Biomedical subjects
Publications and source records attributed to Luca Laurenti.
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BACKGROUND AND OBJECTIVES: Methylenetetrahydrofolate reductase (MTHFR) is one of the enzymes involved in folate metabolism and DNA methylation and synthesis. Some genotypes of this highly polymorphic enzyme are associated with decreased activity. Previous studies have suggested that individuals with the MTHFR 677TT, 1298AC and 1298CC have a lower risk of adult acute lymphoblastic leukemia (ALL). DESIGN AND METHODS: In order to test this association we studied the presence of the C677T and A1298C mutant alleles in 174 patients with acute lymphoblastic leukemia and in 110 controls from central Italy. RESULTS: We did not find any association between the different polymorphisms and susceptibility to ALL. In multivariate analysis different genotypes did not show any correlation with the risk of ALL. The adjusted odds ratios and 95% confidence intervals for MTHFR C677T were 0.69 (0.4-1.19) for 677CT versus 677CC wild type, and 0.99 (0.50-1.97) for 677TT versus 677CC. The corresponding values for MTHFR A1298C were 0.93 (0.56-1.53) for 1298AC versus 1298AA wild type and 1.14 (0.36-3.61) for 1298CC versus 1298AA. INTERPRETATION AND CONCLUSIONS: These results do not support the suggestion that populations carrying different genotypes of the two MTHFR polymorphisms, C677T and A1298C, have a different susceptibility to ALL, at least in the Mediterranean area.
BACKGROUND AND OBJECTIVES: Although alemtuzumab (campath-1H) has been successfully used in patients with untreated or previously treated chronic lymphocytic leukemia (CLL), a variable incidence of cytomegalovirus (CMV) reactivation has been described. No prospective reports currently provide results of the use of oral ganciclovir as pre-emptive therapy in patients with CMV reactivation during alemtuzumab treatment. DESIGN AND METHODS: We designed a prospective study in 12 patients with pretreated CLL with the aim of evaluating the incidence of CMV reactivation during alemtuzumab treatment and the role of oral ganciclovir as pre-emptive therapy and in preventing CMV organ disease. RESULTS: In the 12 CLL patients being treated with alemtuzumab, 8 patients (66%) had CMV reactivation, as detected by antigenemia and/or CMV DNA. No patient showed clinical evidence of CMV disease. The alemtuzumab was discontinued and the patients were immediately treated with oral ganciclovir 1000 mg tid. After a median of 14 days of antiviral therapy all patients achieved negative CMV polymerase chain reaction (PCR) assays and/or antigenemia. No patients showed further CMV reactivation up to the end of the study. INTERPRETATION AND CONCLUSIONS: CMV reactivaction, studied with periodic analysis of antigenemia and PCR, is frequent in previously treated CLL patients receiving alemtuzumab therapy although only sporadic cases of CMV disease have been reported. Using oral ganciclovir, the response to therapy was prompt, there was no progression to CMV disease, and no relevant clinical toxicity, thus sparing unnecessary hospitalization. Oral ganciclovir may be used as pre-emptive therapy in all patients who develop CMV reactivation during alemtuzumab treatment.
BACKGROUND AND OBJECTIVES: Glutamine (gln), a non-essential amino acid, has recently received increasing attention because it becomes essential during stress and catabolic states: glutamine seems to modulate immune function and to promote faster intestinal healing after chemotherapy. We designed two consecutive randomized clinical trials to evaluate the role of glutamine-enriched parenteral nutrition (GEPN) in patients with hematologic malignancies submitted to high dose chemotherapy and autologous peripheral blood stem cell transplantation (aPBSCT) or immunoselected CD34+ aPBSCT. DESIGN AND METHODS: In study1, the Gln group (12 patients) received total parenteral nutrition (TPN) enriched with glutamine 20 g from day +1 after aPBSCT, while the placebo group (15 patients) received TPN lacking in glutamine (placebo). In study2, the Gln group (10 patients) received TPN enriched with glutamine 13.46 g from day +1, while the placebo group (11 patients) received a placebo. RESULTS: In the first study, a lymphocyte count >0.5 109/L was achieved on day 16.5 in the Gln group and on day 29 in the placebo group (p=0.005); in the second study, the lymphocyte count >0.5 109/L was achieved on day 18 in the Gln group and on day 29 in the placebo group (p=0.009). Lymphocyte subset analysis showed an increase of CD3+ and CD4+ and normalization of the CD16+CD56+ subset. Furthermore patients receiving GEPN showed a decrease in the mucositis severity peak calculated by the DMS (daily mucositis score: sum of the daily score of signs and symptoms) (p=0.047). INTERPRETATION AND CONCLUSIONS: GEPN is safe and effective and improves lymphocyte recovery after aPBSCT; further studies are needed to assess the clinical benefits of such an approach in order to justify its economic impact.
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We investigated the role of stem cell purification and G-CSF (early vs. delayed vs. no G-CSF) administration on hemopoietic recovery and supportive care requirements after stem cell transplantation. Thirty-two patients submitted to autologous CD34(+) peripheral blood stem cell transplantation (PBSCT) were studied, and data were compared to patients undergoing unfractionated peripheral blood stem cell transplantation (uPBSCT) matched for age, disease, and conditioning regimen. Except for PMN, hemopoietic recovery was significantly slower and supportive care requirements were significantly higher after CD34(+) PBSCT. Median time to PMN >0.5 x 10(9)/l was 13 days (range 9-27) and 13 d (range 9-23); reticulocytes (Ret) >1% was 14.5 d (range 12-34) and 12 d (range 10-27); high-fluorescence reticulocytes (HFR) >5% was 12 d (range 9-26) and 9 d (range 7-11); platelets >50 x 10(9)/l and >100 x 10(9)/l was 20 d (range 10-240), 12 d (range 9-60) and 33 d (range 15-720), 15 d (range 11-210). When the analysis was performed on subgroups of patients (early/delayed/no G-CSF), early G-CSF significantly promoted PMN recovery (>0.5 x 10(9)/l and >1.0 x 10(9)/l) compared to no G-CSF, without affecting RBCs or platelet recovery. Delayed G-CSF did not improve PMN recovery compared to patients not receiving G-CSF, did not result in a significant reduction of drug requirements, and had a negative impact on erythroid and platelet recovery. In conclusion, these preliminary data suggest that G-CSF is useful if given early after CD34(+) PBSCT. CD34(+) PBSCT may overall require a significant increase of resource utilization that should be outweighed by proven clinical benefit.
OBJECTIVE: To evaluate the safety, feasibility, and efficacy of allogeneic stem cell transplantation (SCT) for acute myelogenous leukemia (AML) in a young female coinfected by HIV and HCV undergoing highly active antiretroviral therapy (HAART). PATIENTS AND METHODS: A 33-year-old female HIV(+), HCV(+) in complete remission after standard chemotherapy was submitted to CD34(+) selected allogeneic transplantation from her HLA-identical HIV(-) brother after myeloablative regimen. HAART was started before transplantation, achieving a reduction of HIV load to undetectable levels. GVHD prophylaxis was carried out with cyclosporine A alone. RESULTS: The patient achieved prompt and durable engraftment with acute GVHD grade II easily managed with steroids; CMV prophylaxis was prolonged, no clinically relevant infectious complications developed early after transplantation and during follow-up. HIV viremia was controlled by HAART although medication adherence was reduced early after transplantation and required drug adjustment. There was a gradual recovery of immune cells with normal CD4-cell count 39 months after engraftment, a significantly higher level than before transplantation. At 39 months post-transplantation follow-up the patient is alive and in continuous complete remission with undetectable levels of plasma HIV RNA on HAART. CONCLUSION: The introduction of HAART has recently changed the paradigm of AIDS, allowing the control of HIV replication, the reduction of opportunistic infections, and the overall improvement of survival. One may therefore reconsider the current exclusion of patients with AIDS and a concomitant lethal malignancy from programs of high-dose chemotherapy and stem cell transplantation, as suggested by this report.
BACKGROUND AND OBJECTIVES: To analyze the results of standard versus alternative myeloablative conditioning regimens in allogeneic hematopoietic stem cell transplantation for high-risk acute leukemia. DESIGN AND METHODS: From October 1986 to February 2000, 104 consecutive patients (male: n = 63; median age: 21, range 1.3-44.2 years) with high-risk acute leukemia underwent a non-T-cell depleted graft from an HLA-identical sibling following a standard or alternative myeloablative conditioning regimen. Sixty patients were affected by acute lymphoblastic leukemia (ALL) and 44 by acute myeloid leukemia (AML); the phase at transplant was >= 2nd complete remission (CR) in 76, untreated 1st relapse with < 20% blasts in 11, refractory leukemia or overt resistant relapse in 17. Pre-transplant regimens consisting of either 12 Gy fractionated total body irradiation (TBI) or 16 mg/kg busulphan (BU) combined with cyclophosphamide (CY) were defined standard (n = 38), whereas all other myeloablative regimens (TBI plus 60 mg/kg etoposide and three-drug combinations) were considered alternative (n = 66). RESULTS: No significant differences in terms of baseline characteristics, incidence and severity of either acute or chronic graft-versus-host disease (GVHD) were observed between the two groups, but a significantly higher proportion of patients prepared with an alternative regimen were not evaluable for chronic GVHD (36% vs 16%) (p = 0.026). Sixty-six patients died, 38 of relapse, 26 of transplant-related mortality (TRM) and 2 of other causes. Thirty-eight patients are still alive with a follow-up ranging from 0.7 to 13.8 years (median, 7.1 years); only 1 of 39 patients who relapsed after transplant is alive in CR at 5.7 years from relapse. At the median follow-up, the actuarial probabilities of overall survival, relapse and TRM for patients conditioned with standard and alternative regimens are respectively 52% vs 25% (95% CI, 36-68% vs 13-37%; p = 0.0163), 34% vs 58% (95% CI, 18-51% vs 43-73%; p = 0.0377) and 25% vs 32% (95% CI, 9-40% vs 19-44%; p = ns). After adjustment for diagnosis, age, period, leukemia phase, duration of 1st CR, GVHD prophylaxis and donor-recipient sex combination, the multivariate analysis showed that alternative regimens are associated with a significantly worse survival (hazard ratio 2.31; p = 0.0071) and relapse rate (hazard ratio 2.75; p = 0.0187). INTERPRETATION AND CONCLUSIONS: From this retrospective analysis we can conclude that the alternative myeloablative conditioning regimens we used did not improve the outcome of patients transplanted for high-risk acute leukemia.
BACKGROUND AND OBJECTIVES: Myelodysplastic syndrome (MDS), secondary acute myeloid leukemia (sAML) and clonal karyotypic abnormalities, have been recognized as relatively frequent and potentially serious complications of autologous peripheral blood progenitor cell transplantation (PBPCT) for Hodgkin's disease (HD), non-Hodgkin's lymphoma (NHL) or multiple myeloma (MM). DESIGN AND METHODS: We analyzed 66 patients, undergoing PBPCT for HD, NHL, MM or chronic lymphocytic leukemia (CLL). Patients reported in this study had to be in continuous complete remission after transplantation without receiving chemo-radiotherapy or other biological response modifiers, had to show absence of cytogenetic abnormalities and myelodysplastic features at transplantation and had to have at least 12 months of follow-up. We evaluated the bone marrow, peripheral blood, cytogenetics and clonality (HUMARA) 12 months after the transplant and thereafter every 12 months or every 6 months if lineage dysplasia, clonal or cytogenetic abnormalities were detected. RESULTS: We did not observe MDS/sAML, according to the FAB classification, in 163 assessments of 66 patients over a median follow-up of 25 months (range 12-106) after PBPCT. Twelve patients showed lineage dysplasia: six patients had dyserythropoiesis, 2 patients dysgranulopoiesis, one dysmegakaryocytopoiesis, two patients showed double lineage dysplasia (erythroid and granulocytic), and one patient showed dysgranulopoiesis at the first control acquiring dyserythropoiesis at the next follow-up. We found three cytogenetic abnormalities in the absence of concomitant dysplastic features: transient -5q, -Y, fra(10)(q25). The female patient with the cytogenetic abnormality -5q showed transient unbalanced clonality by HUMARA assay; further controls documented normalization of both clonality and cytogenetics. INTERPRETATION AND CONCLUSIONS: The occurrence of MDS/sAML depends on a variety of risk factors such as the number and type of prior courses of chemo-radiotherapy, total body irradiation in conditioning regimen, cytogenetic and morphologic alterations prior to transplant. This may account for the difference in reporting MDS/sAML after transplantation. The lack of exposure to recognized risk factors for MDS/sAML in our patients may account for the absence of this complication in this study. We consider that the use of stringent morphologic criteria, especially during the first period after PBPCT, combined with cytogenetic, clonality and FISH analyses are necessary for a correct diagnosis of MDS and to overcome the limitations of the FAB and WHO classifications in this setting.
BACKGROUND AND OBJECTIVES: Although widely used, serological typing of HLA loci does not always produce uequivocal results. This may be particularly the case for cord blood since samples may be of small volume and poor quality, and contaminated. DESIGN AND METHODS: We typed 220 cord blood units (CBU) for HLA class I antigens using the serological technique. For those samples giving doubtful results we repeated the HLA typing by polymerase chain reaction with sequence specific primers (PCR-SSP). RESULTS: Results were satisfactory for 181 samples (82.3%). For the remaining 39 (17.7%) we had a doubtful antigen assignment for A locus in 9/39 cases (23.1%) and for B locus in 22/39 cases (56.4%). Eight of the 39 samples (20.5%) could not be analyzed by serology due to the high mortality of the cell suspension. Using PCR-SSP we obtained clear definition of class I antigens in all cases. All CBU were typed for HLA class II alleles by PCR-SSP with clear results in 100% of cases. INTERPRETATION AND CONCLUSIONS: In our experience, PCR-SSP can resolve the limitations of serology but, at the moment, it cannot substitute the latter in routine practice. The best strategy, in cord blood typing, is to perform both serological and molecular typing in order to obtain an accurate and clear result.
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