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Several guidelines have been published about management of chronic GvHD (cGvHD), but the clinical practice still remains demanding. The Gruppo Italiano Trapianto di Midollo Osseo (GITMO) has planned a prospective observational study on cGvHD, supported by a dedicated software, including the updated recommendations. In view of this study, two surveys have been conducted, focusing the management of cGvHD and ancillary therapy in cGvHD, to address the current ‘real life’ situation. The two surveys were sent to all 57 GITMO centers, performing allografting in Italy; the response rate was 57% and 66% of the interviewed centers, respectively. The first survey showed a great disparity especially regarding steroid-refractory cGvHD, although extracorporeal photo-apheresis resulted as the most indicated treatment in this setting. Another challenging issue was the strategy for tapering steroid: our survey showed a great variance, and this disagreement could be a real bias in evaluating outcomes in prospective studies. As for the second survey, the results suggest that the ancillary treatments are not standardized in many centers. All responding centers reported a strong need to standardize management of cGvHD and to participate in prospective trials. Before starting observational and/or interventional studies, a detailed knowledge of current practice should be encouraged.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) represents the only curative treatment for patients with myelodysplastic syndrome (MDS), but involves non-negligible morbidity and mortality. Crucial questions in clinical decision-making include the definition of optimal timing of the procedure and the benefit of cytoreduction before transplant in high-risk patients. We carried out a decision analysis on 1728 MDS who received supportive care, transplantation or hypomethylating agents (HMAs). Risk assessment was based on the revised International Prognostic Scoring System (IPSS-R). We used a continuous-time multistate Markov model to describe the natural history of disease and evaluate the effect of different treatment policies on survival. Life expectancy increased when transplantation was delayed from the initial stages to intermediate IPSS-R risk (gain-of-life expectancy 5.3, 4.7 and 2.8 years for patients aged ⩽55, 60 and 65 years, respectively), and then decreased for higher risks. Modeling decision analysis on IPSS-R versus original IPSS changed transplantation policy in 29% of patients, resulting in a 2-year gain in life expectancy. In advanced stages, HMAs given before transplant is associated with a 2-year gain-of-life expectancy, especially in older patients. These results provide a preliminary evidence to maximize the effectiveness of allo-SCT in MDS.

VEPs were examined in ALL patients in order to test their usefulness in the detection of early and late CNS changes due to combined cranial X-irradiation and chemotherapy.

Because recent data indicate that erythropoietin (Epo) production is defective in allogeneic bone marrow transplant (BMT) patients, we investigated the role of the immunosuppressant, nephrotoxic, agent cyclosporin A (CsA) on renal Epo production using an animal model. Mice were injected with 1.0 to 40.0 mg/kg/d CsA for 15 days. Thereafter, circulating Epo levels were evaluated in both intact animals and in mice made anemic with phenylhydrazine (PHZ). Serum Epo levels measured in CsA-treated animals were then compared with the predicted levels, which had been calculated in a reference population of normal, either intact or anemic, mice. In CsA-treated, intact animals both hematocrit and serum Epo levels were not significantly different from controls. However, serum Epo levels in CsA-treated, anemic mice were significantly lower than those expected in a control population of untreated, anemic mice with similar degrees of anemia. No significant increase in serum creatinine was recorded even at the highest doses of CsA used, nor were we able to document signs of renal toxicity by histologic examination of the kidneys. Therefore, therapeutical doses of CsA appear to affect the production of Epo under conditions in which the demand of the hormone is increased, as in response to anemia. We suggest that a subclinical kidney toxicity produced by CsA might have a role in the pathogenesis of the impaired Epo production observed in BMT patients, and may contribute to a delayed erythroid engraftment in at least some BMT patients.

There is evidence that the inadequate erythropoietin (Epo) production observed in patients undergoing allogeneic bone marrow transplantation (BMT) might be ascribed to an inhibitory effect caused by the immunosuppressive drug cyclosporin A (CsA). In this in vitro study, we have evaluated the effects of CsA on the release of Epo in the culture medium by the human Hep3B hepatoma cell line. In cultures incubated with both CsA and the nonimmunosuppressive CsA analog MeAla-6, but not with the CsA-unrelated immunosuppressive agent FK-506, the levels of Epo in the medium were significantly reduced in comparison with controls, at concentrations (0.01 to 1.6 mumol/L) not affecting total protein synthetic rate nor the constitutive secretion of alpha- fetoprotein. Hep3B cells were found to contain a CsA-binding molecule, with an M(r) of 18 Kd, as assessed by high performance liquid chromatography (HPLC) and ligand-blotting analysis. CsA did not affect the expression of the Epo gene, as judged by Northern blot analysis, but caused a significant amount of Epo to remain unsecreted within the cells; almost all (97% of total) of the intracellular Epo was associated with the plasma membrane subcellular fraction. We conclude that: (1) CsA is able to inhibit Epo release in vitro by Hep3B cells, further supporting the hypothesis that the drug might have a role in the inappropriately low Epo levels observed in BMT patients; (2) the inhibitory effect appears to be specific and not caused by a general impairment of protein synthesis and/or secretion; and (3) the reduced Epo levels found in the medium of CsA-treated Hep3B cultures are supposed to be the consequence of an inability of the cells to correctly process Epo molecules for the secretory pathway.

Purpose. A major complication of allogenic bone marrow transplantation (BMT) is graft-versus-host disease (GVHD), characterized principally by involvement of the eyes, producing a Sjögren-like syndrome (SLS). This study assessed the predictive role of the eye involvement in the onset of GVHD.Methods. Thirty-five patients transplanted for hematological malignancies were routinely examined for ocular manifestation of dry eye. Examination includes the Schirmer I test, break-up time, Lissamine Green staining, fluorescein test, lactoferrin test and impression cytology. A threshold was established for quantitative analysis of SLS.Results. Fifteen of 35 patients (40%) developed SLS during long-term follow-up. Ten of these (77%) developed acute or chronic GVHD.Conclusions. The possible etiology of SLS includes three factors: total body irradiation, ocular toxicity of chemotherapy and GHVD. A correlation was found between poor-prognosis GVHD and the occurrence of SLS.

Abstract: We report a method providing access to high molecular weight, polymerase chain reaction (PCR)-amplifiable genomic DNA from brains stored in formalin for many years. It consists mainly of an intensive proteinase K treatment of ground tissue previously embedded in agarose plugs, followed by a washing and an elution step. The method was tested on brains fixed and stored in formalin for up to 46 years. All extracted DNA show an identical pattern of degradation ranging from well-preserved (more than 20 kb) to 400-bp-long fragments. This was demonstrated for DNA extracted from the cerebellums of elderly psychiatric and geriatric patients (of more than 60 years of age), male and female, demented or not, with postmortem delays longer than 1 h and shorter than 1 day. In all these cases PCR amplification of a 838-bp-long β-actin product was successfully performed when proteinase K treatment was sufficiently effective to generate pure DNA. Thus, high molecular weight, PCR-amplifiable genomic DNA can be extracted from brains stored in formalin for almost half a century.

Nine patients affected from IgD myeloma were studied retrospectively in order to elucidate the incidence and peculiar traits of related nephropathy. Eight patients developed chronic renal failure, and as many as 5 were already suffering from renal failure since first admission to the hospital. In 3 cases acute renal failure was the major presenting symptom of the disease. Five patients underwent a regular dialytic treatment. We suggest that the high incidence of renal involvement found in IgD myeloma is related to the high incidence of Bence-Jones proteinuria observed in this disease. Presenting atypical symptoms, among which renal failure is the most important, are misleading and characteristic of the disease. Survival time seems to be negatively influenced by the presence of renal failure at the time of diagnosis.

The issue of the role of erythropoietin (Epo) in the erythroid reconstitution after bone marrow transplantation (BMT) has been addressed in several recent studies. A defective Epo production in response to anemia has been shown to occur in patients undergoing allogeneic BMT unlike in most of those subjected to an autologous rescue. The factors involved in the inadeguate Epo production in BMT are discussed, with particular attention to the role of the immunosuppressive drug cyclosporin-A, which has been shown to inhibit Epo production in both in vivo and in vitro models. The observation of defective Epo production eventually led to the development of clinical trials of recombinant human Epo (rhEpo) administration in BMT patients; the aims of these studies were to stimulate erythroid engraftment, hence reducing blood transfusion exposure. Although the number of patients studied up to now is relatively small, a benefit from rhEpo administration in terms of accelerated erythroid engraftment seems very likely, and it may also be associated with decreased transfusional needs in most treated patients. However, further studies are needed to better define indications, dosages and schedules of rhEpo in BMT patients.

Nonmyeloablative (NM) regimens extended the application of allogeneic transplantation (AT) to older and/or medically unfit patients ineligible for high-dose conditionings. Moreover, several patients are offered AT after failure of prior lines of therapy. We retrospectively evaluated 108 patients, median age 51 (16–67), with advanced or heavily pre-treated hematological cancers [19 acute myeloblastic (AML) and 1 lymphoblastic leukemia (ALL); 8 myelodysplastic syndrome (MDS); 9 chronic myeloid (CML) and 9 chronic lymphocitic leukemia; 3 myelofibrosis (MF); 48 myeloma beyond first line treatment; 8 Hodgkin’s and 8 non-Hodgkin’s lymphoma) who underwent NM-AT at 12 Italian transplant Centres. Median time between diagnosis and transplant was 20 months. Sixty-one% of patients had failed at least one prior line of therapy, including 36 refractory or relapsed patients after 1 or more autologous transplants. At allografting, 15 patients had disease at lower risk of relapse (AML and ALL in first complete remission (CR), MDS without blast excess, CML in first chronic phase, untreated MF). Forty-two patients had active disease. The comorbidity score was evaluated with an AT-specific comorbidity index (CI) as described by Sorror et al: 51 patients had CI=0, 42 CI=1–2 and 15 CI≥3. Patients were conditioned with fludarabine 90 mg/m2 and 2 Gy total body irradiation. GVHD prophylaxis consisted of cyclosporine and mycophenolate mophetile. Graft failure was observed in 1 patient and rejection after disease recurrence in 4. After a median follow-up of 28 months post-allografting, 58 (54%) had refractory/progressive disease and 36 (33%) were in CR, including 23 who were not in CR at transplant (p<0,001). Cumulative incidences of grade II–IV acute GVHD and extensive chronic GVHD were 35% and 60% respectively. Fourteen patients (13%) died of transplant-related causes (TRM) and 36 (33%) of disease progression (DRM). Two-year TRM was 12% and was higher in patients with CI≥3 (HR 2.84, p=0.08) whereas DRM was 31% and was significantly influenced by disease status at transplant (HR 0.37 for patients in partial (PR) or CR, p=0.003). Median event-free (EFS) and overall survivals (OS) were 11 (95% Cl: 8–15) and 35 months (95% Cl: 21–42) respectively. OS was significantly better in patients in remission (HR 0.44, p=0.004) and a trend for better OS was also observed in patients with CI<3 (HR 0.73, p=n.s.). By multivariate analysis, disease remission at transplant was associated with better OS and EFS (HR 0.39, p=0.001 and HR 0.41, p<0.001 respectively) and there was a trend for worse EFS in patients with CI≥3 (HR 1.88, p=0.08). Age, number of prior therapies and time between diagnosis and AT did not affect OS and EFS. In summary, though retrospective, this report confirms that disease-status and comorbidity scores predict transplant outcome. The use of AT specific comorbidity scores in prospective studies is imperative to select patients who most benefit from this procedure.

Nonmyeloablative (NM) regimens extended the application of allogeneic transplantation (AT) to older and/or medically unfit patients ineligible for high-dose conditionings. Moreover, several patients are offered AT after failure of prior lines of therapy. We retrospectively evaluated 108 patients, median age 51 (16–67), with advanced or heavily pre-treated hematological cancers [19 acute myeloblastic (AML) and 1 lymphoblastic leukemia (ALL); 8 myelodysplastic syndrome (MDS); 9 chronic myeloid (CML) and 9 chronic lymphocitic leukemia; 3 myelofibrosis (MF); 48 myeloma beyond first line treatment; 8 Hodgkin's and 8 non-Hodgkin's lymphoma) who underwent NM-AT at 12 Italian transplant Centres. Median time between diagnosis and transplant was 20 months. Sixty-one% of patients had failed at least one prior line of therapy, including 36 refractory or relapsed patients after 1 or more autologous transplants. At allografting, 15 patients had disease at lower risk of relapse (AML and ALL in first complete remission (CR), MDS without blast excess, CML in first chronic phase, untreated MF). Forty-two patients had active disease. The comorbidity score was evaluated with an AT-specific comorbidity index (CI) as described by Sorror et al: 51 patients had CI=0, 42 CI=1–2 and 15 CI≥3. Patients were conditioned with fludarabine 90 mg/m2and 2 Gy total body irradiation. GVHD prophylaxis consisted of cyclosporine and mycophenolate mophetile. Graft failure was observed in 1 patient and rejection after disease recurrence in 4. After a median follow-up of 28 months post-allografting, 58 (54%) had refractory/progressive disease and 36 (33%) were in CR, including 23 who were not in CR at transplant (p<0,001). Cumulative incidences of grade II–IV acute GVHD and extensive chronic GVHD were 35% and 60% respectively. Fourteen patients (13%) died of transplant-related causes (TRM) and 36 (33%) of disease progression (DRM). Two-year TRM was 12% and was higher in patients with CI≥3 (HR 2.84, p=0.08) whereas DRM was 31% and was significantly influenced by disease status at transplant (HR 0.37 for patients in partial (PR) or CR, p=0.003). Median event-free (EFS) and overall survivals (OS) were 11 (95% Cl: 8–15) and 35 months (95% Cl: 21–42) respectively. OS was significantly better in patients in remission (HR 0.44, p=0.004) and a trend for better OS was also observed in patients with CI<3 (HR 0.73, p=n.s.). By multivariate analysis, disease remission at transplant was associated with better OS and EFS (HR 0.39, p=0.001 and HR 0.41, p<0.001 respectively) and there was a trend for worse EFS in patients with CI≥3 (HR 1.88, p=0.08). Age, number of prior therapies and time between diagnosis and AT did not affect OS and EFS. In summary, though retrospective, this report confirms that disease-status and comorbidity scores predict transplant outcome. The use of AT specific comorbidity scores in prospective studies is imperative to select patients who most benefit from this procedure.

Fourteen patients diagnosed with neoplastic disease (5 breast cancers, 9 lymphomas) were treated with Ifosphamide 12 g/sqm, Carboplatin 1500mg/sqm and VP-16 1800mg/sqm, followed by either PBSC (n=9) or Bm (n=5) rescue. In 8 PBSC infused pts, the cells were collected after a 4 days G-CSF course (15mcg/kg), without any mobilization chemotherapy. The pts infused with BM received G-CSF (5mcg/kg) starting on +6. All patients were able to complete the regimen: major toxicity was represented by vomiting and mucositis (grade 1–3); 7 required TPN. Transitory increase of hepatic enzymes was also observed. All pts achieved complete hematopoietic reconstitution, with an advantage of PBSC in platelets recovery. Median hospitalization time after the infusion was 14 days (range 11–22).