Latest developments in blood and marrow transplantation

The first morning session started with highlights from the 2013 American Society of Hematology (ASH) Meeting.

Umbilical cord blood transplant in infant leukaemia was found to be a suitable option for infants with acute leukaemia in remission. Transplant-related mortality is higher for infants with acute lymphoblastic leukaemia compared with acute myeloid leukaemia. Patients with AML had a better prognosis than those with ALL, which is in contrast to what is seen in older paediatric patients.

Calcineurin inhibitor-free graft-versus-host disease (GvHD) prophylaxis achieves consistent donor engraftment, low rates of infectious complications and low incidence of chronic GvHD (cGvHD), rapid withdrawal of immunosuppression and low rate of relapse. A post-transplant cyclophosphamide combined with sirolimus prophylactic regimen is a safe and effective alternative to standard treatment.

The use of bortezomib with prednisone in cGvHD was feasible and well tolerated as first-line cGvHD therapy. A high overall response rate after 15 weeks of therapy, most notably in skin and liver, was observed. One year after the end of therapy, 25% of patients were off prednisone, 10% on low-dose prednisone and 50% required additional therapy for cGvHD.

The use of defibrotide for treatment of veno-occlusive disease (VOD) in HSCT patients improves outcomes. The early initiation of defibrotide is important once VOD is suspected. Defibrotide is well tolerated with markedly lower rates of GvHD than expected.

Advanced age does not appear to prohibit haploidentical haematopoietic stem cell transplantation (HSCT) in older patients. There was no apparent worsening in overall outcomes in older patients compared to those aged 50 years and older. Haploidentical HSCT may be an attractive option.

A first study in HSCT to identify relationship between cumulative days of voriconazole exposure and development of cutaneous squamous cell carcinoma showed that no real causality could be established so far. Further studies

are necessary.

Clofarabine, bendamustine and gemcitabine are discussed. Clofarabine was evaluated in myeloablative, reduced intensity and non-myeloablative regimens in paediatric and adult patients. Toxicity data revealed reversible transaminitis, unexpected renal toxicity, and rare capillary leak syndrome. Favourable results compared with historical fludarabine-based controls were obtained in terms of efficacy.

Bendamustine has been included in regimens for auto- and allo-HSCT (lymphoid malignancies and myeloma). There was minimal non-hematologic toxicity and low transplant related mortality and bendamustine had favourable outcomes.

The gemcitabine–busulfan–melphalan combination may provide improved outcomes in Hodgkin lymphoma patients. Dose-limiting toxicity was mucositis and there were increased rates of toxicity compared to Bu Mel, but mostly reversible. Common toxicities observed were skin-toxicities and transaminitis.

Other emerging agents are ibritumomab tiuxetan (radioimmunoconjugate targeting CD20), ofatumumab (fully human monoclonal antibody targeting CD20), vorinostat (histone deacetylase inhibitor), azacitidine (hypomethylating agent), brentuximab vedotin (antibody drug conjugate targeting CD30).

Economic, clinical and humanistic outcomes – the so-called ‘ECHO’ model – is discussed. Pharmacist responsibilities in different centres include daily rounding chemotherapy order, writing/review, admission counselling, initial chemotherapy notes, PK and TDM. For the outpatient clinic, duties include: the assessment of all patients prior to chemotherapy (for example, reviewing laboratory results, medication reconciliation), compounding check, committee participation, education of pharmacy students and residents, and providing patient education materials.

Challenges are the expanding role of pharmacy services in outpatient bone marrow transplantation (BMT), defining value and quality in pharmacy initiatives and services and documenting and evaluating interventions. Future directions are focused on establishing a pharmacy oral chemotherapy clinic and survey providers to determine the humanistic value of the pharmacist.

The conclusion of this session was that there are many opportunities to examine and define the impact and contributions pharmacists make to patients’ care in the BMT setting, no matter the size or complexity of the institution.

The unique medical and psychosocial issues and the differences in outcome of stem cell transplantation in adolescents and young adults (AYA) compared with children were the subject of a presentation. AYA Oncology Recommendations to improve outcomes are:

The latest issues on infectious diseases show that there are few new antibiotics (ceftobiprole, ceftolozane/tazobactam, tedizolid phosphate), especially for gram-negative micro-organisms. The emergence of echinocandin resistance in Candida glabrata and the issues on combination therapy for invasive aspergillosis were discussed.

The second day started with a presentation summarising that immune reconstitution after HSCT in HIV-positive patients is similar to non-HIV patients for autologous HSCT and appears satisfactory for allogeneic HSCT; however, opportunistic infections may be more common, mandating careful post-HSCT surveillance.

Minimal residual disease (MRD) after stem cell transplantation is now routinely performed in the setting of haematologic malignancies. MRD presence can predict disease recurrence in some but not all instances. Although frequently done, the impact of early intervention based on MRD assessment is only effective in CML. Both patients and physicians should be encouraged to participate in clinical trials.

ATG dosing and controversies were discussed. The use of ATG in HSCT preparative regimens should be individualised based on stem cell source, preparative regimen intensity, primary disease, ATG preparation, dose and schedule. Horse ATG is the preferred ATG preparation for immunosuppressive therapy in aplastic anaemia. Changing ATG formulations from horse to rabbit should not be used as a strategy to manage positive skin tests.

Best practice for outpatient conditioning for autologous and allogeneic HCT was discussed. The aim of the presentation was to review elements of an outpatient HSCT conditioning regimen and discuss patient attributes associated with success when using these regimens. In addition, the speakers compared and contrasted the elements of supportive care and immune suppression between centres that perform outpatient HSCT conditioning. They concluded that outpatient HSCT can work in very different settings and volumes. The success relies on multidisciplinary collaboration. Furthermore, there are continuing challenges with the ever-changing reimbursement landscapes.

Significant drug interactions in HSCT involve interactions with busulfan, cyclophosphamide, etoposide, antifungals, immunosuppressives and antibiotics. Checking the patient’s medication profile every day is advised, alongside close monitoring of drug levels when interacting medication is started or stopped. Pharmacists should assess for adverse effects when interacting medication is started or stopped. Empirically, dosage regimens should be altered when applicable, or should be switched to alternative therapy when concomitant administration is contraindicated.

A session devoted to present and future trends in immunosuppression covered principles of immunosuppression and historic and current standards of care for GvHD prophylaxis and therapy in the setting of allogeneic stem cell transplantation. Risks of adverse outcomes owing to GvHD after allogeneic transplantation, as well as the risks and side effects of commonly used immunosuppressive medications,

were identified.

The Pharmacists’ meeting was of great value and its attendance is strongly advised for every pharmacist involved in stem cell transplantation. The 2015 meeting will be in San Diego, California.

Busulfan has been effectively used for HSCT and its safety and efficacy appears to be influenced by pharmacokinetic (PK) parameters of the patient. Intravenous busulfan reduces PK variability and improved outcomes have been linked with precise targeting of busulfan systemic exposure with PK-based dose adjustment. It was concluded that busulfan-based conditioning regimens may be implemented in institutions where the ability to perform in-house pharmacokinetics is not present.

Collection 35–40 hours post-last dose of Plerixafor was superior/comparable to the traditional 11–14 hour window. However, additional studies are needed to determine the effects of plerixafor on CD34+ cells beyond the 11–14 hour period.

The aim of this study was to determine if genotype-directed initial voriconazole dosing would result in decreased time to reach desired target range. In addition, the incidence of adverse effects increasing as a result of higher initial dosing was studied. It was concluded that CYP450-2C19 genotype directed initial dosing and subsequent dose adjustments per the algorithm could successfully achieve prophylactic voriconazole target levels in paediatric patients undergoing HSCT. Despite higher initial dosing and a more aggressive dose adjustment protocol, voriconazole was well tolerated with a minimal side-effect profile. Genotype-directed dosing in HSCT and establishment of a centre-specific protocol are recommended.

A model was developed and validated, describing active Thymoglobulin® pharmacokinetics, yielding accurate predictions. Weight and baseline lymphocytes were defined as important factors influencing the pharmacokinetics. Current dosing regimen results in increasing exposure with higher weight. This is the first step in developing an individualised dosing regimen and dosing regimens will be evaluated in a prospective clinical trial.