Koen van Besien

The emergence of vancomycin-resistant enterococcal bacteremia in hematopoietic stem cell transplant recipients

Abstract As antimicrobial resistance increases, understanding the current epidemiology of bloodstream infections (BSIs) in hematopoietic stem cell transplant (HSCT) recipients is essential to guide empirical antimicrobial therapy. We therefore reviewed microbial etiologies, timing and outcomes of BSIs in patients who were transplanted from September 2007 to December 2011. Vancomycin-resistant enterococci (VRE) were the most common pathogens in allogeneic HSCT recipients and the fourth most common after autologous transplant. VRE did not cause any of 101 BSIs in neutropenic patients who were not receiving antibacterials, but caused 32 (55%) of 58 BSIs in neutropenic patients receiving a broad-spectrum β-lactam agent (p < 0.001). Rates of septic shock and 7-day mortality were 5% and 0% for streptococcal bacteremia, 12% and 18% for VRE bacteremia, and 20% and 14% for Gram-negative bacteremia. In conclusion, VRE bacteremia was the most common BSI in allogeneic HSCT recipients, occurred primarily in neutropenic patients receiving broad-spectrum β-lactams and was associated with poor outcomes.

A novel hematopoietic progenitor cell mobilization and collection algorithm based on preemptive CD34 enumeration

The collection of autologous peripheral blood (PB) stem cells can be challenging in the subgroup of patients deemed “poor mobilizers” with granulocyte–colony‐stimulating factor. Plerixafor, a CXCR‐4 antagonist, is an alternative mobilizing agent, but is costly, and the optimal mobilization algorithm has yet to be determined.

A Phase I Study of CPX-351 in Combination with Busulfan and Fludarabine Conditioning and Allogeneic Stem Cell Transplantation in Adult Patients with Refractory Acute Leukemia

This phase I study evaluated the maximal tolerated dose of CPX-351 when administered sequentially with allogeneic hematopoietic stem cell transplantation (HSCT) in patients with refractory acute leukemia. CPX-351 is a novel liposomal formulation that combines cytosine arabinoside (ara-c) and daunorubicin in a fixed molar ratio of 5:1. Patients in cohorts of 3 were treated with CPX-351 followed by fludarabine and busulfan (Bu/Flu) conditioning at 4-week (schedule A) or 3-week (schedule B) intervals. CPX-351 doses were escalated in 20-U/m(2) increments starting at 60 U/m(2) for 3 doses. Of the 36 patients enrolled, 29 were able to undergo HSCT, and the other 7 (the majority on schedule A) did not proceed to HSCT because of rapid disease progression. The maximal tolerated dose of CPX-351 was not reached at the 120 U/m(2) × 3 dose level. All 29 patients who proceeded to HSCT demonstrated adequate neutrophil and platelet engraftment. The median follow-up on the study for all 36 patients was 205 days (range, 20 to 996 days). The 1-year cumulative incidence of relapse for the 36 patients was 60.1% (95% confidence interval [CI], 43.4% to 77.3%), and that of nonrelapse mortality was 23.8% (95% CI, 10.9% to 47.4%). The 1-year overall survival and leukemia-free survival were 37% (95% CI, 21% to 53%) and 27% (95% CI, 13% to 43%), respectively. Our data suggest that a phase II trial should incorporate CPX-351 120 U/m(2) × 3 dosing on schedule B. Patients with good performance status and those who achieve effective cytoreduction from CPX-351 derived the greatest benefit.

Safety and efficacy of plerixafor dose escalation for the mobilization of CD34+ hematopoietic progenitor cells in patients with sickle cell disease: interim results

Gene therapy for sickle cell disease is limited by the yield of hematopoietic progenitor cells that can be harvested for transduction or gene editing. We therefore performed a phase I dose-escalation study of the hematopoietic progenitor cell mobilizing agent plerixafor to evaluate the efficacy and safety of standard dosing on peripheral blood CD34+ cell mobilization. Of 15 patients enrolled to date, only one was chronically transfused and ten were on hydroxyurea. Of eight patients who achieved a CD34+ cell concentration >30 cells/μL, six were on hydroxyurea. There was no clear dose response to increasing plerixafor dosage. There was a low rate of serious adverse events; two patients developed vaso-occlusive crises, at the doses of 80 μg/kg and 240 μg/kg. Hydroxyurea may have contributed to the limited CD34+ mobilization by affecting baseline peripheral blood CD34 counts, which correlated strongly with peak peripheral blood CD34 counts. Plerixafor administration did not induce significant increases in the fraction of activated neutrophils, monocytes, or platelets. However, increased neutrophils positive for activated β2 integrin and Mac-1 were associated with serious adverse events. In summary, plerixafor was well tolerated but did not achieve consistent CD34+ cell mobilization in this cohort of patients, most of whom were being actively treated with hydroxyurea and only one was chronically transfused. The study will continue with escalation of the dose of plerixafor and modification of hydroxyurea administration. Clinicaltrials.gov identifier: NCT02193191.

Granulocyte Colony-Stimulating Factor Use after Autologous Peripheral Blood Stem Cell Transplantation: Comparison of Two Practices

Administration of granulocyte colony-stimulating factor (G-CSF) after autologous peripheral blood stem cell transplantation (PBSCT) is generally recommended to reduce the duration of severe neutropenia; however, data regarding the optimal timing of G-CSFs post-transplantation are limited and conflicting. This retrospective study was performed at NewYork-Presbyterian/Weill Cornell Medical Center between November 5, 2013, and August 9, 2016, of adult inpatient autologous PBSCT recipients who received G-CSF empirically starting on day +5 (early) versus on those who received G-CSF on day +12 only if absolute neutrophil count (ANC) was <0.5 × 109/L (ANC-driven). G-CSF was dosed at 300 µg in patients weighing <75 kg and 480 µg in those weighing ≥75 kg. One hundred consecutive patients underwent autologous PBSCT using either the early (n = 50) or ANC-driven (n = 50) G-CSF regimen. Patient and transplantation characteristics were comparable in the 2 groups. In the ANC-driven group, 24% (n = 12) received G-CSF on day +12 and 60% (n = 30) started G-CSF earlier due to febrile neutropenia or at the physicians discretion, 6% (n = 3) started after day +12 at the physicians discretion, and 10% (n = 5) did not receive any G-CSF. The median start day of G-CSF therapy was day +10 in the ANC-driven group versus day +5 in the early group (P < .0001). For the primary outcome, the median time to neutrophil engraftment was 12 days (interquartile range [IQR] 11-13 days) in the early group versus 13 days (IQR, 12-14 days) in the ANC-driven group (P = .07). There were no significant between-group differences in time to platelet engraftment, 1-year relapse rate, or 1-year overall survival. The incidence of febrile neutropenia was 74% in the early group versus 90% in the ANC-driven group (P = .04); however, there was no significant between-group difference in the incidence of positive bacterial cultures or transfer to the intensive care unit. The duration of G-CSF administration until neutrophil engraftment was 6 days in the early group versus 3 days in the ANC-driven group (P < .0001). The median duration of post-transplantation hospitalization was 15 days (IQR, 14-19 days) in the early group versus 16 days (IQR, 15-22 days) in the ANC-driven group (P = .28). Our data show that early initiation of G-CSF (on day +5) and ANC-driven initiation of G-CSF following autologous PBSCT were associated with a similar time to neutrophil engraftment, length of stay post-transplantation, and 1-year overall survival.

Combined Haploidentical and Umbilical Cord Blood Allogeneic Stem Cell Transplantation for High-Risk Lymphoma and Chronic Lymphoblastic Leukemia

Limited studies have reported on outcomes for lymphoid malignancy patients receiving alternative donor allogeneic stem cell transplants. We have previously described combining CD34-selected haploidentical grafts with umbilical cord blood (haplo-cord) to accelerate neutrophil and platelet engraftment. Here, we examine the outcome of patients with lymphoid malignancies undergoing haplo-cord transplantation at the University of Chicago and Weill Cornell Medical College. We analyzed 42 lymphoma and chronic lymphoblastic leukemia (CLL) patients who underwent haplo-cord allogeneic stem cell transplantation. Patients underwent transplant for Hodgkin lymphoma (n = 9, 21%), CLL (n = 5, 12%) and non-Hodgkin lymphomas (n = 28, 67%), including 13 T cell lymphomas. Twenty-four patients (52%) had 3 or more lines of therapies. Six (14%) and 1 (2%) patients had prior autologous and allogeneic stem cell transplant, respectively. At the time of transplant 12 patients (29%) were in complete remission, 18 had chemotherapy-sensitive disease, and 12 patients had chemotherapy-resistant disease. Seven (17%), 11 (26%), and 24 (57%) patients had low, intermediate, and high disease risk index before transplant. Comorbidity index was evenly distributed among 3 groups, with 13 (31%), 14 (33%), and 15 (36%) patients scoring 0, 1 to 2, and ≥3. Median age for the cohort was 49 years (range, 23 to 71). All patients received fludarabine/melphalan/antithymocyte globulin conditioning regimen and post-transplant graft-versus-host disease (GVHD) prophylaxis with tacrolimus and mycophenolate mofetil. The median time to neutrophil engraftment was 11 days (range, 9 to 60) and to platelet engraftment 19.5 days (range, 11 to 88). Cumulative incidence of nonrelapse mortality was 11.6% at 100 days and 19 % at one year. Cumulative incidence of relapse was 9.3% at 100 days and 19% at one year. With a median follow-up of survivors of 42 months, the 3-year rates of GVHD relapse free survival, progression-free survival, and overall survival were 53%, 62%, and 65%, respectively, for these patients. Only 8% of the survivors had chronic GVHD. In conclusion, haplo-cord transplantation offers a transplant alternative for patients with recurrent or refractory lymphoid malignancies who lack matching donors. Both neutrophil and platelet count recovery is rapid, nonrelapse mortality is limited, excellent disease control can be achieved, and the incidence of chronic GVHD is limited. Thus, haplo-cord achieves high rates of engraftment and encouraging results.

The eIF4E inhibitor ribavirin as a potential antilymphoma therapeutic: early clinical data*

Sarah C. Rutherford, Eric N. Stewart, Zhengming Chen, Amy Chadburn, Natasha E. Wehrli, Koen van Besien, Peter Martin, Richard R. Furman, John P. Leonard and Leandro Cerchietti Department of Medicine, Division of Hematology and Oncology, Meyer Cancer Center, Weill Cornell Medicine and New YorkPresbyterian Hospital, New York, NY, USA; Department of Healthcare Policy and Research, Division of Biostatistics and Epidemiology, Weill Cornell Medical College, New York, NY, USA; Department of Pathology and Laboratory Medicine, Division of Hematopathology, Weill Cornell Medical College, New York, NY, USA; Department of Radiology, Weill Cornell Medical College, New York, NY, USA

A renaissance for autologous transplantation in follicular lymphoma

Over the decades the management of patients with follicular lymphoma, the most common form of nonHodgkin lymphoma, has oscillated between attempts at curative therapy, watchful waiting and minimal intervention, and most recently efforts to identify high-risk subpopulations to be targeted for innovative therapies [1]. Early studies of alkylating agent chemotherapy demonstrated the exquisite sensitivity of this disorder [2]. But few remissions were durable; cure or even prolongation of life could not be convincingly demonstrated. Hence the emerging recommendation for watchful waiting in asymptomatic and low tumor-burden cases, and a consensus that follicular lymphoma was not curable. Interferon, the first drug shown to prolong survival – when combined with intensive anthracycline-containing chemotherapy – did not find wide usage in the United States or elsewhere [3]. Autologous transplant was also tested and prolonged remissions were demonstrated, particularly in those where the bone marrow could be purged of contaminating lymphoma cells. Elegant early studies conducted at Dana Farber Cancer Center in Boston [4] and at Saint Bartholomew’s hospital in London, [5] showed a plateau in the disease-free survival curve. This plateau persisted with very prolonged follow-up demonstrating that autologous transplantation can cure a fraction of patients with follicular lymphoma [6]. In the prerituximab era, a randomized study showed improved survival for patients with recurrent follicular lymphoma undergoing autologous transplants compared to conventional salvage [7]. However, randomized studies of transplant consolidation for young patients in complete remission failed to show improvement in survival compared to conventional chemotherapy, and there was an increased incidence of therapy-related myelodysplastic syndrome and acute myeloid leukemia [8–11] Shortly thereafter rituximab was introduced and had a dramatic impact on the long-term survival of patients with follicular lymphoma [12]. Numerous other new drugs followed, and interest in pursuing potentially curative therapy dwindled, particularly in the United States. More interest has been devoted to developing novel salvage therapies utilizing ‘targeted’ agents. A 2015 ASH review stated that the National Cancer Therapy Network Lymphoma Working Group was studying novel agents/combinations for high risk and early relapse patients and that ‘it is hoped that if the novel therapy is effective in inducing a CR in this high-risk group, transplant would be delayed to better ascertain the long-term effectiveness of this therapy’[13]. In this regard, the paper by Manna et al in this issue of Leukemia and Lymphoma challenges that objective and suggests that there remains an important role for high-dose therapy and autologous transplants in patients with high-risk follicular lymphoma [14]. The investigators identified from the Provincial Alberta Cancer Registry and Alberta Lymphoma Database in Canada, 517 patients with follicular lymphoma under the age of 70, of whom 84 had a relapse within 24 months from completing first-line chemo-immunotherapy. This is a group of patients with a profoundly adverse prognosis [15]. Five-year survival was superior for 50 patients who received autologous transplantation compared to 34 nontransplanted patients within the early relapse group (85.4% vs. 57.9%, p1⁄4 .001). A similar benefit could not be shown for patients who had later relapses beyond the 24-month cut-point. Two other groups have recently reported quite similar data. CIBMTR in collaboration with the National LymphoCare study compared the outcomes for early relapse patients who underwent transplant or alternatively further conventional chemotherapy. Patients undergoing stem cell transplant early in the course of their disease had superior survival

Mycobacterial spindle cell pseudotumour: epidemiology and clinical outcomes

Introduction Mycobacterial spindle cell pseudotumour (MSP) is a rare disease characterised by tumour-like local proliferation of spindle-shaped histiocytes containing acid-fast positive mycobacteria. The aim of this literature review is to describe the clinical parameters and treatment outcomes of patients with MSP. Methods A literature search was conducted using the search terms related to mycobacteria and spindle cell tumours. A previously unreported stem cell transplant recipient from our institution diagnosed with MSP was also included. Demographics, comorbidities, site of infection, treatment and clinical outcomes were analysed. Results Fifty-one patients were analysed. Twenty-six (51%) had HIV infection. Mycobacterium avium complex was the most frequent organism isolated in 24 (47.1%) followed by Mycobacterium tuberculosis complex in eight (16%) cases. Lymph nodes were the most common site of infection (45.1%). Twenty (39.2%) patients received antimycobacterial agents, 12 (23.5%) underwent surgical resection and six (11.8%) received antimycobacterial agents plus surgery. Treatment was successful in 24 (47.1%) patients and failed in 15 (29.4%); 13 of these 15 patients died. Antimycobacterial therapy was significantly associated with successful outcome compared with surgical resection or no treatment (P<0.001). Conclusion MSP is a rare condition associated primarily with immunodeficiencies. Antimycobacterial therapy is significantly associated with successful outcome.