Michela Cerno

Incidence, outcome, and risk factors of late-onset noninfectious pulmonary complications after unrelated donor stem cell transplantation

Summary:We evaluated the incidence, the risk factors, and the outcome of late-onset noninfectious pulmonary complications (LONIPCs) among 50 patients who underwent allogeneic stem cell transplantation from unrelated donors. Of the 39 patients surviving at least 3 months, 10 (26%) fulfilled the diagnostic criteria of LONIPCs and were further subclassified as having bronchiolitis obliterans (four patients), bronchiolitis obliterans with organizing pneumonia (four patients), and interstitial pneumonia (two patients). Two patients had a durable partial remission after treatment with prednisone and cyclosporine; the remaining eight patients did not respond to treatment and five of them died of respiratory failure. Advanced stage of disease at transplant and chronic extensive graft-versus-host disease (GVHD) were significantly associated with the development of LONIPCs. Pulmonary function test (PFT) results before transplantation were similar in all patients, but patients with LONIPCs had a significant decrease in PFT indexes at the third month after BMT compared with controls. Moreover, the rate of cyclosporine taper during the fourth and fifth months after BMT was significantly more rapid in patients with LONIPCs than in controls, suggesting that the risk of LONIPCs may be influenced by a faster reduction of GVHD prophylaxis.

Dendritic cell recovery after autologous stem cell transplantation

There is persistent immunosuppression not only in allogeneic but also in autologous stem cell transplantation because humoral and cellular immunity may take a year or more to return to normal, with increased risk of infectious complications. This immune defect may also involve antigen presentation, in particular dendritic cell (DC) function. We evaluated DC subset reconstitution in 58 patients who underwent bone marrow (BM) or peripheral blood (PB) autologous haematopoietic stem cell transplantation (HSCT). In all patients DC type 1 (DC1) and DC type 2 (DC2) were already significantly lower than in normal individuals before conditioning therapy (DC1/μl 3.1 ± 1.0, DC2/μl 3.0 ± 1.1). On day 0 and day +7 the mean DC1 and DC2 numbers were very low in both groups. Patients who received unmanipulated marrow or peripheral blood stem cells reached pre-conditioning levels of DC1 and DC2 cells on day +20. In patients receiving selected CD34 cells, DC increased slowly and pre-transplant counts were observed only on day +60. Nearly ‘normal’ levels of DC1 and DC2 could be observed in the first group from day +180, and were maintained thereafter; in CD34+ selected patients DC1 and DC2 counts remained lower than normal. Our data emphasise that circulating antigen presenting cells (APC) recover quickly. It remains to be determined if DC frequency in PB reflects their tissue function. The relatively low incidence of infections in patients undergoing autologous transplantation, despite defective lymphocyte reconstitution, could be related to functionally efficient DC.

Prognostic factors and outcome of Epstein–Barr virus DNAemia in high-risk recipients of allogeneic stem cell transplantation treated with preemptive rituximab

This study assessed incidence, predictive factors, and outcome of Epstein–Barr virus (EBV) DNAemia in 100 recipients of allogeneic hematopoietic stem cell transplant. A total of 68 patients received anti‐thymocyte globulin before unrelated grafts.

The therapy of primary adult systemic CD30-positive anaplastic large cell lymphoma: results of 40 cases treated in a single center.

The outcome of a series of adult patients, affected by primary systemic CD30-positive anaplastic large cell lymphoma (ALCL), treated with a sequential intensive therapeutic program, has been analyzed and all data available in the literature have been reviewed. Forty consecutive, unselected patients with ALCL were treated with the F-MACHOP regimen, followed by radiotherapy (RT) for residual mediastinal disease (15 cases) and by autologous stem cell transplantation (ASCT) conditioned with BAVC (29 cases). Eighty-nine percent (32/36) of the patients younger than 60 years were eligible for completing the sequential treatment. Since then, 3 patients in CR refused ASCT, 1 was excluded for cardiac toxicity and 3 progressed and died of disease. Thus, 29 have been so far submitted to the transplant procedure. CR and PR rates were 40% and 45% respectively after CHT; 52.5% and 35% after RT; 80% and 5% after ASCT, with 78% of patients transplanted in PR convertin to a CR. Actuarial overall survival is 85% at 48.5 months (93% at 66 months for the 29 transplanted patients) and disease free survival is 100% at 54 and 64 months respectively, with no relapses observed among patients who reached a CR. Considering our data and those of the literature, it can be concluded that although the role of ASCT in the therapy of ALCL must not be considered as definitive, its efficacy in converting PR into CR and in preventing relapses, suggests that a randomized trial comparing CHT alone vs CHT+ASCT should be undertaken.

Prognostic significance of the detection of tumour cells in peripheral blood stem cell collections in stage II and III breast cancer patients treated with high-dose therapy.

Summary:The purpose of this study was to evaluate the incidence and extent of tumour cell contamination in bone marrow specimens and stem cell collections from 34 breast cancer patients undergoing high-dose therapy as adjuvant treatment, and to determine the prognostic significance for the clinical outcome. Tumour cell contamination was evaluated by flow cytometry using a double-colour test and an anti- Pan cytokeratin (CK) antibody. Two out of 34 (6%) baseline bone marrow specimens, none of seven marrow harvests and nine out of 32 aphereses (28%) mobilised from seven out of 27 patients (26%) contained CK+ cells. Tumour contamination was more frequent in patients with 10 or more involved lymph nodes and in those who received a shorter course of adjuvant chemotherapy before mobilisation. At a median follow-up of 43 months, 24 patients are in complete remission, whereas 10 patients experienced recurrence. Out of the 10 patients who relapsed, five (50%) had CK+ peripheral blood stem cell (PBSC) collections, whereas disease recurrence was seen in only two out of 24 (8%) patients who received CK− products (P=0.02). Moreover, CK+ PBSC collections were associated with a significantly shorter event-free survival and overall survival. CK+ collection is an unfavourable prognostic factor for patients treated with high-dose therapy. Whether the negative impact on clinical outcome depends on reinfusion of tumour cells or whether it simply indicates a larger disease extension is still unclear.

Sequential Intensive Treatment with the F-MACHOP Regimen (± Radiotherapy) and Autologous Stem Cell Transplantation for Primary Systemic CD30 (Ki-1)— Positive Anaplastic Large Cell Lymphoma in Adults

Most of the adult patients with primary systemic CD30 (Ki-1)-positive anaplastic large cell lymphoma (ALCL) reported in the literature have been treated with combination chemotherapy (CHT), with only an occasional patient being autotransplanted, mostly after relapse. Here we report a series of 19 patients treated at our Institution with a sequential intensive therapeutic program including CHT (the F-MACHOP regimen given for 6 cycles), radiotherapy (RT), and autologous stem cell transplantation (ASCT) after conditioning with the BAVC regimen. Eleven of 19 (58%) patients achieved a complete remission (CR) after CHT; 3 after RT and 4 after ASCT (1 patient is still not evaluable for response to ASCT). The actuarial overall survival is 100% at a median of 49 months from diagnosis and the actuarial disease free survival is 100% at a median of 41 months from the time CR was reached. These data suggest that ALCL can be successfully managed with a sequential intensive treatment that prevents early relapses and projects these patients as long-term survivors.

D-verapamil downmodulates P170-associated resistance to doxorubicin, daunorubicin and idarubicin.

Verapamil (VRP) is an effective modulator of P170-associated multidrug resistance (MDR), but its clinical application is limited by cardiovascular side-effects. The D-isomer of VRP (D-VRP) is 10 times less active than the racemic mixture on the cardiovascular system, but retains a MDR modulating activity. Daunorubicin (DNR) and doxorubicin (DX) are two anthracyclines whose cytotoxicity is strongly related with the expression of P170, while their respective lipophylic derivatives idarubicin (IDA) and iododoxorubicin (IDX) are less P170-dependent. We studied the effect of D-VRP on intracellular retention and on the cytotoxicity of these four anthracyclines in two MDR cell systems (LOVO and CEM) by flow cytometry and by a microcultured tetrazolium colorimetric assay (MTT). We found that in MDR cells D-VRP increased intracellular anthracycline concentration and increased the cytotoxicity of DNR, IDA and DX but not of IDX. The effect of D-VRP was dose-related, but it was already consistent at D-VRP concentrations that can be readily maintained in vivo (2–3 μM). These data suggest that at a clinically tolerable concentration D-VRP can downmodulate the resistance to DNR and DX and can restore full sensitivity to IDA.

Prognostic significance of delayed thrombocytopenia after allogeneic stem cell transplant.

Previous studies showed that late-onset thrombocytopenia is a strong negative prognostic indicator of survival in allogeneic hematopoietic stem cell transplant (SCT) recipients and, in particular, in those cases where thrombocytopenia is related to chronic graft versus host disease (cGVHD) [1–12]. To investigate this issue, 71 adult patients who survived for 3 months with median follow-up time of 21 months (range, 3–44 months) after SCT were evaluated. Twenty-seven patients (38%) developed thrombocytopenia with a median platelet count of 29 3 10/L. Patients with and without thrombocytopenia had similar baseline clinical characteristics, transplant type, and status at transplant. The incidence of mortality was significantly higher in patients with post-SCT thrombocytopenia (70% vs. 14%; P 50 < 100 3 10/L in eight patients and 50 3 10/L in 19 among whom 9 had 20 3 10/L. Thrombocytopenia was transient in 5 and persistent in 22 patients; in this last group the median duration of thrombocytopenia was three months. Patients with and without thrombocytopenia were similar in baseline clinical characteristics, type of transplant, and status at transplant (Table II). Thrombocytopenia was associated with cGVHD in 10 out of 24 patients (42%) (three patients with thrombocytopenia were not evaluable for cGVHD), disease relapse in seven patients (26%; five acute leukemia and two lymphomas), CMV infection in four patients (15%), graft failure in two patients, and microangiopathy in one patient; three patients had idiopathic thrombocytopenia. Thrombocytopenia was complicated with major intestinal bleeding and cerebral bleeding in four and two patients, respectively. The incidence of mortality was significantly higher in patients with postSCT thrombocytopenia compared with patients without thrombocytopenia (19 out of 27 [70%] vs. 6 out of 44 [14%] patients; P < 0.0001) (Fig. 1). The cause of mortality in patients with thrombocytopenia included: primary disease in 11 patients (58%; acute leukemia in five patients, lymphoma in three patients, one patient each myelodysplasia, chronic myeloid leukemia, and multiple myeloma), cGVHD in three patients (16%), infections in two patients (10.5%), one patient each with cerebral bleeding, cardiac stroke and multiorgan failure. Patient survival after 12, 24, and 33 months was 93%, 87%, and 87% in patients without thrombocytopenia vs. 41%, 41%, and 7% in patients with thrombocytopenia, respectively (P < 0.0001) (Fig. 1). In univariate analysis using Cox proportional hazard model, overall survival (OS) showed a significant association with status at transplant (no response/progression vs. complete remission Hazard Ratio [HR] 2.74; 95% confidence interval [CI], 1.11–6.79; P 5 0.03) and thrombocytopenia (HR 9.77; 95% CI, 3.63–26.33; P < 0.0001). In multivariate analysis only thrombocytopenia was significantly associated with OS (HR 9.77; 95% CI, 3.63–26.33; P < 0.0001). In order to eliminate possible bias related to disease-related mortality we repeated the analysis excluding 15 patients who died because of primary diseases and not for SCT related mortality. Fifteen out of the remaining 56 patients developed post SCT thrombocytopenia and again, the incidence of mortality was significantly higher in patients with thrombocytopenia, i.e. 8 out of 15 (53%) vs. 4 out of 41 (10%) (P 5 0.001). In univariate analysis using Cox proportional hazard model, thrombocytopenia resulted the only variable significantly associated with OS (HR 7.83; 95% CI, 2.34–26.00; P 5 0.001). TABLE I. Summary of Patients’ Clinical and Transplant Baseline Characteristics

Autologous stem cell transplantation for aggressive non-Hodgkin’s lymphomas in first complete or partial remission: a retrospective analysis of the outcome of 52 patients according to the age-adjusted International Prognostic Index

The aim of the study was to retrospectively evaluate the outcome of patients with aggressive non-Hodgkin’s lymphoma (NHL), undergoing autologous stem cell transplantation (ASCT) in first complete (CR) or partial (PR) remission, according to the age-adjusted International Prognostic Index (IPI). Fifty-two consecutive patients, aged less than 60 years, with intermediate- or high-grade NHL, and at least one of the following adverse risk factors: bulky disease, B symptoms or Ann Arbor stage III–IV, and at least a PR after CHT (and radiotherapy (RT) on residual mediastinal mass when required), underwent ASCT conditioned with BAVC. Sixty-five percent (33/52) of the patients achieved CR after CHT; 69% (36/52) after CHT + RT; 90% (47/52) after CHT ± RT + ASCT. One death during conditioning and three major toxic events after ASCT were recorded. Overall survival (OS) is 98% at 37 months (16–88); disease-free survival (DFS) is 100% at 27 months (7–82). Comparing the observed results with those expected if patients were treated only with CHT, the sequential treatment including ASCT conferred an advantage in terms of CR rate of 14, 23 and 54%, respectively, in the low-intermediate (LI), high-intermediate (HI) and high (H)-risk groups, respectively. The 2-year OS advantage is 10, 21, 31 and 63%, respectively, and the 2-year DFS advantage is 12, 26, 38 and 39%, respectively. Even more striking is the 5-year projected advantage in the number of patients alive without disease, even when considering only the low (L) (P < 0.0001) and the li (P < 0.0001) risk groups. for patients in the higher (hi + h) risk groups, asct should be included in the initial plan of treatment as consolidation of first cr or pr, but the differences seen in this study suggest a formal comparison in a randomized study also for patients in the li risk group.

Risk Factors and Outcomes of Infections by Multidrug-Resistant Gram-Negative Bacteria in Patients Undergoing Hematopoietic Stem Cell Transplantation

The objective of this study was to determine risk factors and outcomes of infections by multidrug-resistant gram-negative (MDR GN) bacteria in 241 recipients of hematopoietic stem cell transplantation (HSCT). The cumulative incidence of infections was 10.5% (95% CI, 12.0% to 25.8%), with 57% of infections occurring during the period of severe neutropenia (neutrophil count < .1 × 106/L). In multivariate analysis, allogeneic transplant and colonization with MDR GN bacteria at admission to the transplant unit were significantly associated with an increased risk of infection. Although we observed neither transplant-related mortality (TRM) nor deaths due to infections by MDR GN bacteria after autologous transplant, in the allogeneic setting a significant difference was reported in terms of overall survival (OS) and TRM between patients who developed infections and those who did not (1-year OS, 39% versus 68%; 1-year TRM, 42% versus 19%). In multivariate analysis, refractory disease and development of grades III to IV graft-versus-host disease (GVHD) were factors that affected both TRM and OS, whereas occurrence of infections by MDR GN pathogens significantly reduced OS. We conclude that eligibility to allogeneic HSCT in MDR GN bacteria carriers should be carefully evaluated together with all other factors that independently influence outcome (disease status, donor, and GVHD risk).