Extended follow-up of an antibiotic cycling program for the management of febrile neutropenia in a hematologic malignancy and hematopoietic cell transplantation unit.

BACKGROUND: Febrile neutropenia is a common complication during treatment of hematological malignancies and hematopoietic cell transplantation. Empiric antibiotic therapy in this setting, while standard of care, commonly leads to microbial resistance. We have previously shown that cycling antibiotics in this patient population is feasible. This report provides long-term follow-up of cycling antibiotics in this patient population. METHODS: In a prospective cohort of hematological malignancy patients with neutropenic fever, we sought to evaluate the role of empiric antibiotic cycling in preventing antibiotic resistance. Antibiotic cycling was initiated in March 2002 and, until June 2005, antibiotics were cycled every 8 months (Cycling Period A). From July 2005 to December 2009, antibiotics were cycled every 3 months (Cycling Period B). The rates of bacteremia, resistance, and complications were compared to a retrospective cohort (Pre-cycling Period). RESULTS: The rate of gram-negative bacteremia decreased when compared to Cycling Periods A and B (5.3 vs. 2.1 and 3.3 episodes/1000 patient-days, respectively, P < 0.0001), most likely owing to implementation of quinolone prophylaxis. The resistance profile of the gram-negative organisms isolated remained stable over the 3 time periods, with the exception of an increase in quinolone resistance during the cycling periods. Gram-positive bacteremia rates remained stable, but vancomycin-resistant Enterococcus (VRE) increased significantly (0.1 vs. 1.0 and 1.6 episodes/1000 patient-days, respectively, P = 0.005) during cycling periods. Mortality rates were comparable. CONCLUSIONS: Antibiotic cycling for neutropenic fever was effectively implemented and followed over an extended time period. Gram-negative resistance remained stable, but there is some concern for selection of resistant gram-positive bacteria, specifically VRE. Although antibiotic cycling did not seem to cause resistance in our study, further study is necessary to clarify the effect of cycling on antibiotic resistance, patient outcomes, and hospital cost.

Loncastuximab tesirine for diffuse large B-cell lymphoma.

Loncastuximab tesirine-lpyl (ADC Therapeutics), an anti-CD19 antibody-drug conjugate, was recently approved for the treatment of relapsed, refractory diffuse large B-cell lymphoma on the basis of the results of a phase II clinical trial, LOTIS-2. Preclinical data demonstrated the selectivity and efficacy of the drug through in vitro and in vivo models. A phase I clinical trial included relapsed, refractory B-cell non-Hodgkin lymphoma (NHL) and demonstrated a tolerable safety profile, with major adverse effects being neutropenia, thrombocytopenia and elevated gamma-glutamyl transferase (GGT). A dose of 150 µg/kg intravenously every 3 weeks for two cycles followed by 75 µg/kg every 3 weeks was chosen for further testing. The phase II trial, LOTIS-2, recruited relapsed, refractory diffuse large B-cell lymphoma patients and demonstrated no new safety concerns. Overall response rate was 48.3% (24.1% CR), and OS was 9.9 months. Currently, several ongoing clinical trials are evaluating the safety and efficacy of loncastuximab tesirine in a variety of NHL subtypes.

Worldwide Network for Blood and Marrow Transplantation (WBMT) recommendations for establishing a hematopoietic stem cell transplantation program in countries with limited resources (Part II): Clinical, technical and socio-economic considerations.

The development of hematopoietic stem cell transplantation (HSCT) programs can face significant challenges in most developing countries because such endeavors must compete with other government health care priorities, including the delivery of basic services. While this is may be a limiting factor, these countries should prioritize development of the needed expertise to offer state of the art treatments including transplantation, by providing financial, technological, legal, ethical and other needed support. This would prove beneficial in providing successful programs customized to the needs of their population, and potentially provide long-term cost-savings by circumventing the need for their citizens to seek care abroad. Costs of establishing HSCT program and the costs of the HSCT procedure itself can be substantial barriers in developing countries. Additionally, socioeconomic factors intrinsic to specific countries can influence access to HSCT, patient eligibility for HSCT and timely utilization of HSCT center capabilities. This report describes recommendations from the Worldwide Network for Blood and Marrow Transplantation (WBMT) for establishing HSCT programs with a specific focus on developing countries, and identifies challenges and opportunities for providing this specialized procedure in the resource constrained setting.

Is myeloablative dose intensity necessary in allogeneic hematopoietic cell transplantation for lymphomas?

The advent of novel immunotherapy and tyrosine kinase inhibitors has ushered a new era in the treatment of Hodgkin and non-Hodgkin lymphomas. Allogeneic hematopoietic cell transplantation remains, however, a vital component in the management and potential cure of lymphomas, especially in the relapsed setting. Considering the biological and clinical heterogeneity of various subtypes of lymphomas, the optimal intensity of conditioning regimens remains controversial. Reduced intensity conditioning regimens have broadened applicability of the procedure to older and frail patients. Observational studies suggest that although reduced intensity allografting is associated with higher risk of relapse, overall survival is comparable and in some cases even better, than observed with myeloablative regimens. Here, we review the available published data pertaining to allogeneic hematopoietic cell transplantation using reduced intensity or myeloablative conditioning for various lymphoma histologies. Owing to the lack of randomized prospective trials, recommendations are mainly based on registry and single-institution studies. Special emphasis must be given to implementing strategies to prevent relapse when using reduced intensity regimens. Identifying particular patients who may benefit from myeloablative regimens in lymphomas remains to be better defined.

Metabolic syndrome and cardiovascular disease following hematopoietic cell transplantation: screening and preventive practice recommendations from CIBMTR and EBMT.

Metabolic syndrome (MetS) is a constellation of cardiovascular risk factors that increases the risk of cardiovascular disease, diabetes mellitus and all cause mortality. Long-term survivors of hematopoietic cell transplantation (HCT) have a substantial risk of developing MetS and cardiovascular disease, with the estimated prevalence of MetS being 31-49% among HCT recipients. Although MetS has not yet been proven to impact cardiovascular risk after HCT, an understanding of the incidence and risk factors for MetS in HCT recipients can provide the foundation to evaluate screening guidelines and develop interventions that may mitigate cardiovascular-related mortality. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal of reviewing literature and recommend practices appropriate to HCT recipients. Here we deliver consensus recommendations to help clinicians provide screening and preventive care for MetS and cardiovascular disease among HCT recipients. All HCT survivors should be advised of the risks of MetS and encouraged to undergo recommended screening based on their predisposition and ongoing risk factors.

Long-term survival outcomes of reduced-intensity allogeneic or autologous transplantation in relapsed grade 3 follicular lymphoma.

Grade 3 follicular lymphoma (FL) has aggressive clinical behavior. To evaluate the optimal first transplantation approach in relapsed/refractory grade 3 FL patients, we compared the long-term outcomes after allogeneic (allo-) vs autologous hematopoietic cell transplantation (auto-HCT) in the rituximab era. A total of 197 patients undergoing first reduced-intensity conditioning (RIC) allo-HCT or first auto-HCT during 2000-2012 were included. Rituximab-naive patients were excluded. Allo-HCT recipients were younger, more heavily pretreated and had a longer interval between diagnosis and HCT. The 5-year probabilities of non-relapse mortality (NRM), relapse/progression, PFS and overall survival (OS) for auto-HCT vs allo-HCT groups were 4% vs 27% (P<0.001), 61% vs 20% (P<0.001), 36% vs 51% (P=0.07) and 59% vs 54% (P=0.7), respectively. On multivariate analysis, auto-HCT was associated with reduced risk of NRM (relative risk (RR)=0.20; P=0.001). Within the first 11 months post HCT, auto- and allo-HCT had similar risks of relapse/progression and PFS. Beyond 11 months, auto-HCT was associated with higher risk of relapse/progression (RR=21.3; P=0.003) and inferior PFS (RR=3.2; P=0.005). In the first 24 months post HCT, auto-HCT was associated with improved OS (RR=0.42; P=0.005), but in long-time survivors (beyond 24 months) it was associated with inferior OS (RR=3.6; P=0.04). RIC allo-HCT as the first transplant approach can provide improved PFS and OS, in long-term survivors.

Post-autologous transplant maintenance therapies in lymphoid malignancies: are we there yet?

Disease relapse after autologous hematopoietic transplant (auto-HCT) remains the number one cause of post-transplant therapy failure and mortality. The last decade has seen a proliferation of clinical studies looking at the prevention of post-auto-HCT therapy failure with various maintenance strategies. The benefit of such therapies is in turn dependent on disease histology and timing of transplantation. Although high dose therapy (HDT) provides durable responses in chemosensitive relapsed diffuse large B-cell lymphoma (DLBCL), a sizable subset experiences disease relapse. Unfortunately, the addition of rituximab as a post-auto-HCT maintenance strategy did not improve survival outcomes. The preliminary results with programmed death -1 (PD-1) Ab as post-auto maintenance in DLBCL is promising but requires randomized validation. In follicular lymphoma, the 5- and 10-year PFS rates are ~60% and 31%, respectively. Although the addition of rituximab improved PFS, there is no survival benefit, to date. Disease relapse after auto-HCT in mantle cell lymphoma (MCL) is not uncommon. Rituximab maintenance in this setting provides a PFS benefit. Given the poor prognosis of post-auto-HCT failures in MCL, maintenance can be considered on a case-by-case basis. In chemosensitive relapsed Hodgkin lymphoma, addition of brentuximab vedotin after auto-HCT improved 2-year PFS (65 vs 45%) and can be considered as an option for maintenance therapy post auto-HCT, in select higher risk patients. Ongoing trials evaluating the efficacy of post-auto-HCT maintenance with novel agents (for example, immunomodulators, proteasome inhibitors, PD-1 inhibitors, Bruton's tyrosine kinase inhibitors and so on) will likely change the practice landscape for lymphoma patients following HDT and auto-HCT.

A prognostic model predicting autologous transplantation outcomes in children, adolescents and young adults with Hodgkin lymphoma.

Autologous hematopoietic cell transplantation (AutoHCT) is a potentially curative treatment modality for relapsed/refractory Hodgkin lymphoma (HL). However, no large studies have evaluated pretransplant factors predictive of outcomes of AutoHCT in children, adolescents and young adults (CAYA, age <30 years). In a retrospective study, we analyzed 606 CAYA patients (median age 23 years) with relapsed/refractory HL who underwent AutoHCT between 1995 and 2010. The probabilities of PFS at 1, 5 and 10 years were 66% (95% confidence interval (CI): 62-70), 52% (95% CI: 48-57) and 47% (95% CI: 42-51), respectively. Multivariate analysis for PFS demonstrated that at the time of AutoHCT patients with Karnofsky/Lansky score ⩾90, no extranodal involvement and chemosensitive disease had significantly improved PFS. Patients with time from diagnosis to first relapse of <1 year had a significantly inferior PFS. A prognostic model for PFS was developed that stratified patients into low-, intermediate- and high-risk groups, predicting for 5-year PFS probabilities of 72% (95% CI: 64-80), 53% (95% CI: 47-59) and 23% (95% CI: 9-36), respectively. This large study identifies a group of CAYA patients with relapsed/refractory HL who are at high risk of progression after AutoHCT. Such patients should be targeted for novel therapeutic and/or maintenance approaches post-AutoHCT.

Secondary solid cancer screening following hematopoietic cell transplantation.

Hematopoietic stem cell transplant (HCT) recipients have a substantial risk of developing secondary solid cancers, particularly beyond 5 years after HCT and without reaching a plateau overtime. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal to facilitate implementation of cancer screening appropriate to HCT recipients. The working group reviewed guidelines and methods for cancer screening applicable to the general population and reviewed the incidence and risk factors for secondary cancers after HCT. A consensus approach was used to establish recommendations for individual secondary cancers. The most common sites include oral cavity, skin, breast and thyroid. Risks of cancers are increased after HCT compared with the general population in skin, thyroid, oral cavity, esophagus, liver, nervous system, bone and connective tissues. Myeloablative TBI, young age at HCT, chronic GVHD and prolonged immunosuppressive treatment beyond 24 months were well-documented risk factors for many types of secondary cancers. All HCT recipients should be advised of the risks of secondary cancers annually and encouraged to undergo recommended screening based on their predisposition. Here we propose guidelines to help clinicians in providing screening and preventive care for secondary cancers among HCT recipients.

Allogeneic hematopoietic cell transplant for AML: no impact of pre-transplant extramedullary disease on outcome.

The impact of extramedullary disease (EMD) in AML on the outcomes of allogeneic hematopoietic cell transplantation (alloHCT) is unknown. Using data from the Center for International Blood and Marrow Transplant Research, we compared the outcomes of patients who had EMD of AML at any time before transplant, with a cohort of AML patients without EMD. We reviewed data from 9797 AML patients including 814 with EMD from 310 reporting centers and 44 different countries, who underwent alloHCT between and 1995 and 2010. The primary outcome was overall survival (OS) after alloHCT. Secondary outcomes included leukemia-free survival (LFS), relapse rate and treatment-related mortality (TRM). In a multivariate analysis, the presence of EMD did not affect either OS (hazard ratio 1.00, 95% confidence interval (CI) 0.91-1.09), LFS (0.98, 0.89-1.09), TRM (relative risk 0.92, 95% CI 0.80-1.16, P=0.23) or relapse (relative risk=1.03, 95% CI, 0.92-1.16; P=0.62). Furthermore, the outcome of patients with EMD was not influenced by the location, timing of EMD, or intensity of conditioning regimen. The presence of EMD in AML does not affect transplant outcomes and should not be viewed as an independent adverse prognostic feature.

Contribution of chemotherapy mobilization to disease control in multiple myeloma treated with autologous hematopoietic cell transplantation.

In patients with multiple myeloma (MM) undergoing autologous hematopoietic cell transplantation (auto-HCT), peripheral blood progenitor cells may be collected following mobilization with growth factor alone (GF) or cytotoxic chemotherapy plus GF (CC+GF). It is uncertain whether the method of mobilization affects post-transplant outcomes. We compared these mobilization strategies in a retrospective analysis of 968 patients with MM from the Center for International Blood and Marrow Transplant Research database who received an auto-HCT in the US and Canada between 2007 and 2012. The kinetics of neutrophil engraftment (⩾0.5 × 10(9)/L) was similar between groups (13 vs 13 days, P=0.69) while platelet engraftment (⩾20 × 10(9)/L) was slightly faster with CC+GF (19 vs 18 days, P=0.006). Adjusted 3-year PFS was 43% (95% confidence interval (CI) 38-48) in GF and 40% (95% CI 35-45) in CC+GF, P=0.33. Adjusted 3-year OS was 82% (95% CI 78-86) vs 80% (95% CI 75-84), P=0.43 and adjusted 5-year OS was 62% (95% CI 54-68) vs 60% (95% CI 52-67), P=0.76, for GF and CC+GF, respectively. We conclude that MM patients undergoing auto-HCT have similar outcomes irrespective of the method of mobilization and found no evidence that the addition of chemotherapy to mobilization contributes to disease control.

Managing Hodgkin lymphoma relapsing after autologous hematopoietic cell transplantation: a not-so-good cancer after all!

Hodgkin lymphoma (HL) relapsing after an autologous hematopoietic cell transplant (HCT) poses a therapeutic challenge. In this setting, salvage chemotherapy (for example, gemcitabine-based, ifosfamide-containing and others) or immunotherapy (for example, brentuximab vedotin) is essential as a bridging-cytoreduction strategy to an allogeneic HCT. Myeloablative allogeneic hematopoietic cell transplantation in relapsed HL is associated with high rates of non-relapse mortality. In carefully selected patients with chemosensitive disease, allografting following lower-intensity conditioning regimens can provide durable disease control rates of about 25-35%. Promising early results with haploidentical and umbilical cord transplantation are noteworthy and are expanding this procedure to patients for whom HLA-matched related or unrelated donors are not available. Unfortunately, a significant number of HL patients relapsing after an autologous HCT are not candidates for allografting because of the presence of resistant disease, donor unavailability or comorbidities. Brentuximab vedotin is approved for HL relapsing after a prior autograft. Rituximab and bendamustine are also active in this setting, albeit with short durations of remission. Histone deacetylase inhibitors (for example, panobinostat, mocetinostat), mTOR inhibitors (for example, everolimus) and immunomodulatory agents (lenalidomide) have shown activity in phase II trials, but currently are not approved for this indication. Second autologous HCT are rarely performed but this approach should not be considered standard practice at this time. The need for effective agents for post autograft failures of HL largely remains unmet. Continuous efforts to ensure early referral of such patients for allogeneic HCT or investigational therapies are the key to improving outcomes of this not-so-good lymphoma.

Reappraising the role of autologous transplantation for indolent B-cell lymphomas in the chemoimmunotherapy era: is it still relevant?

The role of autologous hematopoietic cell transplantation (auto-HCT) in the management of indolent non-Hodgkin lymphomas (NHL) is shrouded in controversy. The outcomes of conventional therapies for many indolent lymphoma subtypes have dramatically improved over the last several years with the use of monoclonal antibodies, maintenance therapy programs and with the incorporation of radio-immunoconjugates. These significant advances in the armamentarium of lymphoma therapeutics warrant reappraisal of the current role of auto-HCT in the treatment algorithm of indolent NHL. Prospective randomized studies comparing contemporary chemoimmunotherapies against auto-HCT are lacking, leading to significant debate about the role and timing of auto-HCT for indolent NHL in the modern era. Although autografting for follicular lymphoma (FL) in first remission has been largely abandoned, it remains a useful modality for relapsed disease, especially for the subgroup of patients who are not candidates for allogeneic transplantation with a curative intent. Auto-HCT can provide durable disease control in chemosensitive transformed FL and mantle cell lymphoma (MCL) in first remission, with relatively low toxicity, and remains appropriate in chemoimmunotherapy era. Contemporary data are also reviewed to clarify the often underutilized role of autografting in relapsed MCL and other less frequent indolent NHL histologies. The biological basis of the increased risks of second malignancies with auto-HCT are reviewed to identify strategies designed to mitigate this risk by, for example, avoiding exposure to genotoxic agents, planning early stem cell collection/cryopreservation and minimizing the use of TBI with transplant conditioning, and so on. Genetic testing able to identify patients at high risk of therapy-related complications and novel post-transplant immune therapies with the potential of transforming autografting in indolent NHL from a remission-extending therapy to a curative modality are discussed to examine the possibly expanding role of auto-HCT for lymphoid malignancies in the coming years.

Is hematopoietic cell transplantation still a valid option for mantle cell lymphoma in first remission in the chemoimmunotherapy-era?

Modern chemoimmunotherapies have produced higher response rates and improved survival in mantle cell lymphoma (MCL); however, disease relapse remains a challenge. The availability of various post-remission maintenance or consolidation strategies, have led some to question the role of upfront autologous hematopoietic cell transplantation (auto-HCT) consolidation for MCL, in the chemoimmunotherapy-era. A one size fits all approach is no longer appropriate for MCL in first remission, and the choice of preferred post-remission (observation, maintenance or consolidation) strategy is increasingly becoming a factor of patient age, comorbidities and disease risk stratification. In select low-risk patients (based on Mantle cell lymphoma International Prognostic Index (MIPI)), observation following rituximab plus Hyper-CVAD-like inductions seems appropriate. Rituximab maintenance after anthracycline-based chemoimmunotherapies in elderly transplant ineligible patients has shown survival benefit and should be considered a valid option. Limited studies suggest feasibility of radioimmunotherapy consolidation in first remission; however, in the absence of randomized data, this modality remains investigational. In younger, transplant-eligible patients receiving cytarabine-containing inductions, upfront consolidation with auto-HCT has shown survival benefit, and remains a standard-of-care option in the modern-era. Hyper-CVAD associated stem cell mobilization failure is an increasingly recognized problem, underscoring the need for alternative inductions, or consideration for early stem cell collection, when this induction regimen is used. Outcomes of high-risk MIPI patients remain suboptimal with currently available induction and post-remission strategies and represents an area where adoptive immunotherapy in the form of allogeneic-HCT warrants investigation. Incorporation of novel MoAbs and targeted agents (PI3K inhibitors, mTOR inhibitors, BTK inhibitors and so on.) in maintenance and consolidation strategies will build on the significant therapeutic gains of last decade, in coming years.

Comparable efficacy and lower cost of PBSC mobilization with intermediate-dose cyclophosphamide and G-CSF compared with plerixafor and G-CSF in patients with multiple myeloma treated with novel therapies.

Studies comparing the efficacy and cost of stem cell mobilization with intermediate-dose CY (ID-CY) and G-CSF against plerixafor and G-CSF, specifically in multiple myeloma (MM) patients treated in the novel therapy era, are not available. Eighty-eight consecutive patients undergoing mobilization with ID-CY (3-4 g/m(2)) and G-CSF (n=55) were compared with patients receiving plerixafor and G-CSF (n=33). Compared with plerixafor, ID-CY use was associated with higher median peak peripheral blood CD34+ cell count (68 vs 160 cells/µL, P<0.001), and CD34+ cell yield on day 1 of collection (6.9 × 10(6) vs 11.7 × 10(6) cells/kg, P<0.001). Total CD34+ cell yield was significantly higher in the ID-CY patients (median collection 16.6 × 10(6) vs 11.6 × 10(6) cells/kg; P<0.001). ID-CY use was associated with significantly more frequent episodes of febrile neutropenia (16.3% vs 0%; P=0.02), intravenous antibiotic use (16.3% vs 3%; P=0.03) and hospitalizations (P=0.02). The average total cost of mobilization in the plerixafor group was significantly higher compared with the ID-CY group ($28 980 vs $22 504.8; P=0.001). Our data indicate robust stem cell mobilization in MM patients treated with novel agents, with G-CSF and either ID-CY or plerixafor. When compared with plerixafor, ID-CY-containing mobilization was associated with significantly lower average total mobilization costs.