Alessandra Sperotto

Treatment of refractory chronic GVHD with rituximab: a GITMO study

The anti-CD20 chimaeric monoclonal antibody Rituximab has recently been shown to induce significant clinical response in a proportion of patients with refractory chronic graft-versus-host disease (cGVHD). We now report 38 patients, median age 48 years (22–61), receiving Rituximab for refractory cGVHD, assessed for clinical response and survival. Median duration of cGVHD before Rituximab was 23 months (range 2–116), the median number of failed treatment lines was 3 (range 1 to ⩾6) and the median follow-up after Rituximab was 11 months (1–88). Overall response rate was 65%: skin 17/20 (63%), mouth 10/21 (48%), eyes 6/14 (43%), liver 3/12 (25%), lung 3/8 (37.5%), joints 4/5, gut 3/4, thrombocytopaenia 2/3, vagina 0/2, pure red cell aplasia 0/1 and, myasthenia gravis 1/1. During the study period 8/38 died: causes of death were cGVHD progression (n=3), disease relapse (n=1), infection (n=3), sudden death (n=1). The actuarial 2 year survival is currently 76%. We confirm that Rituximab is effective in over 50% of patients with refractory cGVHD and may have a beneficial impact on survival.

Anti-CD20 therapy for chronic lymphocytic leukemia-associated autoimmune diseases.

Rituximab is active in chronic lymphocytic leukemia (CLL) and may interfere with autoantibodies production in some immune diseases. We report the results of rituximab treatment in 7 patients with CLL-associated symptomatic autoimmune diseases refractory to standard immunosuppressive therapies: warm antibody hemolytic anemia (AHA) 4 patients, cold agglutinin disease (CAD) 1, immune thrombocytopenia (IT) I , axonal degenerating neuropathy (ADN) 1. Rituximab was given at the dose of 375mg/m2 per week for 4 weeks. One patient with AHA and one with CAD achieved complete normalization of hemoglobin levels and laboratory signs of haemolysis, with response duration (RD) of 8+ and 38+ months, respectively. In the patient with IT, complete remission was reached after the first week of treatment and RD was 6 months. The patient with ADN achieved a marked neurological improvement after rituximab therapy, with RD of 12 months. Retreatment of both patients with IT and ADN was effective. Rituximab may be an alternative agent for the treatment CLL-associated autoimmune diseases.

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.

Allogeneic hematopoietic stem cell transplantation in myelofibrosis: the 20-year experience of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO).

In this GITMO study, Patriarca and coworkers evaluated the outcome of patients with myelofibrosis who underwent allogeneic stem cell transplantation, and the impact of prognostic factors. They conclude that the outcome of myelofibrosis patients who underwent allogeneic stem cell transplantation significantly improved after 1996 due to the reduction in transplant-related mortality. See related perspective article on page 1449. Background Allogeneic stem cell transplantation is a potentially curative treatment for myelofibrosis, although its use is limited by a high rate of transplant-related mortality. In this study, we evaluated the outcome of patients with myelofibrosis who underwent allogeneic stem cell transplantation, and the impact of prognostic factors. Design and Methods One hundred patients were transplanted in 26 Italian centers between 1986 and 2006. We analyzed the influence of the patients’ characteristics and the clnical features of their disease before stem cell transplantation and of transplant procedures on transplant-related mortality, overall survival, and relapse-free survival by means of univariate and multivariate analyses. Results The median age of the patients at the time of stem cell transplantation was 49 years (range, 21–68) and 90% of them had an intermediate or high Dupriez score. Forty-eight percent received a myeloablative conditioning regimen and 78% received stem cells from matched sibling donors. The cumulative incidence of engraftment at day 90 after transplant was 87% (95% CI, 0.87–0.97). The cumulative 1-year and 3-year incidences of transplant-related mortality were 35% and 43%, respectively. The estimated 3-year overall and relapse-free survival rates after stem cell transplantation were 42% and 35%, respectively. In multivariate analysis, negative predictors of transplant-related mortality were year of stem cell transplantation before 1995, unrelated donor, and a long interval between diagnosis and transplantation. There was a trend towards longer overall and relapse-free survival in patients receiving peripheral blood stem cells rather than bone marrow as the source of their graft (p=0.070 and p=0.077, respectively). The intensity of the conditioning regimen (myeloablative versus reduced intensity regimens) did not significantly influence the outcome. Conclusions We conclude that the outcome of myelofibrosis patients who underwent allogeneic stem cell transplantation significantly improved after 1996 due to the reduction in transplant-related mortality. We observed that a reduction in transplant-related mortality was associated with the choice of a matched sibling donor, whereas longer overall survival was associated with the use of peripheral blood as the source of stem cells.

Lamivudine allows completion of chemotherapy in lymphoma patients with hepatitis B reactivation.

Reactivation of hepatitis B virus in patients receiving chemotherapy for non‐Hodgkins lymphoma (NHL) may give rise to hepatitis, hepatic failure and death, and prevent further chemotherapy. We report four patients with NHL in whom hepatitis flare‐up was observed after two (three patients) and six (one patient) cycles of chemotherapy. After spontaneous recovery, they were treated with Lamivudine (100 mg/day), which enabled completion of chemotherapy without further hepatitis B reactivation. In one patient, high‐dose chemotherapy and autologous stem cell transplantation was also performed. These data suggest a possible role for Lamivudine in preventing hepatitis B reactivation during chemotherapy administration to chronic carriers of the hepatitis B virus. Moreover, it enabled the completion of both standard and high‐dose chemotherapy in patients with previous hepatitis B reactivation.

Allogeneic Stem Cell Transplantation in Multiple Myeloma Relapsed after Autograft: A Multicenter Retrospective Study Based on Donor Availability.

Allogeneic stem cell transplantation (allo-SCT) using reduced-intensity conditioning (RIC) is a feasible procedure in selected patients with relapsed multiple myeloma (MM), but its efficacy remains a matter of debate. The mortality and morbidity related to the procedure and the rather high relapse risk make the use of allo-SCT controversial. In addition, the availability of novel antimyeloma treatments, such as bortezomib and immunomodulatory agents, have made allo-SCT less appealing to clinicians. We investigated the role of RIC allo-SCT in patients with MM who relapsed after autologous stem cell transplantation and were then treated with a salvage therapy based on novel agents. This study was structured similarly to an intention-to-treat analysis and included only those patients who underwent HLA typing immediately after the relapse. Patients with a donor (donor group) and those without a suitable donor (no-donor group) were compared. A total of 169 consecutive patients were evaluated retrospectively in a multicenter study. Of these, 75 patients found a donor and 68 (91%) underwent RIC allo-SCT, including 24 from an HLA-identical sibling (35%) and 44 from an unrelated donor (65%). Seven patients with a donor did not undergo allo-SCT for progressive disease or concomitant severe comorbidities. The 2-year cumulative incidence of nonrelapse mortality was 22% in the donor group and 1% in the no-donor group (P < .0001). The 2-year progression-free survival (PFS) was 42% in the donor group and 18% in the no-donor group (P < .0001). The 2-year overall survival (OS) was 54% in the donor group and 53% in the no-donor group (P = .329). In multivariate analysis, lack of a donor was a significant unfavorable factor for PFS, but not for OS. Lack of chemosensitivity after salvage treatment and high-risk karyotype at diagnosis significantly shortened OS. In patients who underwent allo-SCT, the development of chronic graft-versus-host disease had a significant protective effect on OS. This study provides evidence for a significant PFS benefit of salvage treatment with novel drugs followed by RIC allo-SCT in patients with relapsed MM who have a suitable donor.

Long‐lasting complete remission of hepatitis C virus (HCV) infection and HCV‐associated immunocytoma with alpha‐interferon treatment

Several epidemiological data suggest the involvement of hepatitis C virus (HCV) in the pathogenesis of some histotypes of B‐cell non‐Hodgkins lymphomas, in particular immunocytoma. We report a patient with HCV‐associated immunocytoma, first treated with six courses of fludarabine. A partial response was achieved and subsequent therapy with alpha‐interferon resulted in the clearance of the virus and a long‐lasting complete clinical and histological remission of the lymphoproliferative disease.

Meningeal and cerebral involvement in multiple myeloma patients

Abstract. Cerebral involvement is an unusual complication in multiple myeloma: herein four patients who presented myelomatous meningitis with multiple intraparenchymal lesions or a localized cerebral plasmacytoma are described. Two of these patients relapsed with meningeal involvement and a very limited disease outside the central nervous system after an initial complete remission obtained with induction chemotherapy. In the other two cases, the cerebral tumor appeared during first-line treatment. Cytological examination of the cerebrospinal fluid and magnetic resonance were essential for diagnosis. Different modalities of treatment were used, including intrathecal chemotherapy, cranial irradiation, and systemic chemotherapy with high-dose methotrexate and cytarabine, achieving improvement of neurological symptoms in three of four patients.

Nilotinib and donor lymphocyte infusion in the treatment of Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) relapsing after allogeneic stem cell transplantation and resistant to imatinib.

Prognosis of patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) relapsing after allogeneic stem cell transplantation (SCT) is dismal. Immunotherapy with donor lymphocyte infusion (DLI) and imatinib are rarely and/or transiently effective. Here we describe the case of a patient with imatinib-resistant post-transplant relapse of ALL, who received a combination of standard dose nilotinib and monthly DLI infusion. Therapy was well tolerated and the patient achieved and maintained a complete molecular remission. Our case provides a rationale for the combined use of a second line tyrosine kinase inhibitor and DLI in the treatment of relapsed Ph+ ALL.

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.