Mauro Montanari

Haploidentical, unmanipulated, G-CSF–primed bone marrow transplantation for patients with high-risk hematologic malignancies

UNLABELLED Eighty patients with high-risk hematologic malignancies underwent unmanipulated, G-CSF–primed BM transplantation from an haploidentical family donor. Patients were transplanted in first or second complete remission (CR, standard-risk: n =45) or in > second CR or active disease (high-risk: n =35). The same regimen for GVHD prophylaxis was used in all cases. The cumulative incidence (CI) of neutrophil engraftment was 93% 0.1%. The 100-day CIs for II-IV and III-IV grade of acute GVHD were 24% 0.2% and 5% 0.6%, respectively. The 2-year CI of extensive chronic GVHD was 6% 0.1%. The 1-year CI of treatment-related mortality was 36% 0.3%. After a median follow-up of 18 months, 36 of 80 (45%) patients are alive in CR. The 3-year probability of overall and disease-free survival for standard-risk and high-risk patients was 54% 8% and 33% 9% and 44% 8% and 30% 9%, respectively. In multivariate analysis, disease-free survival was significantly better for patients who had standard-risk disease and received transplantations after 2007. We conclude that unmanipulated, G-CSF–primed BM transplantation from haploidentical family donor provides very encouraging results in terms of engraftment rate, incidence of GVHD and survival and represents a feasible, valid alternative for patients with high-risk malignant hematologic diseases, lacking an HLA identical sibling and in need to be urgently transplanted. KEY POINTS Haploidentical, unmanipulated, G-CSF-primed bone marrow transplantation. Haploidentical hematopoietic stem cell transplantation for hematologic malignancies.

Infectious complications after autologous peripheral blood progenitor cell transplantation followed by G-CSF

Infectious complications after autologous peripheral blood progenitor cell transplantation (PBPCT) have been reported in a few studies including small patient numbers. The present study was performed to assess the incidence, types, outcome and factors affecting early and late infections in 150 patients aged 18 to 68 years (median 46.5) who underwent high-dose therapy, with G-CSF. Patients were kept in reverse isolation rooms and received antimicrobial chemoprophylaxis with oral quinolone and fluconazole. One hundred and fifteen patients (76.7%) developed fever (median 3 days, range 1–29); 20 patients (55.5%) had Gram-positive and 13 (36.2%) Gram-negative bacterial infections. There were no fungal infections or infection-related deaths. Mucositis grade II–IV (P = 0.0001; odds ratio 3.4) and >5 days on ANC<100/μl (P = 0.0001; odds ratio 2.3) correlated with development of infection. Only days with ANC <100/μl affected infection outcome (P = 0.0024) whereas the antibiotic regimen did not. After day +30 there were four cases of bacterial pneumonitis (2.7%), one case of fatal CMV pneumonia (0.8%) and 20 of localized VZV infection (13.3%). Reduction of neutropenia duration with PBPCT and G-CSF is not enough to prevent early infectious complications since only a few days of severe neutropenia and mucositis are related to development of early infections. However, no infection-related deaths were seen. Although Gram-positive organisms were the major cause of bacteremia, a glycopeptide in the empirical antibiotic regimen did not affect infection outcome. In PBPCT recipients, early and late opportunistic infections were notably absent, which was at variance with what was seen with bone marrow recipients. Efforts should be made to prevent mucositis and neutropenia and identify new strategies of antibacterial prophylaxis.

Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial.

BACKGROUND The standard busulfan-cyclophosphamide myeloablative conditioning regimen is associated with substantial non-relapse mortality in patients older than 40 years with acute myeloid leukaemia who are undergoing allogeneic stem-cell transplantation. Because the combination of busulfan plus fludarabine has been proposed to reduce non-relapse mortality, we aimed to compare this treatment with busulfan plus cyclophosphamide as a preparative regimen in these patients. METHODS We did an open-label, multicentre, randomised, phase 3 trial for patients with acute myeloid leukaemia at 25 hospital transplant centres in Italy and one in Israel. Eligible patients were aged 40-65 years, had an Eastern Cooperative Oncology Group performance status less than 3, and were in complete remission. Patients were randomly assigned 1:1 to receive intravenous busulfan plus cyclophosphamide or busulfan plus fludarabine. Treatment allocations were not masked to investigators or patients. Randomisation was done centrally via a dedicated web-based system using remote data entry, with patients stratified by donor type and complete remission status. Patients allocated to busulfan plus cyclophosphamide received intravenous busulfan 0·8 mg/kg four times per day during 2 h infusions for four consecutive days (16 doses from days -9 through -6; total dose 12·8 mg/kg) and cyclophosphamide at 60 mg/kg per day for two consecutive days (on days -4 and -3; total dose 120 mg/kg). Patients allocated to busulfan plus fludarabine received the same dose of intravenous busulfan (from days -6 through -3) and fludarabine at 40 mg/m(2) per day for four consecutive days (from days -6 through -3; total dose 160 mg/m(2)). The primary endpoint was 1-year non-relapse mortality, which was assessed on an intention-to-treat basis; safety outcomes were assessed in the per-protocol population. This trial has been completed and is registered with ClinicalTrials.gov, number NCT01191957. FINDINGS Between Jan 3, 2008, and Dec 20, 2012, we enrolled and randomly assigned 252 patients to receive busulfan plus cyclophosphamide (n=125) or busulfan plus fludarabine (n=127). Median follow-up was 27·5 months (IQR 9·8-44·3). 1-year non-relapse mortality was 17·2% (95% CI 11·6-25·4) in the busulfan plus cyclophosphamide group and 7·9% (4·3-14·3) in the busulfan plus fludarabine group (Grays test p=0·026). The most frequently reported grade 3 or higher adverse events were gastrointestinal events (28 [23%] of 121 patients in the busulfan plus cyclophosphamide group and 26 [21%] of 124 patients in the busulfan plus fludarabine group) and infections (21 [17%] patients in the busulfan plus cyclophosphamide group and 13 [10%] patients in the busulfan plus fludarabine group had at least one such event). INTERPRETATION In older patients with acute myeloid leukaemia, the myeloablative busulfan plus fludarabine conditioning regimen is associated with lower transplant-related mortality than busulfan plus cyclophosphamide, but retains potent antileukaemic activity. Accordingly, this regimen should be regarded as standard of care during the planning of allogeneic transplants for such patients. FUNDING Agenzia Italiana del Farmaco.

Primary nodal marginal zone B-cell lymphoma: clinical features and prognostic assessment of a rare disease

This study defined the clinical features and assessed the prognosis of 47 patients (17 males, 30 females, median age 63 years) with primary nodal marginal zone B‐cell lymphoma. Forty‐five per cent had stage IV disease. Hepatitis C virus serology was positive in 24%. According to the Follicular Lymphoma International Prognostic Index (FLIPI), 33% were classified as low‐risk, 34% as intermediate‐risk, and 33% as high‐risk. The 5‐year overall survival (OS) was 69%. In univariate analysis worse OS was associated with: FLIPI (P = 0·02), age > 60 years (P = 0·05) and raised lactate dehydrogenase (P = 0·05). In multivariate analysis, only FLIPI predicted a worse OS (P = 0·02).

Paroxysmal atrial fibrillation after high-dose melphalan in five patients autotransplanted with blood progenitor cells

Among the drugs used in conditioning regimens for stem cell transplantation, high-dose melphalan (HDM) plays an important role for both its strong myeloablative effect and for its favourable dose–response ratio. Here we report five cases of high frequency atrial fibrillation (AF) developing after HDM. Duration of the arrhythmia was always very short, beginning at variable intervals after the administration of HDM, in the absence of other factors potentially able to trigger AF. In all patients sinus rhythm was restored within 72 h and the follow-up did not show any cardiac damage. To the best of our knowledge, this side-effect has never been reported to occur after HDM.

Common and rare side-effects of low-dose thalidomide in multiple myeloma: focus on the dose-minimizing peripheral neuropathy

Objectives:  Thalidomide has demonstrated a remarkable efficacy in the treatment of multiple myeloma but its use may cause several toxicities. We have investigated the common and rare side‐effects, especially analysing peripheral neuropathy, in order to optimise the thalidomide dose for minimizing this harmful side‐effect.

Salvage therapy with an outpatient DHAP schedule followed by PBSC transplantation in 79 lymphoma patients: an intention to mobilize and transplant analysis

Chemotherapy followed by autologous transplantation may be an efficient salvage treatment in malignant lymphomas. We investigated the feasibility, tolerability and efficacy of an outpatient schedule of dexamethasone, cytarabine and cisplatin (DHAP), followed by peripheral blood progenitor cell autografting as salvage treatment in patients with high grade (HG), low grade (LG) non‐Hodgkins lymphoma (NHL) and Hodgkins Disease (HD). A total of 159 DHAP courses (median: 2, range: 1–5), was administered on outpatient basis to 79 patients (31 LG‐NHL, 28 HG‐NHL and 20 HD), with the intention to mobilize and to transplant. A successful collection was not achieved in 40% LG‐NHL, 10% HD and 20% HG‐NHL patients. The risk to fail the collection was significantly related to the number of previous chemotherapy courses (>6) (P = 0.005, RR = 1.4), to the pretransplant status (P = 0.04, RR = 13.5) and to the previous fludarabine administration (P = 0.01, RR = 20). High dose therapy (HDT) was feasible in 60 patients (76%). The overall treatment related mortality was 3.8%. The overall response rate (ORR) was 81% with a 57.6% overall survival (OS) at 62 months (95% CI: 45–69.3%) and a progression free survival (PFS) of 42% at 74 months (95% CI: 26.7–58%). The diagnosis of HG‐NHL and the non‐response to DHAP resulted to reduce respectively the OS (P = 0.007, RR = 2.8) and PFS probability (P = 0.01, RR = 4.1). In conclusion this outpatient schedule of DHAP is a well tolerated, efficient salvage and mobilizing regimen not only in HG‐NHL, but also in LG‐NHL and in HD. Randomized studies are needed to better define the role of DHAP in LG‐NHL and HD patients.

A Predictive Model of Varicella-Zoster Virus Infection after Autologous Peripheral Blood Progenitor Cell Transplantation

Varicella-zoster virus (VZV) frequently causes severe infections in patients who have undergone bone marrow transplantation. The frequency of, characteristics of, and risk factors for this infection were studied in 164 patients undergoing autologous peripheral blood progenitor cell transplantation (PBPCT). Twenty-six patients (15.8%) developed VZV infection, and the actuarial risk was 10% at 1 year. No patient had visceral dissemination or died because of VZV, although one-third of the patients developed postherpetic neuralgia. By multivariate analysis, a CD4(+) lymphocyte count of <200 cells/microL (P<.0001; odds ratio [OR], 2.0) and a CD8(+) lymphocyte count of <800 cells/microL (P=.0073; OR, 2.0) at day 30 after transplantation were factors associated with VZV infection. Patients with both these adverse factors had an actuarial risk of VZV of 48% at 1 year. Patients with deficiency in both CD4(+) and CD8(+) lymphocytes are at high risk of VZV infection. These patients should be considered as candidates for preventive therapy, but whether for antiviral therapy or vaccination remains to be investigated.

Long-term hematologic reconstitution after autologous peripheral blood progenitor cell transplantation: a comparison between controlled-rate freezing and uncontrolled-rate freezing at 80°C

BACKGROUND : The most widely used system for peripheral blood progenitor cell (PBPC) cryopreservation is controlled‐rate freezing (CRF). Uncontrolled‐rate freezing (URF) at –80°C has also been used, but its clinical impact has not been studied sufficiently yet.

Very low toxicity and good quality of life in 48 elderly patients autotransplanted for hematological malignancies: a single center experience.

Between May 1994 and May 2000, we autotransplanted 48 consecutive patients, 21 females and 27 males aged over 60 years (range: 60–78, median: 63). Sixteen patients had multiple myeloma (MM), 14 high-grade non-Hodgkins lymphoma (HGNHL), six low-grade non-Hodgkins lymphoma (LGNHL), nine acute myeloid leukemia (AML), one chronic lymphocytic leukemia (CLL), one Hodgkins disease (HD) and one breast cancer; the performance status (WHO) was 0–1. Seventeen patients were in 1st CR (35.4%) and one in 2nd CR (2.1%), 25 in PR (52.1%), while five patients had been transplanted with progressive disease (10.4%); seven patients with MM received a double transplant. Patients received high-dose therapy including melphalan alone (13) or associated with other drugs (26), busulfan-cyclophosphamide (three), BEAM (11) and TBI (two). All patients took a median of 11 (range: 8–25) days to reach neutrophils >500/μl, 13 (range: 9–83) days to reach platelets >20 000/μl and 17 (range: 11–83) days to reach platelets >50 000/μl. Hematological toxicity, hospital stay and supportive care did not differ from those of a cohort of younger patients. At present, 31 patients are alive (14 in CR, five in PR, five in PD and seven in relapse) and 16 died from PD at a median follow-up of 37 months (1–67). Only one patient died from transplant-related toxicity. Quality of life, evaluated using a QLQ-C30 questionnaire in 25 patients at day +90, was good. In our experience PBPC mobilization and transplantation is feasible in patients aged ⩾60 years and the toxicity of this procedure is acceptable, with an early transplant-related mortality of 1.8%; therefore patients with hematological malignancies potentially curable with high-dose therapy (HDT) should also be candidates for HDT. Bone Marrow Transplantation (2001) 27, 1189–1195.