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Updates from the 2014 American Society for Blood and Marrow Transplantation Tandem Meeting

Alex Shillingburg, PharmD
Clinical Specialist BMT/ Hematologic Malignancy
WVU Healthcare, Morgantown, WV

Susanne E. Liewer, PharmD BCOP
Clinical Pharmacy Coordinator, Blood & Marrow Transplant Service
Nebraska Medical Center
Clinical Assistant Professor
University of Nebraska Medical Center College of Pharmacy
Omaha, NE

Practitioners of all hematologic malignancy and bone marrow transplant disciplines convened for the 2014 American Society for Blood and Marrow Transplant (ASBMT) Tandem Meeting in Grapevine, TX, at the end of February. A myriad of concurrent meetings and workshops, including the primary scientific program, Foundation for the Accreditation of Cellular Therapy (FACT) accreditation workshop, and Fundamentals of Hematopoietic Stem Cell Transplantation course by the National Marrow Donor Program (NMDP), were held to address several unique subgroups, such as clinical trial network (CTN) coordinators and investigators, data managers, information technology (IT) professionals, pediatric transplant, pharmacists, nurses, and center administrators. The following are highlights from the pharmacists’ portion of the meeting.

Update on the ASBMT Pharmacy Special Interest Group

Since its initiation in 2012, the Pharmacy special interest group (SIG) of ASBMT has played a major role in creating several new educational sessions at both the HOPA and ASBMT annual conferences. The boot camp course offered at the 2013 HOPA Annual Conference was met with great success with 77 registered participants. Of the boot camp attendees, 80% indicated that this conference provided information that would improve their clinical practice. The success of the fundamentals course offered in 2013 at the ASBMT annual meeting supported the continuation and expansion of this course at the 2014 meeting. The Pharmacy SIG also published a peer-reviewed article on pharmacist and physician collaborative practice agreements in the Biology of Blood and Marrow Transplantation journal. The other major achievement of the SIG was the inclusion of pharmacists in the FACT Accreditation Standards. Current initiatives include regularly publishing the Pharmacy SIG newsletter, increasing membership, establishing a Web page, and promoting pharmacy research and advocacy.

Best Pharmacy Abstracts

Four abstracts authors were selected to give an oral presentation of their research, with the best abstract selected later in the conference. Ashley Teusink, PharmD, Cincinnati Children’s Hospital Medical Center, presented “Pharmacogenetic-Directed Dosing Leads to Optimized Voriconazole Levels in Pediatric Patients Receiving Hematopoietic Stem Cell Transplants,” which was awarded best pharmacy abstract. Investigators evaluated 20 patients according to their CYP450-2C19 genotype and dosed their voriconazole using an algorithm designed to target those polymorphisms. Results indicated a statistically significant improvement in the time to reach target levels (8 days versus 30 days, p <.001). “Intravenous (IV) Busulfan (BU) Pharmacokinetics Using Busulfan and Fludarabine (Flu) Conditioning in Institutions Where the Capability of Doing Pharmacokinetics Is Not Present,” “Efficacy of Late Hematopoietic Stem Cell Mobilization 35–40 Hours After Administration of Plerixafor,” and “Population Pharmacokinetic Modeling of Thymoglobulin in Children Receiving Allogeneic Hematopoietic Cell Transplantation (HCT): Towards Individualized Dosing to Improve Survival” were the other abstracts presented at the meeting.

Highlights in Infectious Disease

During the past several years, it has been commonplace for new oncology agents to come to market; however, our infectious disease colleagues have not enjoyed a similar benefit with antifective agents. A few noteworthy agents that entered development this past year were discussed during the Highlights in Infectious Disease session. Ceftolozane/tazobactam is a novel, antipseudomonal cephalosporin and a well-established b-lactamase inhibitor in development for the treatment of complicated urinary tract infection, intraabdominal infections, and ventilator-associated pneumonia. Ceftolozane/tazobactam has activity against E. coli, K. pneumoniae, and Pseudomonas aeruginosa, including strains resistant to carbapenems, piperacillin/tazobactam, and other cephalosporins, as well as strains that are multidrug resistant. Tedizolid phosphate is an oral and intravenous agent related to linezolid that is being investigated in phase 3 trials for methicillin-resistant Staphylococcus aureus infections, and it likely results in much less myelosuppresion. Clinical and Laboratory Standards Institute breakpoints for echinocandins have changed during the past year to better detect known resistance mechanisms. New breakpoints have markedly lower minimum inhibitory concentrations and are no longer uniform over the class but do differ based on the specific agent. Susceptible break points for albicans, tropicalis, and krusei are now <0.25 (rather than<2), and susceptibility for glabrata is now <0.12 for anidulafungin and caspofungin and <0.06 for micafungin. This session concluded with the presentation of studies showing improved outcomes with combination therapy for invasive aspergillosis with voriconazole and an echinocandin.

Emerging Drugs for Hematopoietic Stem Cell Transplantation Conditioning

Several exciting studies utilizing newer agents in stem cell transplant conditioning regimens were presented. The three drugs that were highlighted were clofarabine, bendamustine, and gemcitabine. Clofarabine can be advantageous in this setting because of its improved stability, increased intracellular retention, direct induction of apoptosis, synergy with alkylating agents, and increased potency and less neurotoxicity than fludarabine. Dose-limiting toxicities include hand-foot syndrome, liver function test abnormalities, and rarely capillary leak syndrome. Studies evaluating clofarabine in combination with a busulfan-based regimen showed high activity in high-risk patients and acceptable engraftment rates. Evaluated in combination with melphalan and alemtuzumab as a nonablative regimen, clofarabine showed immunosuppression and efficacy comparable to historical controls, although unexpectedly higher rates of renal failure occurred. Bendamustine has a unique mechanism of action and has shown great efficacy in its treatment of chronic lymphocytic leukemia and non-Hodgkin lymphoma. Studies evaluating bendamustine in combination with fludarabine and rituximab for conditioning of lymphoid malignancies show that it is well-tolerated, has low treatment-related mortality, and may lend itself well to outpatient conditioning or use in older patients as a nonablative preparatory regimen. Dose-limiting toxicities include thrombocytopenias and cardiotoxicity. Evaluation of the BEAM (BCNU, etoposide, Ara-C, melphalan) regimen with bendamustine replacing carmustine showed a very acceptable safety profile with no dose-limiting toxicities and was effective when compared against historical data. Gemcitabine shows a synergy with alkylating agents, increased potency compared with cytarabine, and minimal nonhematologic toxicities. Investigations of gemcitabine with melphalan and busulfan showed a maximal tolerated dose of gemcitabine of 2,775mg/m2/dose for two doses. Mucositis was the only dose-limiting toxicity, and rash and LFT elevation were common. Favorable results were shown in lymphoma patients compared with historical data. Most of the studies presented were single-arm studies compared with historical data with further phase 3 studies ongoing.

Stem Cell Transplant in HIV-Positive Patients

Patients infected with human immunodeficiency virus (HIV) have a higher incidence of cancer for both AIDS-defining and non-AIDS- defining malignancies. Prior to combination antiretroviral therapies (cARTs), HIV-positive patients diagnosed with lymphoma had poor outcomes including higher rates of relapse, increased opportunistic infections, and decreased overall survival. The incorporation of cART into HIV therapies has had a dramatic effect on outcomes. Patients diagnosed with lymphoma are now better able to tolerate standard chemotherapy, and their outcomes are similar to those of lymphoma patients who are HIV negative. Similarly, stem cell transplant has curative potential for many patients diagnosed with hematologic malignancies, but prior to cART, many HIV patients had poor outcomes associated with high-dose chemotherapy and transplant. With improved supportive care and cART, outcomes such as overall survival for HIV-positive patients postautologous stem cell transplant are similar to those of patients who are HIV negative. Allogeneic stem cell transplant can present greater challenges in the HIV- positive patient population, including chronic immunosuppression, risk of infection, and complex drug interactions between cART and immunosuppressive agents. Currently, there is no evidence that cART adversely affects allogeneic transplant outcomes; however, each patient must be monitored for drug-drug interactions. Initial data in this unique patient population suggest that immune system reconstitution is satisfactory; however, opportunistic infections may be more common and necessitate post-HSCT surveillance. To ensure HIV-positive patients have optimal outcomes, it is essential that there be multidisciplinary management between oncologists, HIV physicians, and pharmacists.

Minimal Residual Disease After Stem Cell Transplantation

Minimal residual disease (MRD) is generally referred to as low levels of disease that are detected by nontraditional methods either during or after chemotherapy. Currently, there are two broad approaches for monitoring MRD that can detect abnormal genetic (polymerase reaction chaing [PCR]) or phenotypic expression (flow cytometry). For some cancers, the presence of MRD is important because it can predict a higher relapse rate after chemotherapy or hematopoietic stem cell transplant. However, the prognostic value of MRD has not been clearly defined for each of the hematologic malignancies. MRD monitoring is well established in patients with chronic myelogenous leukemia (CML). PCR positivity in patients with CML can predict disease progression or relapse. Treatment initiated at the start of relapse has been reported to result in superior response rates and improved survival rates. In both adult and pediatric acute lymphoblastic leukemia (ALL), the monitoring of MRD is well established. In adults, it has been reported that MRD is an independent prognostic feature of disease-free survival (DFS) in nontransplant patients. There are fewer studies evaluating the role of MRD in the setting of allogeneic transplant for ALL patients. MRD that is detected before and after stem cell transplant in patients with ALL has been associated with a poor DFS. Monitoring for MRD in patients with AML can be more challenging. Unlike CML, which has the BCR-ABL mutation in the majority of patients, there are an abundance of cytogenetic and molecular mutations in patients with AML or advanced MDS that make standard surveillance more difficult. Several potential markers for these diseases have been identified and remain under investigation. MRD assessment is now routinely performed in the setting of many hematologic malignancies. Although its presence can predict disease recurrence, it has not been consistently reported in all patient populations. It is important to encourage patient enrollment in clinical trials to gain a better understanding of MRD in patients with hematologic malignancies.

Present and Future Trends in Immunosuppression

Patients undergoing an allogeneic stem cell transplant are at risk for graft-versus-host disease (GVHD) and require immunosuppression to prevent this complication. Many transplant centers rely on a calcineurin inhibitor (cyclosporine or tacrolimus) combined with methotrexate or mycophenolate mofetil (MMF) to prevent GVHD. Despite immunosuppression and improvements in identifying matched donors for recipients, GVHD remains a common complication post stem cell transplant. Novel prophylaxis combinations remain an active area of investigation for prevention of GVHD. The use of sirolimus as prophylaxis for stem cell transplant has several potential advantages including the promotion of T-regulatory cells and antiviral and antineoplastic properties. The Blood and Marrow Transplant Clinical Trials Network published their results of the 0402 trial—a phase 3, randomized, multicenter prophylaxis trial of sirolimus and tacrolimus versus tacrolimus and methotrexate in patients with hematologic malignancies receiving a matched related peripheral blood stem cell transplant. In this trial, substituting sirolimus for methotrexate/MMF did not demonstrate superiority in progression-free survival or overall survival. However, the sirolimus group may have benefited in the incidence of grade II GVHD, but this was at the expense of toxicities such as thrombotic microangiopathy/thrombotic thrombocytopenia purpura and hyperlipidemia. Other novel agents have been investigated as prophylaxes against GVHD. One agent, vorinostat, was combined with tacrolimus/MMF in a phase 2 trial. The authors reported that when vorinostat was combined with standard of care the cumulative incidence of grade II-IV GVHD was reduced by day 100.1 However, before any novel prophylaxis strategy can be incorporated into front- line therapy outside of a clinical trial, the results need to be confirmed by phase 3 prospective randomized trials. GVHD is a common com- plication after transplant and contributes to the morbidity and mortality of allogeneic transplant patients. The standard of care for the initial therapy of GVHD is still methyprednisolone or prednisone. Novel GVHD therapy approaches that selectively inhibit T-cells remain under investigation. Graft manipulations, graft enrichment with regulatory T-cells, and photopheresis have shown promising results. In the past several years, there have been many advances in the understanding of immunology and cellular therapies. Novel approaches to GVHD prophylaxis and treatment are likely to yield more selective immunosuppression and positive outcomes for patients.

The 2014 ASBMT Tandem Meeting in Grapevine, TX, provided practitioners the opportunity to understand the newest advances in the field of stem cell transplant. This meeting provides education and updates for a variety of specialized fields and encourages interdisciplinary learning through its special interest group conferences. More information about the ASBMT Tandem Meeting and the Pharmacy SIG can be found on the ASBMT website at www. asbmt.org.

References

1. Choi SW, DiPersio JF, Braun TM, et al. Targeting histone deacetylases as a new strategy for graft versus host disease prevention. Blood (ASH Annual Meeting Abstracts). 2012;120:740.

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