was a remarkably high mortality from pneumonia (54%) and a low mortality in patients with sepsis (6%) (p less than 0.0001). The number of FE was lower in patients with autografts than those with allografts (p = 0.08). 33% of the FE in patients with allografts were coincident with acute or chronic graft-versus-host disease, and in two thirds of them infections was confirmed. CONCLUSIONS: Infection represents a major complication of BMT. The different antimicrobial treatments used in association with bone marrow grafting allowed us to control most FEs. Pneumonia was the most severe infective localization and the leading cause of death. Mortality rate due to sepsis was small.
Theoretical considerations and preliminary results of clinical trials support the earlier use of autologous bone marrow transplantation (ABMT) in poor prognosis non-Hodgkin's lymphoma (NHL). A prognostic analysis of 50 patients with intermediate or high grade NHL younger than 60 years, who achieved at least one complete remission and were not treated with BMT, was performed. Patients with bulky tumor at diagnosis and/or serum LDH greater than or equal to 600 U/l do poorly with conventional chemotherapy. Twelve patients with these high-risk initial characteristics in first complete remission (CR) and six patients in second or third CR were treated with cyclophosphamide (60 mg/kg x 2) and total body irradiation (1000-1200 cGy) followed by ABMT. Overall disease-free survival was 65% at a median follow-up of 35 months. No differences were found between the first and later CR patients. The rate of toxic death was 11%. Disease-free survival after first CR was better for 1st CR ABMT patients than for a historical chemotherapy control group with similar poor prognosis features (p = 0.008). These results support the use of ABMT in selected, high-risk NHL patients in first CR.
Fifteen bone marrow autotransplants (BMAT) in patients with acute myeloblastic leukemia (AML) were performed after the first remission. The mean age was 37 years (range 12 to 60 years). According to the morphological classification FAB, 8 patients had monocytic leukemia (M4, M5) and 7 myeloid leukemia (M1, M2, M3). The mean interval elapsed between the date of complete remission and the BMAT was 3.9 months (range 1 to 5-9 months). In 8 patients this interval was longer than 6 months and in 7 cases it was shorter than 6 months. After achievement of the complete remission all patients underwent certain cycles of intensification before the BMAT. Eight patients received only a cycle whereas 7 patients received more than one cycle (between 2 and 4). The conditioning protocol consisted of cyclophosphamide (CP) (60 mg/kg x 2) and total body radiotherapy (TBR) (10 Gy) in 9 patients; CP and busulfan in five; and CP, cytarabine at high doses and melphalan in one case. Marrow extraction was performed after completion of chemotherapy of intensification. In 5 cases the bone marrow was depleted of leukemic cells by previous in vitro treatment with ASTA-Z. There are at present 8 alive patients. The survival free of illness was 51.8%. Seven patients died: 3 cases because relapse of the leukemia, 3 due to attachment failure of the transplantation, and one patient suffered a viral myocarditis. The survival free of illness was significantly longer in those patients transplanted after 6 months of the complete remission.