Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C19 and Voriconazole Therapy.

Voriconazole, a triazole antifungal agent, demonstrates wide interpatient variability in serum concentrations, due in part to variant CYP2C19 alleles. Individuals who are CYP2C19 ultrarapid metabolizers have decreased trough voriconazole concentrations, delaying achievement of target blood concentrations; whereas poor metabolizers have increased trough concentrations and are at increased risk of adverse drug events. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of voriconazole for treatment based on CYP2C19 genotype (updates at https://cpicpgx.org/guidelines/ and www.pharmgkb.org).

Pre-existing invasive fungal infection is not a contraindication for allogeneic HSCT for patients with hematologic malignancies: a CIBMTR study.

Patients with prior invasive fungal infection (IFI) increasingly proceed to allogeneic hematopoietic cell transplantation (HSCT). However, little is known about the impact of prior IFI on survival. Patients with pre-transplant IFI (cases; n=825) were compared with controls (n=10247). A subset analysis assessed outcomes in leukemia patients pre- and post 2001. Cases were older with lower performance status (KPS), more advanced disease, higher likelihood of AML and having received cord blood, reduced intensity conditioning, mold-active fungal prophylaxis and more recently transplanted. Aspergillus spp. and Candida spp. were the most commonly identified pathogens. 68% of patients had primarily pulmonary involvement. Univariate and multivariable analysis demonstrated inferior PFS and overall survival (OS) for cases. At 2 years, cases had higher mortality and shorter PFS with significant increases in non-relapse mortality (NRM) but no difference in relapse. One year probability of post-HSCT IFI was 24% (cases) and 17% (control, P<0.001). The predominant cause of death was underlying malignancy; infectious death was higher in cases (13% vs 9%). In the subset analysis, patients transplanted before 2001 had increased NRM with inferior OS and PFS compared with later cases. Pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT but significant survivorship was observed. Consequently, pre-transplant IFI should not be a contraindication to allogeneic HSCT in otherwise suitable candidates. Documented pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT. However, mortality post transplant is more influenced by advanced disease status than previous IFI. Pre-transplant IFI does not appear to be a contraindication to allogeneic HSCT.

Association of mannose-binding lectin levels and invasive fungal disease in hematologic malignancy patients receiving myelosuppressive chemotherapy or allogeneic hematopoietic stem cell transplantation.

Several studies have suggested an association of mannose-binding lectin (MBL) deficiency with infections. In this study, we investigated the association between MBL deficiency and invasive fungal disease (IFD) in hematologic malignancy patients receiving myelosuppressive chemotherapy or hematopoietic stem cell transplant. MBL levels were quantified at the start of treatment in 152 patients who were followed for 6 months and scored as developing IFD or not. Forty-five patients (29.6%) developed IFD, of which 21 (46.7% of IFD cases and 13.8% of patients) were proven or probable IFD. Fifty-nine (38.8%) had MBL levels <1000 ng/mL. The rates of all IFD in patients with MBL levels below and above 1000 ng/mL were 33.9% and 26.9%, respectively (P=0.356). The rates of proven or probable IFD in patients with MBL levels below and above 1000 ng/mL were 11.9% and 15.1%, respectively (P=0.579). MBL levels <1000 ng/mL were not predictors of death (P=0.233). As expected, IFD was associated with death (P<0.0001). Our findings indicate that MBL levels <1000 ng/mL were not associated with an increased risk of developing IFD or overall survival.

The incidence, mortality and timing of Pneumocystis jiroveci pneumonia after hematopoietic cell transplantation: a CIBMTR analysis.

Pneumocystis jiroveci pneumonia (PJP) is associated with high morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Little is known about PJP infections after HSCT because of the rarity of disease given routine prophylaxis. We report the results of a Center for International Blood and Marrow Transplant Research study evaluating the incidence, timing, prophylaxis agents, risk factors and mortality of PJP after autologous (auto) and allogeneic (allo) HSCT. Between 1995 and 2005, 0.63% allo recipients and 0.28% auto recipients of first HSCT developed PJP. Cases occurred as early as 30 days to beyond a year after allo HSCT. A nested case cohort analysis with supplemental data (n=68 allo cases, n=111 allo controls) revealed that risk factors for PJP infection included lymphopenia and mismatch after HSCT. After allo or auto HSCT, overall survival was significantly poorer among cases vs controls (P=0.0004). After controlling for significant variables, the proportional hazards model revealed that PJP cases were 6.87 times more likely to die vs matched controls (P<0.0001). We conclude PJP infection is rare after HSCT but is associated with high mortality. Factors associated with GVHD and with poor immune reconstitution are among the risk factors for PJP and suggest that protracted prophylaxis for PJP in high-risk HSCT recipients may improve outcomes.

Risk factors and impact of non-Aspergillus mold infections following allogeneic HCT: a CIBMTR infection and immune reconstitution analysis.

Risk factors for non-Aspergillus mold infection (NAMI) and the impact on transplant outcome are poorly assessed in the current era of antifungal agents. Outcomes of 124 patients receiving allogeneic hematopoietic cell transplantation (HCT) diagnosed with either mucormycosis (n=72) or fusariosis (n=52) between days 0 and 365 after HCT are described and compared with a control cohort (n=11 856). Patients with NAMI had more advanced disease (mucormycois: 25%, fusariosis: 23% and controls: 18%; P=0.004) and were more likely to have a Karnofsky performance status (KPS) <90% at HCT (mucormycosis: 42%, fusariosis: 38% and controls: 28%; P=0.048). The 1-year survival after HCT was 22% (15-29%) for cases and was significantly inferior compared with controls (65% (64-65%); P<0.001). Survival from infection was similarly dismal regardless of mucormycosis: 15% (8-25%) and fusariosis: 21% (11-33%). In multivariable analysis, NAMI was associated with a sixfold higher risk of death (P<0.0001) regardless of the site or timing of infection. Risk factors for mucormycosis include preceding acute GvHD, prior Aspergillus infection and older age. For fusariosis, increased risks including receipt of cord blood, prior CMV infection and transplant before May 2002. In conclusion, NAMI occurs infrequently, is associated with high mortality and appears with similar frequency in the current antifungal era.

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.

Alternative donors extend transplantation for patients with lymphoma who lack an HLA matched donor.

Alternative donor transplantation is increasingly used for high-risk lymphoma patients. We analyzed 1593 transplant recipients (2000-2010) and compared transplant outcomes in recipients of 8/8 allele HLA-A, -B, -C and DRB1 matched unrelated donors (MUDs; n=1176), 7/8 allele HLA mismatched unrelated donors (MMUDs; n=275) and umbilical cord blood donors (1 or 2 units UCB; n=142). Adjusted 3-year non-relapse mortality of MMUD (44%) was higher as compared with MUD (35%; P=0.004), but similar to UCB recipients (37%; P=0.19), although UCB had lower rates of neutrophil and platelet recovery compared with unrelated donor groups. With a median follow-up of 55 months, 3-year adjusted cumulative incidence of relapse was lower after MMUD compared with MUD (25% vs 33%, P=0.003) but similar between UCB and MUD (30% vs 33%; P=0.48). In multivariate analysis, UCB recipients had lower risks of acute and chronic GVHD compared with adult donor groups (UCB vs MUD: hazard ratio (HR)=0.68, P=0.05; HR=0.35; P<0.001). Adjusted 3-year OS was comparable (43% MUD, 37% MMUD and 41% UCB). These data highlight the observation that patients with lymphoma have acceptable survival after alternative donor transplantation. MMUD and UCB can extend the curative potential of allotransplant to patients who lack suitable HLA matched sibling or MUD.

Clinical guide to fertility preservation in hematopoietic cell transplant recipients.

With broadening indications, more options for hematopoietic cell transplantation (HCT) and improvement in survival, the number of long-term HCT survivors is expected to increase steadily. Infertility is a frequent problem that long-term HCT survivors and their partners face and it can negatively impact on the quality of life. The most optimal time to address fertility issues is before the onset of therapy for the underlying disease; however, fertility preservation should also be addressed before HCT in all children and patients of reproductive age, with referral to a reproductive specialist for patients interested in fertility preservation. In vitro fertilization (IVF) and embryo cryopreservation, oocyte cryopreservation and ovarian tissue banking are acceptable methods for fertility preservation in adult women/pubertal females. Sperm banking is the preferred method for adult men/pubertal males. Frequent barriers to fertility preservation in HCT recipients may include the perception of lack of time to preserve fertility given an urgency to move ahead with transplant, lack of patient-physician discussion because of several factors (for example, time constraints, lack of knowledge), inadequate access to reproductive specialists, and costs and lack of insurance coverage for fertility preservation. There is a need to raise awareness in the medical community about fertility preservation in HCT recipients.

Aztreonam for febrile neutropenia in patients with beta-lactam allergy.

BACKGROUND: Beta-lactam antibiotics are the mainstay of empiric therapy for febrile neutropenia. Aztreonam may benefit certain patients because of a lack of cross-hypersensitivity to penicillins and cephalosporins. This is the first study, to our knowledge, to evaluate the efficacy of aztreonam as monotherapy for febrile neutropenia (FN). METHODS: Our study was a single-center retrospective chart review of patients ≥18 years of age receiving aztreonam for the treatment of FN. Primary outcome was treatment success of aztreonam monotherapy. Secondary analyses included need for modification to antimicrobial therapy, patients transitioned to aztreonam from another empiric regimen, and patients receiving aztreonam in combination with other antibacterial agents. RESULTS: In patients prescribed aztreonam for first fever, 11 of 27 (40.7%) patients who received aztreonam alone and 19 of 40 (47.5%) given aztreonam plus another antibiotic responded within 96 h (P = 0.62). Twenty-four (89%) patients prescribed aztreonam monotherapy were alive when FN resolved or treatment ended. Infectious mortality was low (1 patient, 3.7%). In patients prescribed aztreonam monotherapy following an adverse reaction to cefepime, 6 of 11 (54.5%) responded within 96 h of initiating aztreonam; 10 (91%) were alive when FN resolved or treatment ended. CONCLUSION: Aztreonam monotherapy may be acceptable for use in patients with a history of beta-lactam hypersensitivity or following an adverse reaction with another beta-lactam. Further studies are needed to compare efficacy of aztreonam monotherapy with other therapies for the treatment of FN.

Continuous infusion cyclophosphamide and low-dose total body irradiation is a safe and effective conditioning regimen for autologous transplant in multiple myeloma.

We present the results of a novel conditioning regimen in multiple myeloma (MM) patients undergoing tandem autologous stem cell transplant (ASCT). MM patients were enrolled in a prospective phase II clinical trial. After initial ASCT, disease response was assessed by day +100. Patients achieving very good partial remission (VGPR) were offered maintenance therapy. If patients achieved VGPR, they were offered a second ASCT using continuous intravenous cyclophosphamide (CICy) 6 g/m(2) over 4 days and low-dose total body irradiation (ldTBI) 600 rads over 2 days. Total body irradiation was replaced by melphalan 140 mg/m(2) if patients had received prior radiation. Twenty-one patients received tandem ASCT. Three patients received CICy and melphalan. Median duration of neutropenia with CICy/ldTBI was 11 days. Fifteen patients (71.4%) developed febrile neutropenia while grade 1 to 2 diarrhea was the next most common adverse event (42.9%). There was no treatment-related mortality. Four patients had entered complete remission (19%) and 6 achieved VGPR (28.6%). In conclusion, this conditioning regimen is safe and effective and may be useful in patients who do not benefit from first ASCT using more traditional conditioning regimen.

Physician perceptions and practice patterns regarding fertility preservation in hematopoietic cell transplant recipients.

Physician practice variation may be a barrier to informing hematopoietic cell transplant (HCT) recipients about fertility preservation (FP) options. We surveyed HCT physicians in the United States to evaluate FP knowledge, practices, perceptions and barriers. Of the 1035 physicians invited, 185 completed a 29-item web-survey. Most respondents demonstrated knowledge of FP issues and discussed and felt comfortable discussing FP. However, only 55% referred patients to an infertility specialist. Most did not provide educational materials to patients and only 35% felt that available materials were relevant for HCT. Notable barriers to discussing FP included perception that patients were too ill to delay transplant (63%), patients were already infertile from prior therapy (92%) and time constraints (41%). Pediatric HCT physicians and physicians with access to an infertility specialist were more likely to discuss FP and to discuss FP even when prognosis was poor. On analyses that considered physician demographics, knowledge and perceptions as predictors of referral for FP, access to an infertility specialist and belief that patients were interested in FP were observed to be significant. We highlight variation in HCT physician perceptions and practices regarding FP. Physicians are generally interested in discussing fertility issues with their patients but lack educational materials.

Umbilical cord blood graft enhancement strategies: has the time come to move these into the clinic?

Umbilical cord blood (UCB) is an attractive stem cell graft option for patients who need allogeneic hematopoietic stem cell support, but lack a suitable HLA-matched donor. However, the limited number of hematopoietic progenitor cells in a single cord blood unit can lead to an increased risk of graft failure, delayed hematological recovery and prolonged immunosuppression, particularly in adult patients. Several strategies to overcome these potential limitations are being evaluated. In this review, we discuss promising ex vivo manipulations to enhance cord blood engraftment capacity such as culture of UCB cells with stimulatory cytokines and growth factors, mesenchymal cells, Notch ligand, copper chelators, prostaglandins, complement components, nicotinamide and CD26/DPPIV inhibitors. All these approaches are now in early clinical trials. However, despite the fact that several cord blood enhancement strategies have resulted in increased numbers of progenitor cells and faster neutrophil recovery, the ability of these techniques to significantly shorten engraftment time and permit the use of cord units with low numbers of total nucleated cells, or accomplish reliable engraftment with a single cord, have yet to be convincingly demonstrated. The ultimate clinical value of ex vivo cord blood expansion or manipulation has not been defined yet, and the current data do not permit predicting which technology will prove to be the optimal strategy. Nevertheless, expectations remain high that eventually ex vivo enhancement will be able to improve clinical outcomes and significantly extend the applicability of UCB transplantation.

Second malignancies after autologous hematopoietic cell transplantation in children.

Childhood autologous hematopoietic cell transplant (auto-HCT) survivors can be at risk for secondary malignant neoplasms (SMNs). We assembled a cohort of 1487 pediatric auto-HCT recipients to investigate the incidence and risk factors for SMNs. Primary diagnoses included neuroblastoma (39%), lymphoma (26%), sarcoma (18%), central nervous system tumors (14%) and Wilms tumor (2%). Median follow-up was 8 years (range, <1-21 years). SMNs were reported in 35 patients (AML/myelodysplastic syndrome (MDS)=13, solid cancers=20, subtype missing=2). The overall cumulative incidence of SMNs at 10 years from auto-HCT was 2.60% (AML/MDS=1.06%, solid tumors=1.30%). We found no association between SMNs risk and age, gender, diagnosis, disease status, time since diagnosis or use of TBI or etoposide as part of conditioning. OS at 5-years from diagnosis of SMNs was 33% (95% confidence interval (CI), 16-52%). When compared with age- and gender-matched general population, auto-HCT recipients had 24 times higher risks of developing SMNs (95% CI, 16.0-33.0). Notable SMN sites included bone (N=5 SMNs, observed (O)/expected (E)=81), thyroid (N=5, O/E=53), breast (N=2, O/E=93), soft tissue (N=2, O/E=34), AML (N=6, O/E=266) and MDS (N=7, O/E=6603). Risks of SMNs increased with longer follow-up from auto-HCT. Pediatric auto-HCT recipients are at considerably increased risk for SMNs and need life-long surveillance for SMNs.

Extramedullary disease in plasma cell myeloma: the iceberg phenomenon.

Extramedullary (EM) plasmacytomas (EMPs) that are not progression of intramedullary (IM) plasma cell myeloma (PCM) are usually indolent. In contrast, EM spread of IM PCM is associated with a poor prognosis. The recently introduced Durie-Salmon PLUS staging system includes EM disease in the poor prognosis category. One study noted an increase in EM disease both at diagnosis and during follow-up of PCM in 2000-2007 compared with previous years raising concerns that adoption of novel agents (thalidomide, lenalidomide and bortezomib) and greater use of hematopoietic cell transplantation (HCT) might be contributory to this. It is uncertain if this is a true increase or merely greater detection due to the increasing use of more sensitive imaging techniques (computerized tomography, magnetic resonance imaging and ¹8F-fluorodeoxyglucose positron emission tomography) or a reflection of the evolving natural history of PCM in an era when patients are living longer (median overall survival before 1996 was 29.9 months vs 44.8 months after 1996). Recent studies suggest there are important biological differences between PCM with or without EM spread that are offering clues that might explain the propensity for dissemination and a more aggressive clinical course. For example, EM relapse in PCM with and without deletion 13 was 30.8 vs 5.6%, suggesting the biology of a plasma cell subclone before HCT can affect the nature of the relapse after HCT. This article will explore the clinical, biological and treatment implications of EM spread of PCM. In addition, the impact of extramedullary disease on the outcomes of autologous and allogeneic HCT for PCM will be analyzed. Allogeneic HCT early in the course of high-risk PCM with EM disease is a consideration since graft vs myeloma effects may be essential to achieve maximal survival benefits.

No increased mortality from donor or recipient hepatitis B- and/or hepatitis C-positive serostatus after related-donor allogeneic hematopoietic cell transplantation.

Limited data exist on allogeneic transplant outcomes in recipients receiving hematopoietic cells from donors with prior or current hepatitis B (HBV) or C virus (HCV) infection (seropositive donors), or for recipients with prior or current HBV or HCV infection (seropositive recipients). Transplant outcomes are reported for 416 recipients from 121 centers, who received a human leukocyte antigen-identical related-donor allogeneic transplant for hematologic malignancies between 1995 and 2003. Of these, 33 seronegative recipients received grafts from seropositive donors and 128 recipients were seropositive. The remaining 256 patients served as controls. With comparable median follow-up (cases, 5.9 years; controls, 6.7 years), the incidence of treatment-related mortality, survival, graft-versus-host disease, and hepatic toxicity, appears similar in all cohorts. The frequencies of hepatic toxicities as well as causes of death between cases and controls were similar. Prior exposure to HBV or HCV in either the donor or the recipient should not be considered an absolute contraindication to transplant.

Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation.

Advances in hematopoietic cell transplantation (HCT) technology and supportive care techniques have led to improvements in long-term survival after HCT. Emerging indications for transplantation, introduction of newer graft sources (eg, umbilical cord blood) and transplantation of older patients using less intense conditioning regimens have also contributed to an increase in the number of HCT survivors. These survivors are at risk for developing late complications secondary to pre-, peri-, and posttransplant exposures and risk factors. Guidelines for screening and preventive practices for HCT survivors were published in 2006. An international group of transplantation experts was convened in 2011 to review contemporary literature and update the recommendations while considering the changing practice of transplantation and international applicability of these guidelines. This review provides the updated recommendations for screening and preventive practices for pediatric and adult survivors of autologous and allogeneic HCT.

Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation.

Advances in hematopoietic cell transplantation (HCT) technology and supportive care techniques have led to improvements in long-term survival after HCT. Emerging indications for transplantation, introduction of newer graft sources (for example, umbilical cord blood) and transplantation of older patients using less intense conditioning regimens have also contributed to an increase in the number of HCT survivors. These survivors are at risk for developing late complications secondary to pre-, peri- and post-transplant exposures and risk factors. Guidelines for screening and preventive practices for HCT survivors were published in 2006. An international group of transplant experts was convened in 2011 to review contemporary literature and update the recommendations while considering the changing practice of transplantation and international applicability of these guidelines. This report provides the updated recommendations for screening and preventive practices for pediatric and adult survivors of autologous and allogeneic HCT.

Reduced-intensity conditioning using fludarabine with either antithymocyte globulin and BU, or low-dose TBI allowing allogeneic hematopoietic SCT.

In a single-center study, we analyzed the outcomes of 66 patients with advanced hematological malignancies receiving two reduced-intensity conditioning regimens for allogeneic transplantation: fludarabine and low-dose TBI (flu/TBI, n=25), or fludarabine, antithymocyte globulin and BU (flu/ATG/BU, n=41). The selection criteria were based on the hypothesis that flu/TBI patients were expected to achieve autologous recovery in the event of non-engraftment. Sixty-three patients (95%) engrafted. Regimen-related mortality at day 100 and 1 year was 6 and 15%, respectively. With median follow-up of 50.4 months, survival did not differ by regimen. Multivariate analysis confirmed that the type of regimen did not affect relapse. In patients achieving full donor chimerism by day 30, those conditioned with flu/TBI showed greater overall survival (P=0.02). Engraftment failure occurred in two patients (3%), both of whom received flu/TBI. We conclude that conditioning with flu/TBI or flu/ATG/BU yields comparable survival and remission outcomes. By contrast to our hypothesis, patients receiving flu/TBI who subsequently failed engraftment did not achieve autologous recovery. Yet, rapid attainment of full donor chimerism after flu/TBI is associated with greater survival than after flu/ATG/BU. Further, larger prospective randomized studies are required to define the advantage of one regimen over the other.