Abstract: PURPOSE: To compare doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) versus bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) versus cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxirubicin, vincristine, procarbazine, vinblastine, and bleomycin (COPPEBVCAD; CEC) for advanced Hodgkin's lymphoma (HL). PATIENTS AND METHODS: Three hundred seven patients with advanced HL (stage IIB, III, and IV) were randomly assigned to receive six courses of ABVD, four escalated plus two standard courses of BEACOPP, or six courses of CEC, plus a limited radiation therapy program. RESULTS: After a median follow-up of 41 months, BEACOPP resulted in a superior progression-free survival (PFS), with a significant reduction in risk of progression (hazard ratio [HR] = 0.50) compared with ABVD. No differences between BEACOPP and CEC, or CEC and ABVD were observed. The 5-year PFS was 68% (95% CI, 56% to 78%), 81% (95% CI, 70% to 89%), and 78% (95% CI, 68% to 86%), for ABVD, BEACOPP, and CEC, respectively (BEACOPP v ABVD, P = .038; CEC v ABVD and BEACOPP v CEC, P = not significant [NS]). The 5-year overall survival was 84% (95% CI, 69% to 92%), 92% (95% CI, 84% to 96%), and 91% (95% CI, 81% to 96%) for ABVD, BEACOPP, and CEC, respectively (P = NS). BEACOPP and CEC resulted in higher rates of grade 3-4 neutropenia than ABVD (P = .016); BEACOPP was associated with higher rates of severe infections than ABVD and CEC (P = .003). CONCLUSION: As adopted in this study BEACOPP is associated with a significantly improved PFS compared with ABVD, with a predictable higher acute toxicity.
Abstract: BACKGROUND:: Recent experience has suggested that there has been a stepwise improvement in the survival outcomes of patients who have follicular lymphoma with the introduction of new treatment options. In the current study, the authors report the results of 2 subsequent phase 2 trials of 238 previously untreated patients. METHODS:: In a trial of bleomycin, epidoxorubicin, cyclophosphamide, vincristine, and prednisone (BACOP) plus fludarabine, mitoxantrone, and dexamethasone (FND), 144 patients received 2 BACOP treatments followed by 4 FND treatments. In a trial of BACOP plus fludarabine and rituximab (FR), 94 patients received 3 BACOP treatments followed by 4 FR treatments. RESULTS:: The complete remission (CR) rate for BACOP/FND was 62%. After a median follow-up of 60 months, the failure-free survival (FFS) and overall survival (OS) rates at 4 years were 53% and 77%, respectively. The CR rate for BACOP/FR was 79%. After a median follow-up of 36 months, the FFS and OS rates at 4 years were 56% and 97%, respectively, which were significant compared with the CR and OS rates achieved with BACOP/FND. Twenty-five of 42 bcl-2-positive patients attained a molecularly negative CR and had improved FFS. No significant differences were observed between the 2 trials in the percentage of infections or neutropenia. CONCLUSIONS:: The CR and OS rates achieved with BACOP/FR were better, and overall toxicity did not increase. Furthermore, patients who received rituximab had a better FFS compared with patients who received chemotherapy alone. Finally, although conclusions between nonrandomized groups may depend on differences in observed and unobserved prognostic features, the current results suggested that the addition of rituximab to anthracycline-fludarabine-containing regimens have a favorable effect on the prognosis of patients with advanced follicular lymphoma. Cancer 2009. (c) 2009 American Cancer Society.
Abstract: PURPOSE: In the pre-positron emission tomography era, the Gruppo Italiano Studio Linfomi (GISL) investigated the feasibility and efficacy of a treatment based on a response-tailored number of doxorubicin/bleomycin/vinblastine/dacarbazine (ABVD) courses in 218 intermediate-stage Hodgkin lymphoma patients. PATIENTS AND METHODS: Patients with stage I/II showing at least one adverse prognostic factor and stage IIIA without adverse prognostic factors were recruited. Treatment included a first step of 3 ABVD courses, followed by an early-restaging. Patients in CR/CRu received 1 additional ABVD cycle, patients in PR received 3 more ABVD, and nonresponder patients went off study. Involved-field radiation therapy (RT) was recommended on chemotherapy completion. RESULTS: The median age was 30 years (range, 15-68 years) and 131 patients (61%) were female. Seven percent of patients were in stage I, 78% in stage II, and 15% in stage III; B-symptoms, bulky tumor and erythrocyte sedimentation rate > 30 were recorded in 20%, 26%, and 43% of cases, respectively. The CR/CRu rate was 62% at early restaging, 72% at the end of chemotherapy, and 95% following RT. With a median follow-up of 74 months (range, 6-193 months), 7-year overall survival, relapse-free survival, and freedom from treatment failure were 91.8% (95% CI, 86%-95.5%), 89.2% (95% CI, 82.8%-93.3%), and 81.8% (95% CI, 75.2%-86.7%), respectively. Patients in CR/CRu on early restaging, receiving 4 ABVD, had an excellent outcome with 7-year RFS and cause-specific survival similar to those of the late responders treated with 6 ABVD (RFS, 87.5% vs. 90.5% and CSS, 96.6% vs. 92.7%, respectively). CONCLUSION: The response-guided ABVD program we report, based on standard clinical staging procedures, proved to be feasible and safe in patients with intermediate-stage Hodgkin lymphoma.
Abstract: We conducted a retrospective study on treatment-related ovarian failure in 61 women with Hodgkin lymphoma who were under treatment from 1994 to 2006. To minimize the risk of treatment-related gonadotoxicity, triptorelin (Decapeptyl), a gonadotropin-releasing hormone analog (GnRHa), was administered monthly. All patients were treated with frontline polychemotherapy with or without radiotherapy. Seven refractory or relapsed patients received salvage treatment, and six of these patients further received peripheral blood stem cell transplantation. Fifty patients (82%) recovered regular menses, four patients (6%) reported menstrual abnormalities, and seven patients (12%) who were under salvage treatment became amenorrheic. We found a clear correlation between age at the time of treatment, advanced disease, cumulative therapeutic load and ovarian failure. After the completion of treatment, 13 patients who attempted conception conceived. GnRHa may preclude ovarian damage and infertility in young women receiving frontline polychemotherapy alone or in combination with supradiaphragmatic radiotherapy. In refractory or relapsed patients, GnRHa does not seem to be very effective, and further experimental approaches are required for fertility preservation.
Abstract: BACKGROUND: Improved treatment has increased the life expectancy of patients with non-Hodgkin's lymphoma, but few studies have addressed the issue of second cancer in patients treated for diffuse large B-cell lymphoma. The aims of this study were to determine the incidence and time free of second cancers in this subset of patients. DESIGN AND METHODS: We evaluated a cohort of 1280 patients with diffuse large B-cell lymphoma who were first treated between 1988 and 2003. We utilized the central database of the Gruppo Italiano Studio Linfomi, which includes data on demographics, clinical characteristics, laboratory parameters, treatment and follow-up of all patients with non-Hodgkin's lymphoma enrolled in clinical trials. RESULTS: After a median follow-up of 51 months, 48 patients had developed a second cancer: 13 hematologic malignancies and 35 solid tumors. The overall standardized incidence ratio in our cohort (with a median age of 58 years) matched that of the general Italian population. The incidence ratio of second tumors was age related, and the age groups 20-39 and 40-59 years showed an increased risk. Overall, the cumulative incidence of second cancer was 8.2% at 15 years. A multivariate analysis showed that older age at the time of diagnosis of lymphoma had a negative influence on the time free of second tumors. CONCLUSIONS: In our cohort, only young patients showed an increased incidence ratio of second malignancies, while the incidence ratio in patients aged over 59 years matched the incidence in the Italian general population. Demographics, baseline characteristics, laboratory parameters and treatment modalities did not have any significant impact on the incidence ratio of a second cancer.
Abstract: BACKGROUND: It is unclear whether new treatment modalities have improved the survival of follicular lymphoma patients. Some data show that there has been no improvement in survival in the last 3 decades of the 20th century, whereas the results of recent retrospective studies suggest that evolving therapy has improved the outcome for follicular lymphoma patients. METHODS: To evaluate the impact of evolving therapies for follicular lymphoma, particularly the introduction of rituximab, the overall survival (OS), failure-free survival (FFS), and survival after recurrence (SAR) was analyzed in 438 advanced-stage follicular lymphoma patients enrolled in consecutive Gruppo Italiano Studio Linfomi (GISL) trials between 1988 and 2004. RESULTS: A stepwise improvement in FFS and a significant reduction in the hazard ratio was observed with succeeding studies. Cox regression analysis showed an improvement over time for OS, with a decline in the hazard ratio particularly evident in the group treated with rituximab. Furthermore, the SAR significantly improved in the group of patients treated with chemotherapy + rituximab. CONCLUSIONS: After adjusting for all parameters with an impact on FFS and OS, the results of multivariate analysis suggest that rituximab therapy has a favorable effect on the prognosis of follicular lymphoma. The data show that FFS and OS have significantly improved in advanced-stage follicular lymphoma patients treated on GISL protocols during the last 18 years. These improvements are related to evolving front-line and salvage therapies, particularly the introduction of rituximab in combination with chemotherapy.
Abstract: Over a period of 28 months, we observed five cases of osteonecrosis of the jaw (ONJ) in cancer patients treated with bisphosphonates (BP) at our institution. This prompted us to undertake a retrospective, multicenter study to analyse the characteristics of patients who exhibited ONJ and to define the frequency of ONJ in multiple myeloma (MM). We identified 35 cases in Gruppo Italiano Studio Linfomi centers during the period 2002 - 05. The median time from cancer diagnosis to the clinical onset of ONJ was 70 months. In these 35 cases of ONJ, 24 appeared 20 - 60 months after starting BP treatment. The time for the onset of ONJ was significantly shorter for patients treated with zoledronic acid alone than for those treated with pamidronate followed by zoledronic acid. The frequency of ONJ in the MM group during the study period was 1.9%, although the nature of the present study may have resulted in an underestimation of ONJ cases. Our analysis strongly suggested an association between the use of BP and the occurrence of ONJ, although we were unable to identify any definite risk factors with a retrospective study. The most frequently ONJ-associated clinical characteristics were chemotherapy treatment, steroid treatment, advanced age, female sex, anemia, parodonthopaties/dental procedures and thalidomide (in the case of MM patients).
Abstract: GISL recently conducted an exhaustive survey of 1078 patients with Hodgkin's Lymphoma (HL) enrolled between 1988 and 2002 in different prospective trials. Treatment failure was observed in 82 out of 1078 patients; of these 82 patients with refractory HL, complete information was available for 72, who form the evaluable population of the present study. After the initial therapy failure, 51 patients were treated with conventional salvage chemotherapy (CC) (n = 24) or high-dose chemotherapy (HDC) (n = 27); 4-year overall survival (OS) was 81% in the HDC group versus 38% in the CC group (P = 0.019). The remaining 21 patients had rapidly progressive disease and died. After a median follow-up of 2.8 years, the projected OS for all 72 patients is 58 and 49% at 3 and 5 years, respectively. Age <45 years, the absence of systemic symptoms and a PS <1 predicted a significantly longer OS. Interestingly, the majority of patients with two or three negative prognostic factors did not receive potentially curative therapy. In conclusion, HDC seems to be a reasonable option for selected patients with refractory HL, although the majority of them did not receive a transplant. Finally, patients with a high-risk score had little chance of receiving potentially curative treatment.
Abstract: We treated 30 consecutive untreated patients aged > 70 years with advanced aggressive non-Hodgkin's lymphoma with 6 courses of cyclophosphamide, mitoxantrone, etoposide, bleomycin, vinblastine and dexamethasone (D-VICEMB). The global response was 93%. The 6-year overall survival and progression-free survival were 50%, and disease-free survival was 63%.
Abstract: At present we report the results of a prospective, non-randomized open trial, conducted on follicular lymphoma (FL) patients by the Gruppo Italiano per lo Studio dei Linfomi (GISL), after a median follow-up of 62.6 months. Seventy-three patients with FL were registered to the study and treated with combination chemotherapy consisting of cyclophosphamide, epidoxorubicin, vincristine, bleomycin and prednisone, weekly administered every 4 weeks. After chemotherapy, involved-field radiotherapy was delivered in case of either localized, bulky and extranodal disease at presentation or limited residual disease at the end of chemotherapy. Patient received four or eight chemotherapy courses in case of localized or advanced disease, respectively. The overall response rate at the end of the treatment program was 97.3%, with 78.1% CR and 19.2% PR. CR rate was 94.3 and 63.1% in stage I-II and III-IV, respectively (p = 0.006). Beside the stage, response rate was significantly influenced by bone marrow involvement, and the number of extranodal sites. Relapse free survival was 60.8% at 5 years in the whole series; in localized disease it was 70.3 vs. 44.8% in advanced disease (p = 0.044). Relapse free survival was significantly influenced by stage, bone marrow involvement, number of extranodal sites and International Prognostic Index (IPI) score. The overall 5-year survival rate was 90.2%; being 95.6% for patients with stage I-II and 85.1% for those III-IV (p = 0.0133). In addition, both IPI and Italian Lymphoma Intergroup (ILI) score had a significant impact on survival. The toxicity profile of the treatment was acceptable. From the results of this prospective study it is possible to conclude that this regimen and the whole treatment program is effective as first line therapy for the general population of FL. In particular the BACOP schedule is a valid anthracycline-containing regimen, and in this respect suitable to be considered as a treatment option.
Abstract: Euthyroid sick syndrome is related to profound changes in thyroid metabolism induced by nonthyroidal diseases. To determine whether children with newly diagnosed Hodgkin disease might present thyroid abnormalities and to establish their predictive value, the authors performed regular thyroid function testing. Seven children (5 M, 2 F) with a mean age of 10.4 years (range: 4.6-15 years) at diagnosis were studied for a period of 6.9 years (4.2-10.5 years). Five patients presented at diagnosis with euthyroid sick syndrome characterized by borderline low thyroxine circulating levels (T3 0.8-1.3 ng/mL, FT3 1.5-1.7 pg/mL) and mildly raised TSH (4.6-5 microU/mL). Thyroid function turned normal within 6 months of therapy. Subsequently, 3 children developed overt hypothyroidism (T4 35-40 ng/mL, FT4 2-7 pg/mL, TSH 5.5-11 microU/mL) requiring substitution therapy. Euthyroid sick syndrome was not associated with a poorer outcome in terms of survival or long-term thyroid consequences. Thyroid function testing should be performed routinely at diagnosis and thereafter in children with Hodgkin disease to detect subtle abnormalities.
Abstract: BACKGROUND AND OBJECTIVE: The subset of non-follicular non-Hodgkin's lymphoma (NHL) includes patients with varied prognoses, thus suitable for different therapeutic approaches. The International Prognostic Index (IPI), originally proposed for aggressive NHL, has been demonstrated to be of prognostic relevance also in follicular NHL. The main aim of the study was to validate the IPI in this histologic category; in addition, the specific prognostic classification, currently employed in the Gruppo Italiano per lo Studio dei Linfomi (GISL) prospective therapeutic trials and based on different features, more similar to those applied to chronic lymphocytic leukemia, was analyzed. DESIGN AND METHODS: The present series consists of 137 evaluable patients affected by Working Formulation group A NHL out of 256 cases referred to the GISL Registry. The retrospective prognostic study included the evaluation by both univariate and multivariate analyses of overall survival, response to therapy and response duration. The IPI was applied as originally proposed. The GISL definition of indolent and aggressive disease at diagnosis was based on the presence of B symptoms, bulky disease, anemia and thrombocytopenia. RESULTS: The distribution of patients in IPI risk groups was rather unbalanced with 18%, 47%, 28% and 7% of cases classified as low (L), intermediate-low (IL), intermediate-high (IH) and high (H) risk, respectively. The median overall survival was not reached in either L or IL risk groups, and was 84.1 and 7.4 months for IH and H risk groups, respectively (p=0. 0005). A simplified IPI model was designed merging patients in both intermediate risk groups and the statistical difference of survival retained its significance. GISL prognostic stratification was demonstrated to have a significant association with survival, with a median survival of 71.3 months in aggressive disease and a median survival not reached at 152 months in indolent disease. Both the simplified IPI model and the GISL risk definition retained their significance in multivariate analysis for overall survival, while for response to therapy only the simplified IPI model resulted to be of statistical significance. In addition, the GISL prognostic stratification identified patients with different outcomes within the IPI intermediate risk group, with a median survival of 70.2 months for patients with aggressive disease wheras the median survival for those with indolent disease was not reached. Finally, a prognostic score resulting from the integration of the simplified IPI and the GISL system was statistically validated. INTERPRETATION AND CONCLUSIONS: The retrospective analysis of this series demonstrates the validity of the IPI in non-follicular indolent NHL and the usefulness of integrating the IPI parameters with disease specific prognostic variables.
Abstract: BACKGROUND AND OBJECTIVES: To evaluate the feasibility, toxicity and preliminary results of a potentially less toxic variant of the MOPPEBVCAD chemotherapy regimen for advanced Hodgkin's disease: MOPPEBVCyED, in which cyclophosphamide and etoposide replace lomustine and melphalan, respectively, with the remaining components being unaltered. DESIGN AND METHODS: The study was multicenter, prospective and randomized, and enrolled 67 patients with newly diagnosed stage IIB, III, IV Hodgkin's disease (62 were expected on the grounds of statistical considerations). Radiotherapy was restricted to sites of bulky involvement or to areas that responded incompletely to chemotherapy. Median follow-up was 48 months. RESULTS: Comparing MOPPEBVCAD vs. MOPPEBVCyED, the results were as follows: complete remissions 35/35 vs. 30/32 (plus one partial remission and one disease progression); relapses 5 vs. 8; deaths 2 (one of myelodysplasia) vs. 2; delivered mean dose intensity (DI): lomustine 0.79+/-0.67 vs. cyclophosphamide 0.82+/-0.32; melphalan 0.80+/-0.13 vs. etoposide 0.86+/-0.18; average DI of the 7 drugs common to both regimens 0.73+/-0.10 vs. 0.83+/-0.11; all 9 drugs 0.75+/-0.13 vs. 0.84+/-0.09 (p=0.002); projected 5-year failure-free survival 0.79 vs 0.62; second cancers, two myelodysplasias vs. one carcinoma of the kidney. Toxicities were not statistically different except for heavier thrombocytopenia being recorded with MOPPEBVCAD. INTERPRETATION AND CONCLUSIONS: The higher cumulative and single drug DI recorded with MOPPEBVCyED may reflect better short-term tolerability, but it does not lead to better disease control. Its late toxicity may be expected to be lower in the future but at present it does not seem to be a sufficient reason to substitute MOPPEBVCyED for MOPPEBVCAD.
Abstract: BACKGROUND AND OBJECTIVE: Although in recent years anaplastic large-cell lymphoma (ALCL) has emerged as a distinct clinico-pathological entity, a gold standard for treatment has still not been defined. Goals of our histologic, phenotypic and clinical study were to present clinical findings, treatment outcome and survival rates of a small, but highly homogeneously treated, series of patients. DESIGN AND METHODS: From April 1991, 36 newly diagnosed adult patients with systemic ALCL CD30+, entered a prospective non-randomized trial in one of the institutions participating in a GISL (Gruppo Italiano per lo studio dei Linfomi) study and were treated with a MOPP/EBV/CAD hybrid scheme. Chemotherapy (CHT) was administered every 28 days, for a total of 6 cycles. After CHT, 19 patients received radiation therapy (RT) to the site of previously involved fields. Kaplan and Meier and log-rank tests were used for statistical analysis. RESULTS: The overall complete remission rate was 78%, the partial remission rate was 6%. The overall survival rate at 74 months was 69%. No statistically significant differences in response or survival rates were noted comparing ALCL-HL and -CT subgroups, T+ Null- and B- subtypes, or ALCL-HL and -CT, with different phenotypes. In the analysis of patients with T+ Null phenotype treated with CHT+RT in comparison with B-ALCL patients who had the same treatment, we observed statistically significant differences in the survival rate (p=0.048). No prognostic factors predictive of response or survival were identified. INTERPRETATION AND CONCLUSIONS: Our results show that using MOPP/ABV/CAD the results, in terms of remission rate and survival, are similar to those obtained with 3rd generation CHT regimens. The diagnosis of T and Null ALCL is the most important prognostic factor, because it is associated with a very good survival, even in patients with a high prognostic index. Finally, we believe that longer follow-ups are needed to evaluate long-term survival and toxicity with different treatments.
Abstract: To determine the late effects of treatment on thyroid function in children who survive acute lymphoblastic leukemia, we assessed plasma levels of thyroid hormones in 24 children (15 girls and 9 boys) who had received combination of chemotherapy along with 18-24 Gy of irradiation to the cranium. The children were aged between 1 and 10.5 years (mean 3.1) at diagnosis and thyroid status was investigated between 1.3 and 13 years (mean 6.8) after completion of therapy. Six children showed a low peak of plasma thyroid stimulating hormone (TSH), after stimulation with thyrotrophin-releasing hormone (TRH). Three children showed a low basal plasma TSH concentration. Serum levels of thyroxine (T4, fT4) and triiodothyronine (T3, fT3) were normal in all patients. The frequency of thyroid hypofunction (low peak response of TSH to TRH) was more common in children receiving 24 compared to 18 Gy cranial irradiation (50% vs 14%; odds ratio = 7) and those who had completed therapy more than 5 years ago (31.3% vs 12.5%, odds ratio 3.18) although no significant association could be found (95% IC: 0.27-65.8 and 0.24-90 respectively). Because of the low mean age at diagnosis of our population no significant association could be found between children younger than 3 years of age at diagnosis and thyroid hypofunction (odds ratio = 0.14; 95% IC: 0.01-1.48). We conclude that treatment for acute lymphoblastic leukemia including cranial irradiation may lead to TRH/TSH dysfunction and therefore long term survivors should be followed for a long period after completion of therapy.
Abstract: PURPOSE: To test the adequacy of the CVPP four-drug regimen as ancillary chemotherapy associated with extended-field radiotherapy in the treatment of early, unfavorable, clinically staged Hodgkin's disease. PATIENTS AND METHODS: The population of this prospective, multicenter study consisted of 49 patients with stage I-II disease, associated with bulky involvement or unfavorable histology (lymphocyte-depleted nodular sclerosis or lymphocyte depletion), systemic symptoms or extranodal involvement, or presenting with stage III A favorable-histology disease, with or without extranodal involvement. RESULTS: Complete remission was achieved in 39 patients, partial remission in 2, while 8 patients did not respond. Four patients have relapsed so far (median follow-up: 43 months), all of whom were subsequently rescued with different salvage treatments. Dose intensity (mean +/- SD: 0.83 +/- 0.12) and hematological toxicity (including 2 deaths from infection) were higher when RT followed CT than when it was interposed in the middle of the 6 cycles. No growth factors were used. Nonhematological toxicity was very low and fully tolerable. CONCLUSIONS: Results confirmed the mild neurological and gastroenteric side effects of CVPP that make it an interesting MOPP-variant regimen. This combination seems most indicated when a regimen devoid of cardiac and pulmonary toxicity is required for association with full-dosage mediastinal radiotherapy, as is often the case in early, unfavorable Hodgkin's disease. The optimal sequence consists of radiotherapy administered after completion of the chemotherapy program. The use of growth factors for correction (or prevention) of marked leukopenia seems appropriate.
Abstract: Twenty two patients with thalassemia major who received successful bone marrow transplantation (BMT) were followed to verify the impact of the transplant procedure on subsequent growth and development. The transplant preparative regimen consisted of busulphan and cyclophosphamide. Growth and endocrinological function were assessed during the first 4 years following BMT. At the time of transplant most patients showed growth retardation. The median difference between chronological age and bone age was -9.5 months for the boys and -8.5 months for the girls. Patients > 7 years old at the time of BMT showed a significant worsening of their growth delay at 48 months following BMT compared with 12 months before transplantation. Patients < 7 years at the time of BMT had their growth retardation constant over time span after transplantation. Moreover six of 11 younger patients showed an improvement of their growth delay compared with one of 11 older patients. The outcome of height standard deviation score at 24 and 48 months following BMT was strictly correlated with the level of serum transaminases and ferritin. Sixteen patients had impaired growth hormone secretion after a provocative test evaluated at 24 months after transplant. At 48 months there was no significant increase in the mean peak GH levels. This study confirms that the growth retardation of patients with thalassemia major is multifactorial.
Abstract: A patient undergoing BMT for acute non-lymphocytic leukemia (ANLL) developed bloody diarrhea due to amebiasis. The infection was successfully treated with intensive and prolonged antiparasitic therapy.
Abstract: Attempts to identify an early and discriminating marker of acute graft-versus-host disease (aGvHD) have been unsuccessful. The levels of soluble CD4 and soluble CD8 in serum correlate with T cell subset activation and may be important in monitoring and characterizing immunological processes. We determined serum soluble CD4 (sCD4) and sCD8 levels with a two-site sandwich enzyme immunoassay on patients' serum samples collected prior to bone marrow transplantation and weekly after transplantation until day +28. No significant increment of sCD4 was documented in each determination. sCD8 rose significantly before diagnosis or development of maximal clinical symptoms in patients with grade II-III aGvHD than grade 0-I aGvHD [at day +21--median value 447 IU/ml; range 94-713; versus 1136 IU/ml, range 790-1416 (P = 0.002); at day +28--median value 443 IU/ml, range 73-992, versus 1164 IU/ml, range 625-1960 (P = 0.005)]. On the day of marrow infusion the sCD8 levels were significantly higher in patients who subsequently developed grade II-III than in patients with grade 0-I aGvHD (median value 155 IU/ml, range 10-332, versus 350 IU/ml, range 283-830; P = 0.003). Careful monitoring of sCD8 is a useful tool for a prompt aGvHD diagnosis and may be used in a clinical bone marrow transplantation setting.
Abstract: In this paper the impact of hemapheresis technology on 238 allogeneic bone marrow transplants performed in Pescara from 1982 through 1993 is described. Granulocyte transfusions were limited to patients with neutrophil level < 0.2 x 10(9)/L. An average of 4 units of packed red blood cells were required to maintain adequate hemoglobin levels. Patients with major ABO incompatibility showed an increased requirement of red blood cell support as compared to patients ABO-matched and ABO minor mismatched. For platelet support single-donor platelets collected on a blood-cell separator were given. A total of 1548 platelet transfusions were examined. The median number of platelet transfusions for each patient was 5. Platelet refractoriness occurred in 44% of patients. The hemorrhage related mortality was 0.9%. The advancement made in the field of hemapheresis technology, as well as the improved transplant technique, have contributed to increase the post-transplant survival from 17% in the early experience (1976-1982) to 88% in the recent years (1992-1993).
Abstract: Two episodes of meningitis due to penicillin-resistant Streptococcus pneumoniae occurring in two patients with chronic graft-versus-host disease (GVHD) are reported. Both patients were treated with ceftazidime. The first patient died, unresponsive to therapy. The second patient showed clinical improvement, reverting to her baseline mental status. This report draws attention to the fact that in chronic GVHD patients: (1) bacterial prophylaxis does not ensure protection against encapsulated bacteria; (2) rapid microbiological investigation is recommended with any upper respiratory tract infections.
Abstract: A 26-year-old man with AIDS-related complex (ARC) was treated with high-dose busulphan and cyclophosphamide, followed by allogeneic bone marrow transplantation. For 3 months before transplantation he received a combination of four drugs considered active against human immunodeficiency virus (HIV) to reduce the viral burden: zidovudine, acyloguanosine, fusidic acid and phenylidantoin. Although in reduced doses in coincidence with marrow engraftment, zidovudine therapy was scheduled after transplantation in order to protect donor cells from infection with HIV. Engraftment rapidly occurred and was documented by cytogenetic analyses. The post-transplant course was characterized by severe acute GvHD with irreversible hepatorenal failure. The patient died on day 48 after transplantation. Polymerase chain reaction analyses for detecting HIV DNA showed the persistence of positivity at day +30 and +45 after transplantation. Antibodies to specific HIV proteins evaluated with Western blot testing also persisted at days +21 and +35 after transplantation. Circulating immunocomplexes disappeared on day +31, and an increase in the CD4/CD8 ratio occurred. The short survival of the patient, affected by chronic hepatitis too, does not allow final conclusions about the role of BMT in HIV disease.
Abstract: Five patients (age range 7-14 years) received allogeneic bone marrow transplantation (BMT) for Fanconi anemia (FA). All patients showed progressive pancytopenia associated with congenital malformations. Diagnosis was confirmed by studies of cellular hypersensitivity to the clastogenic effect of the DNA crosslinking agent diepoxybutane. The conditioning regimen consisted of low dose cyclophosphamide (5 mg/kg x 4) and fractionated total body irradiation (167 cGy x 3). For graft-versus-host disease prophylaxis one patient was given cyclosporin alone while the remaining four patients received a combination of cyclosporin and two doses of methotrexate. Marrow was given unmanipulated from HLA-identical siblings. All patients are alive 18-67 months after grafting with Karnofsky scores of 100% and normal hemopoiesis of donor origin. Modifications in transplant protocols such as those here described have resulted in a decreased risk of severe transplant-related complications. These results confirm that BMT is a curative therapy in FA patients and should be considered as a first choice treatment if an HLA-identical donor is available.
Abstract: The authors report on a sequential cytogenetic study carried out on 31 patients with acute leukemia (20 with acute lymphoblastic leukemia and 11 with acute non-lymphocytic leukemia) who underwent bone marrow transplantation (BMT). Engraftment was documented in all patients with sex-mismatched donors and with donor constitutional aberrations. During the follow-up, ranging from 6 to 110 months, clinical and hematologic relapse was observed in 11 patients (35.5%). Five of these cases showed a normal karyotype, 3 were of undefined relapse origin, 2 were aneuploid karyotypes, and one was donor (male) metaphases. Cytogenetic and immunologic data in the latter patient were suggestive of relapse in donor cells.
Abstract: Recently, the principles of density gradient cell separation have been transferred to the marrow fractionation, and the Ficoll technique by using a COBE 2991 blood cell processor has been developed and widely employed as well. This method is particularly useful in view of a chemical antineoplastic purging intended for autologous marrow transplantation. Forty marrows, which derived from patients suffering with leukemia and lymphoma, were fractionated with Ficoll on a COBE machine and in vitro purged with Mafosfamide at a dose of 50 micrograms/ml/1 x 10e7 MN cells. The density gradient separation enables to reduce the initial volume to 10%, the contaminating RBC to less than 1%, the total nucleated cells to 25% (greater than 80% of MNC) sparing about 80% of the CFU-GM. After purging, the surviving hemopoietic progenitor cells were 2.5%. The clinical effects of the fractionated purged cells were studied in 11 autotransplanted patients and compared with 14 transplants performed with untreated buffy-coat marrow derived cells. Ficoll cells produced less adverse effects at the time of reinfusion, while, as expected, the time of hematopoietic recovery was delayed in these patients (mafosfamide treated cells). These results confirm the usefulness of the gradient density cell separation to reduce the side effects of the DMSO and to make reliable the Mafosfamide purging manoeuvre, preventing the interference of contaminating RBC aldehyde dehydrogenase.
Abstract: Cytogenetic data are reported from 16 patients with Philadelphia chromosome (Ph) positive chronic myelogenous leukemia (CML) treated with bone marrow transplantation (BMT). The usefulness of cytogenetic investigations for the assessment of marrow engraftment is stressed. The significance of persistence or reappearance of Ph after BMT, possibly due to a defective leukemic clone eradication by the conditioning regimen, is also discussed. Generally, Ph-positive cells are damaged and disappear within the first year of BMT. Sometimes, however, the cells may repair the damage and proliferate again, resulting in disease relapse. Rarely, clinical and hematologic relapse does not follow Ph-positive clone expansion although leukemic cells represent more than 50% of marrow metaphases examined. Finally, the effect of interferon on Ph-positive clones after BMT and random chromosome changes, that appear transiently after BMT and are of uncertain significance, are discussed.
Abstract: Allogeneic bone marrow transplantation was carried out on an 11-year-old boy with chronic granulomatous disease and severe chronic pulmonary insufficiency of restrictive type. After preparative regimen with busulfan (13 mg/kg) and cyclophosphamide (200 mg/kg), the patient received marrow cells from his HLA-identical and MLC-nonreactive sister. Durable sustained engraftment of donor hematopoietic and lymphoid populations occurred, as documented by analysis of genetic markers and complete reversal of the neutrophil function defect. No episode of infection occurred in the post-transplant course and, currently, 40 months after transplantation the patient is in excellent health and growing normally and showing an increasing improvement of his respiratory capacity. The successful outcome in this patient demonstrates that marrow transplantation is at present the only curative approach for this congenital disorder of neutrophil function.
