Sequence matters: Total body irradiation (TBI)-based myeloablative conditioning with post-transplant cyclophosphamide may reduce the early nonrelapse mortality compared with pretransplant cyclophosphamide plus TBI.

OBJECTIVES: High-dose total body irradiation (TBI) is considered a cornerstone of myeloablative conditioning for allogeneic stem cell transplantation (allo-SCT). We retrospectively compared the main outcomes of an HLA matched or 1-allele mismatched related or unrelated allo-SCT in adult patients affected by acute leukemia (AL) or myelodysplastic syndromes (MDS). METHODS: Fifty-nine patients received cyclophosphamide (Cy)-TBI (13.5 Gy) and graft-versus-host disease (GVHD) prophylaxis with a calcineurin-inhibitor plus methrotrexate (CyTBI group) and 28 patients received fludarabine-TBI (8.8-13.5 Gy) and GVHD prophylaxis with PTCy and tacrolimus (FluTBI-PTCy group). RESULTS: Median follow-up for survivors was 82 and 22 months. The 12-month probability of overall survival and progression-free survival were similar (p = .18, p = .7). The incidence of Grades 2-4 and 3-4 acute GVHD, and the incidence of moderate-to-severe chronic GVHD were higher in the CyTBI group (p = .02, p < .01and p = .03). Nonrelapse mortality (NRM) at 12 months posttransplant was higher in the CyTBI group (p = 0.05), while the incidence of relapse was similar in both groups (p = 0.7). The number of GVHD-free and relapse-free patients without systemic immunosuppression (GRFS) at 1-year posttransplant was higher in the FluTBI-PTCy group (p = 0.01). CONCLUSIONS: The study confirms the safety and efficacy of a novel FluTBI-PTCy platform with reduced incidence of severe acute and chronic GVHD, and early improvement of NRM.

Successful Outcome in Patients with Myelofibrosis Undergoing Allogeneic Donor Hematopoietic Cell Transplantation Using Reduced Doses of Post-Transplantation Cyclophosphamide: Challenges and Review of the Literature.

Engraftment and nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (allo-HCT) depend greatly on the transplantation platform in patients with myelofibrosis (MF). We report outcomes of 14 consecutive MF patients who received reduced doses of post-transplantation cyclophosphamide (PTCy; 60 mg/kg total dose) and tacrolimus as graft-versus-host disease (GVHD) prophylaxis as part of a new standardized allo-HCT protocol. The median patient age at allo-HCT was 59 years (range, 41 to 67 years), and the median interval from diagnosis to HCT was 19 months (range, 2 to 114 months). All patients received ruxolitinib before HCT, and 71% had no response. Most patients (78%) had symptomatic splenomegaly at HCT. Eighty-six percent received reduced-intensity conditioning, and 64% underwent allo-HCT from an unrelated donor. There were no graft failures, and neutrophil and platelet recovery occurred at a median of 21 days and 31 days, respectively. The cumulative incidence of grade II-IV acute GVHD was 28.6%, and that of grade III-IV acute GVHD was 7%. The 2-year incidence of overall and moderate-severe chronic GVHD was 36% and 14%, respectively. Only 1 patient relapsed after transplantation, and NRM was 7% at 100 days and 14% at 2 years. The GVHD-free/relapse-free and immunosuppression-free incidence at 1 year was 41%. With a median follow-up for survivors of 28 months (range, 8 to 55 months), the 2-year overall survival and progression-free survival were 86% and 69%, respectively. Reduced doses of PTCy as GVHD prophylaxis for high-risk MF patients showed promising results by reducing the incidence of GVHD without any cases of graft failure.

Impact of pre-admission antithrombotic therapy on disease severity and mortality in patients hospitalized for COVID-19.

Anticoagulant therapy is a cornerstone treatment for coronavirus disease 2019 (COVID-19) due to the high rates of thromboembolic complications associated with this disease. We hypothesized that chronic antithrombotic therapy could play a protective role in patients hospitalized for COVID-19. Retrospective, observational study of all patients admitted to our hospital for ≥ 24 h from March 1 to May 31, 2020 with SARS-CoV-2. The objective was to evaluate clinical outcomes and mortality in COVID-19 patients receiving chronic anticoagulation (AC) or antiplatelet therapy (AP) prior to hospital admission. A total of 1612 patients were evaluated. The mean (standard deviation; SD) age was 66.5 (17.1) years. Patients were divided into three groups according to the use of antithrombotic therapy prior to admission (AP, AC, or no-antithrombotic treatment). At admission, 9.6% of the patients were taking anticoagulants and 19.1% antiplatelet therapy. The overall mortality rate was 19.3%. On the multivariate analysis there were no significant differences in mortality between the antithrombotic groups (AC or AP) and the no-antithrombotic group (control group). Patients on AC had lower ICU admission rates than the control group (OR: 0.41, 95% CI, 0.18-0.93). Anticoagulation therapy prior to hospitalization for COVID-19 was associated with lower ICU admission rates. However, there were no significant differences in mortality between the patients receiving chronic antithrombotic therapy and patients not taking antithrombotic medications. These findings suggest that chronic anticoagulation therapy at the time of COVID-19 infection may reduce disease severity and thus the need for ICU admission.

Alemtuzumab in the treatment of fludarabine refractory B-cell chronic lymphocytic leukemia (CLL).

The introduction of immunotherapeutic agents has provided renewed hope for Chronic lymphocytic leukemia fludarabine-refractory patients. Several clinical trials have shown that alemtuzumab is a more effective option compared to combination chemotherapy for treatment of patients who have relapsed or who are refractory to fludarabine, including those with poor prognostic factors. Although there are significant potential toxicities associated with alemtuzumab, such as infusional reactions and the risk of cytomegalovirus (CMV) reactivation, most are manageable. Pre-treatment anti-pyretics and anti-histamines are recommended to prevent or mitigate the acute infusional reactions associated with intravenous infusion. Recent use of alemtuzumab via the subcutaneous route has been shown to be well tolerated and has yielded similar response rates to the infusional method of administration. Prophylaxis with thrimethoprim/sulphamethoxazole (TMP/SMZ) as well as valacyclovir or a similar anti-viral can prevent many of the opportunistic infections seen in early trials. Reactivation of CMV infection can be effectively managed with monitoring and early treatment. Chemo-immunotherapy combination with alemtuzumab has been tested and demonstrated unprecedented clinical results in relapsed and refractory patients. The use of this agent earlier in the algorithm of patients with these characteristics should be considered. Future areas of research will include the use of alemtuzumab in combination with other monoclonal antibodies and other targeted therapies.

Alemtuzumab as consolidation after a response to fludarabine is effective in purging residual disease in patients with chronic lymphocytic leukemia.

PURPOSE: Treatment with alemtuzumab has resulted in negative responses for minimal residual disease (MRD) in patients with chronic lymphocytic leukemia (CLL). In a prior analysis we demonstrated that it is possible to achieved MRD negativity, as assessed by polyclonality of immunoglobulin heavy chain after consolidation with alemtuzumab. This phase II study evaluated 34 patients with CLL who received alemtuzumab consolidation in an effort to improve the quality of their response to fludarabine-based induction. Subsequent peripheral blood stem-cell (PBSC) collection and transplantation, tolerability, and pharmacokinetics also were assessed. PATIENTS AND METHODS: Thirty-four patients younger than 65 years who had a clinical response to fludarabine-based induction therapy received alemtuzumab 10 mg subcutaneously three times per week for 6 weeks. PBSCs were collected after mobilization with cytarabine and granulocyte colony-stimulating factor. Blood samples for pharmacokinetics study were taken between days 1 and 31. RESULTS: The complete response rate improved from 35% after fludarabine induction to 79.4% after alemtuzumab consolidation, including 19 patients (56%) who achieved MRD negativity. The most common adverse events were injection-site reactions and fever. Cytomegalovirus reactivation occurred in 18 patients, all of whom were successfully treated with oral ganciclovir. PBSC collection was successful in 24 (92%) of 26 patients, and 18 patients underwent autologous PBSC transplantation. Alemtuzumab plasma concentrations increased gradually during the first 2 weeks and accumulated more rapidly thereafter. CONCLUSION: Subcutaneously administered alemtuzumab was effective, safe, and well tolerated as consolidation therapy in patients with CLL who responded to fludarabine induction therapy. Subsequent PBSCT was feasible thereafter.

Clinical characteristics and outcome of immunoglobulin M-related disorders.

We analyzed the clinical features and prognostic factors for transformation of immunoglobulin Mrelated disorders (IgM-RDs) to malignant lymphoproliferative disease (MLD) in 83 patients with IgM-RDs. We studied 19 patients with type I cryoglobulinemias, 56 patients with type II cryoglobulinemias, 5 patients with peripheral neuropathies (PNs), and 3 patients with idiopathic thrombocytopenic purpuras. Fourteen patients with cryoglobulinemias presented with mild to moderate hepatomegaly with or without splenomegaly. Fourteen patients with type II cryoglobulinemias had arthralgias and/or vascular purpura (12 receiving corticosteroids), and 7 presented with PN. These latter patients and those with PNs without cryoglobulinemia were treated with steroids, cyclophosphamide, or polychemotherapy with/without plasma-exchange. Cumulative probability of evolution to MLD at 5 years was 15% (95% CI; 5%-25%). At a median of 62 months (12-195 months), 8 cases of IgM-RDs (8.4%) evolved to overt Waldenstrom's macroglobulinemia (n = 6), 1 case to non-Hodgkin's lymphoma, and 1 case to B-cell chronic lymphocytic leukemia. At univariate analysis, male sex (P = 0.02), IgM level > or = 3 g/dL (P < 0.0001), detectable Bence Jones proteinuria (P = 0.0005), lymphocytosis (P = 0.049), and high erythrocyte sedimentation rate (P = 0.003) significantly correlated with the evolution risk. Age, blood cell counts, b2-microglobulin level, degree of marrow lymphoplasmacytic infiltration, type of cryoglobulinemia, and hepatitis C virus positivity did not correlate with transformation. Although IgM-RDs represent a distinct clinical entity frequently requiring treatment in view of the IgM-related symptoms, their evolution probability and prognostic factors for malignant transformation seem to widely overlap those described for asymptomatic IgM monoclonal gammopathies.

Prognostic factors for transformation in asymptomatic immunoglobulin m monoclonal gammopathies.

We evaluated the risk of transformation of asymptomatic immunoglobulin (Ig) M monoclonal gammopathy (aIgM-MG) into symptomatic lymphoproliferative disease in 384 patients, in subgroups of patients with IgM MG of undetermined significance (MGUS) and smoldering Waldenstrom's macroglobulinemia (sWM). One hundred seventy-two patients with aIgM-MG with bone marrow (BM) histopathology and immunophenotyping were available for analysis. After a median of 45 months (range, 12-233 months), 45 cases of aIgM-MG (11.7%) evolved into lymphoproliferative disease, as follows: symptomatic WM (n = 41), non-Hodgkin's lymphoma (NHL; n = 2), IgM multiple myeloma (IgM-MM; n = 1), and primary amyloidosis (n = 1). Cumulative transformation probability at 5 and 10 years was 8% and 29%, respectively. The parameters significantly correlated with evolution were, at univariate analysis, BM lymphoplasmacytic infiltration, high erythrocyte sedimentation rate, hemoglobin (Hb) level, IgM size, and peripheral lymphocytosis; at multivariate analysis, the parameters were IgM size and peripheral lymphocytosis, with Hb level associated with a trend toward higher progression risk. Of the 138 cases of IgM-MGUS, 14 (10.1%) evolved (13 WM, 1 IgM-MM) after a median of 75 months (range, 12-117 months); of the 34 cases of sWM, 13 (38.2%) progressed to WM after 55 months (range, 13-154 months). In patients with IgM-MGUS, event-free survival at 5 and 10 years was 95% and 83%, respectively, and in patients with sWM, 77% and 42%, respectively (P = 0.0001). Among patients with aIgM-MG, those at high risk of evolution are patients with sWM, a distinct entity with clear BM evidence of NHL.

Risk factors for the development of bacterial infections in multiple myeloma treated with two different vincristine-adriamycin-dexamethasone schedules.

BACKGROUND AND OBJECTIVES: We evaluated bacterial infections (BIs) in patients with multiple myeloma (MM) treated with two different schedules of vincristine-adriamycin-dexamethasone (VAD). DESIGN AND METHODS: Ninety-seven patients were studied during 340 VAD cycles. VAD was given by either continuous intravenous infusion (CII) to hospitalized patients or rapid intravenous infusion (RII) to outpatients. The characteristics of patients and VAD schedules were retrospectively analyzed to detect correlations with the incidence of BI. RESULTS: By analyzing each VAD cycle, we found that profound hypogammaglobulinemia (p=0.06) and post-treatment neutropenia (p=0.08) were associated with a trend for a higher risk of infection, while renal function impairment was significantly correlated with BI risk at both univariate (p<0.02) and multivariate (p<0.002) analyses. Evaluating only the first 4 months of therapy, characterized by a significantly higher incidence of BI than the later period (p<0.0001), previously untreated disease was significantly correlated with BI risk (p<0.04), while male sex (p=0.06), CII schedule (p=0.07), and profound hypogammaglobulinemia (p=0.1) were associated with a tendency to a higher risk of infection; however, at multivariate analysis the latter two parameters independently predicted BI probability (p<0.015 and p<0.03, respectively) as did previously untreated disease (p<0.025). The high probability of CII-related infection was demonstrated to depend on the frequent development of nosocomial infections. INTERPRETATION AND CONCLUSIONS: Patients with profound hypogammaglobulinemia who receive VAD as first line treatment are at a major risk of BI up to the completion of the fourth month of therapy. In this setting hospitalization should be avoided and, if patients require admission, antibacterial prophylaxis with intravenous immunoglobulins could be appropriate and effective.

Smouldering Waldenstrom's macroglobulinemia: factors predicting evolution to symptomatic disease.

Factors predicting evolution to symptomatic disease were investigated in 27 patients with smouldering Waldenstrom's macroglobulinemia (SWM) among 172 patients with Waldenstom's macroglobulinemia (WM), selected on the basis of the following criteria: (1) IgM paraprotein > 3 g/dL, and/or (2) bone marrow (BM) lymphoplasmacytoid (LPC) infiltration >or= 30%, and/or (3) diffuse infiltration pattern on BM biopsy, and (4) no treatment requirement for at least 12 months. Cumulative probability of survival was calculated by means of Kaplan-Meier. The Mantel and Haenszel test and multivariate Cox model were used to identify possible predictors for evolution. At a median follow-up of 79 months (range, 14 to 204), 11 patients (40.7%) showed progression to symptomatic disease, with the median interval from diagnosis being 46 months (range, 12 to 154). Event-free survival (EFS) at 5 and 10 years was 65% (95% confidence interval [CI], 45% to 85%) and 53% (95% CI, 31% to 75%), respectively. At multivariate analysis, paraprotein > 3 g/dL (hazard ratio [HR], 15.1; 95% CI, 3.01 to 75.64; P <.0009) and hemoglobin 3 g/dL and hemoglobin levels