HOPA Publications Committee
Bonnie Labdi, PharmD RPh, Chair
Ashley Glode, PharmD BCOP, Vice Chair
Geroge Carro, RPh MS BCOP, Board Liaison
Megan Bodge, PharmD
Megan Brafford, PharmD BCOP
Morgan E. Culver, PharmD BCOP
Christine Gegeckas, Rph BCOP
Lindsay Hladnik, PharmD BCOP
Lisa Lohr, PharmD BSPharm BCOP BCPS
Katie Long, PharmD
David Reeves, PharmD BCOP
Lisa Savage, PharmD BCOP BCPS
Alexandra Shillingburg, PharmD
Candice Wenzell, PharmD BCOP
Michael Voznial, PharmD BCOP
March is always an exciting month for HOPA! This March marks HOPA’s 11th Anniversary since our founding in 2004. In addition, our Annual Conference is held later this month. I am looking forward to seeing everyone in Austin, TX, for our 11th Annual Conference. HOPA President- Elect Scott Soefje lives in Austin, and it will be a terrific setting for him to begin his presidential term! I have heard great things about Austin, and I can’t wait to see it for myself.
HOPA was extremely excited to announce in February that 39 members were awarded a HOPA travel grant to attend the Annual Conference this month. We received a record number of applications, and a big thank you goes out to our Membership Committee for overseeing the program and making it successful.
In January the board of directors held a strategic planning meeting. This meeting served as an opportunity to pause and reflect on the progress HOPA has made on its current strategic plan and to identify the goals and objectives HOPA should undertake moving for- ward. Work on finalizing the 2015/2016 HOPA Strategic Plan continues, and goals will be shared with the membership in Austin. After the goals, objectives, and strategies are finalized, the completed document will be announced and posted on the HOPA website. We expect this to happen sometime in May 2015.
In January the House of Representatives reintroduced the Pharmacy and Medically Underserved Areas Enhancement Act (H.R. 592) legislation, and the Senate introduced a companion bill (S. 314) for the first time. On the same day H.R. 592 was introduced, I, along with our health policy advisor, Jeremy Scott, met with the office of newly elected Congressman and pharmacist Buddy Carter (R-GA) in Washington, DC. It was a terrific introductory meeting! We had the opportunity to share information about our organization, our members, our Scope of Practice document and to offer our support for H.R. 592. HOPA will continue to actively participate in the Patient Access to Pharmacists’ Care Coalition (PAPCC) and lend our support until these bills are passed. HOPA will be working to advance our Health Policy Agenda by having a HOPA Hill Day at the end of April. HOPA’s Board of Directors and Health Policy Committee members will travel to Washington, DC, for 2 days of planning meetings and Hill visits. Our aim is for each participant to meet with his or her state’s Senators and district’s representative. For more information on these bills, please visit the Health Policy & Advocacy page on the HOPA website.
New HOPA Central Online Community Is Here
I hope you have had a chance to log in and test out the new HOPA online discussion forum, HOPA Central. Recognizing that the HOPA listserv is one of our most valuable member benefits, we realized that the listserv platform was old, provided limited functionality, and presented numerous challenges for searching the archives. HOPA Central is a much needed upgrade providing the functionality we have all come to expect but in a more user friendly interface along with better search capabilities. The Resource Library also al- lows for larger document uploads. Please help us keep a high standard of professional dialogue by reviewing the Code of Conduct and refraining from posting surveys, position announcements, and educational events.
A Goodbye and a Hello
In January we formally said goodbye to Mary Beth Benner. Mary Beth had served as HOPA Director of Operations since 2010, when HOPA became a client of Association Management Center (AMC). Mary Beth remains with AMC, however she will be focusing her efforts on another association. I had the privilege of working with Mary Beth on the Standards Committee and as a board member. Behind the scenes, I credit Mary Beth for transforming HOPA’s policy and procedures into living and breathing documents and, even more importantly, for helping identify the policies and procedures we needed. Mary Beth is engaging, insightful, helpful, and professional in everything she does. HOPA owes Mary Beth a big thank you for moving our organization forward. Thank you Mary Beth, and we wish you the best!
Kris Cichowski assumed the role of HOPA’s Director of Operations in January. Kris most recently was the executive director of the Re- habilitation Institute of Chicago (RIC) Women’s Board and Associate Board. Kris has deep experience in customer service as well as outcomes management having designed and implemented a corporate-wide knowledge management system to access customer satisfaction and functional outcomes. Welcome, Kris! We look forward to working with you.
The Final Lap
In distance-running races, a bell is sometimes rung to signify the last lap of the race. Runners will quicken their pace leading up to an all- out sprint for the finish line. As your HOPA President, I feel the bell is about to be rung. I have found myself going through countless emails to determine what I still need to complete or if I may have missed something I should have already done. While I am looking forward to the Annual Conference at the end of the month, it also signifies passing the presidential responsibilities over to HOPA President-Elect Scott Soefje. It truly has been a privilege and an honor to serve HOPA this past year. As with all presidents before me, we all hope to leave HOPA in a better place than when we started. I feel confident our association is in a better place, and the credit truly goes to the dedicated board of directors who volunteer countless hours and the HOPA staff who help make our vision a reality. Finally I want to thank the HOPA membership for all the sup- port, dedication, time, and effort they give. HOPA is successful because of its tremendous membership!
See you in Austin!
Posttransplant Cyclophosphamide: A Unique Approach for Prevention of Graft-Versus-Host Disease in Allogeneic Hematopoietic Stem Cell Transplantation
Ashley Glode, PharmD BCOP Assistant Professor
University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences
Oncology Clinical Pharmacist
University of Colorado Anschutz Medical Campus
The number of allogeneic hematopoietic stem cell transplants (HSCT) in the United States has steadily increased since the 1990s.1 Allogeneic HSCT is a potentially curative treatment option for various malignant and nonmalignant hematologic conditions. Transplant has expanded as a treatment option for patients because of advancements in conditioning approaches and stem cell sources as well as graft versus-host-disease (GVHD) prevention strategies. Despite these improvements, GVHD remains a major source of posttransplant morbidity and mortality. Specific improvements in GVHD prophylaxis have positively affected acute GVHD, but incidence rates remain in the 20%–60% range.2 Few improvements have been made on the incidence and severity of chronic GVHD, which is reported to occur in up to 80% of patients alive more than 100 days posttransplant. Chronic GVHD is a multisystem disease that can affect a wide variety of tissues. It may involve inflammation and fibrosis of the eyes, oral mucosa, skin, fascia, lungs, liver, gastrointestinal tract, joints, salivary glands, and genitourinary tract. Given all the organ systems potentially involved, it can have a major impact on quality of life. Chronic GVHD management continues to be a significant health-related problem in HSCT survivors because of the increased use of mobilized peripheral blood stem cells as a donor source, which has been associated with higher rates of chronic GVHD compared with bone marrow.2
Calcinuerin inhibitors (CNIs), such as tacrolimus or cyclosporine, combined with methotrexate (MTX) have been employed as GVHD prophylaxis for the past several decades and continue to be the most commonly utilized regimens by transplant centers in the United States. This strategy has resulted in satisfactory prevention rates and survival outcomes but is associated with treatment-related toxicity. Common side effects include nephrotoxicity, hypertension, neurotoxicity, and metabolic abnormalities. Improvements on standard CNI-based regimens for GVHD prophylaxis are needed to decrease GVHD rates and provide alternatives with a better side effect profile.2
The Science Behind Posttransplant Cyclophosphamide
Cyclophosphamide (Cy) has been used for decades as a treatment for several malignancies and is tolerated in a wide range of dosages. It is broken down by the cytochrome P450 system into two metabolites: phosphoramide mustard (the active metabolite) and acrolein. Cy prevents cell growth by crosslinking DNA strands. It is effective throughout the cell cycle but is most effective during the G1 and S phases. Cells rapidly undergoing mitosis are uniquely sensitive to Cy’s mechanism of action because of their reduced ability to replicate the damaged DNA. Aldehyde dehydrogenase is an enzyme required for conversion of phosphoramide mustard to an inactive metabolite, carboxycyclophosphamide. Hematopoietic stem cells possess this enzyme and are therefore resistant to Cy, allowing it to be used after HSCT without impairing engraftment.3
Immune reactions of donor T cells against contrasting host histocompatibility antigens lead to the development of GVHD after allogeneic HSCT. CNI-based GVHD prophylactic strategies weaken alloreactive T cell activation, proliferation, and interleukin-2 (IL-2) production and hinder the apoptosis of alloreactive T cells. The results of these actions cause widespread immunosuppression and delayed induction of transplant tolerance. Of the immunosuppressive agents currently employed, MTX and Cy can induce apoptosis of alloantigen-activated human T cells. Doses of MTX needed for the elimination of alloactivated T cells and tolerance induction cannot safely be given. Fortunately, Cy can be administered in the high doses required for the eradication of alloactivated T cells after allogeneic HSCT.4
Regulatory T cells (Tregs) also play an important role in the establishment of tolerance between the transplant recipient and donor-derived immunity. In animal studies, depletion of Tregs from the stem cell graft resulted in increased GVHD, and an increase in Tregs resulted in GVHD suppression posttransplant. When GVHD occurs in humans, Tregs are at a lower frequency than in patients without GVHD. It is thought that reconstitution of Tregs after HSCT is required to establish a well-balanced immune system that can maintain appropriate levels of tolerance between the transplant recipient and the donor-derived immunity. Studies show that CNIs have negative effects on Treg reconstitution, while mycophenolate mofetil (MMF) and sirolimus may promote posttransplant Treg recovery, making Cy used with either agent an at- tractive GVHD prophylaxis strategy.2
A three-step mechanism to explain the stimulation of early tolerance by posttransplant Cy has been postulated by scientists. In the first step, early proliferating alloreactive donor and recipient T cells are selectively destroyed by the administration of Cy. In the second step, the in-creased Tregs counterbalance the effect of any remaining alloreactive mechanisms. In the final step, the delayed but long-lasting intrathymic clonal removal of antihost T cells maintains long- term tolerance.3
Animal experiments also have shown that the timing of Cy administration is very important.
In mice, administering Cy before or on the same day as the stem cell infusion resulted in sup- pressed antibody production but not the development of tolerance. The optimal time to administer Cy was identified as between graft administration and day +4 post-HSCT as evidenced by maximal effect in improving graft survival. The significance of timing has been carried over into clinical trials.3 When patients do not receive immunosuppression for several days after graft infusion, they are at risk for “engraftment syndrome,” especially with increases in human leukocyte antigen (HLA) mismatch. This may present as pulmonary edema, with or without fever, fluid retention, and renal failure.4 It is important to closely monitor patients during this time.
The culmination of findings from animal experiments has been translated into GVHD prophylactic strategies performed in the setting of haploidentical HSCT in humans. Haploidentical HSCTs are an important option for patients because they expand the donor pool significantly for patients unable to identify a matched related or unrelated donor. An early fundamental trial conducted at Johns Hopkins University treated patients with high-risk hematologic malignancies with T cell– replete haploidentical bone marrow transplants after receiving nonmyeloablative conditioning regimens (fludarabine 30 mg/m2/day on days-6 to -2 and 2 Gray [Gy; a unit of ionizing radiation] total body irradiation [TBI] on day -1). The GVHD prophylactic strategy included Cy 50 mg/ kg on day +3, MMF 15 mg/ kg orally twice daily on days +4 to +35, and tacrolimus adjusted to achieve a therapeutic level of 5–15 ng/mL on day +4 to at least day +50. Two of the three first patients transplanted developed graft rejection; therefore, Cy 14.5 mg/ kg/day was added on days -6 and -5 for the remainder of patients. With this improved regimen, eight of the following 10 patients transplanted achieved sustained engraftment. Among these patients, the median time to neutrophil recovery was 15 days and 14 days for platelets. Of the 13 patients transplanted utilizing posttransplant Cy, 46% developed acute GVHD at a median of 99 days posttransplant, with one patient developing fatal acute GVHD. Chronic GVHD rates were not captured in this trial.5 The results of this study provided supporting evidence for further investigation of posttransplant Cy in haploidentical HSCT.
This method from Johns Hopkins was refined in a subsequent study attempting to identify the optimal dose of Cy to administer posttransplant. Patients with advanced hematologic malignancies (n = 67) or paroxysmal nocturnal hemoglobinuria (n = 1) received T cell–replete haploidentical bone marrow grafts after conditioning with Cy 14.5 mg/ kg/day on days -6 to -5, fludarabine 30 mg/m2/day on days -6 to -2, and 200 cGy of TBI on day -1. For GVHD prophylaxis, patients were administered one (n = 28) or two doses (n = 40) of Cy 50 mg/ kg/day on day +3 or +3 and +4, respectively. In addition to post- transplant Cy, MMF at 15 mg/ kg orally three times per day and tacrolimus adjusted to achieve a therapeutic level of 5–15 ng/mL were both started the day after completion of posttransplant Cy (day +4 or+5). MMF was continued until day +35 and tacrolimus was tapered off by day +180 unless the patient was experiencing active GVHD. Median time to neutrophil recovery was 15 days and 24 days for platelet recovery. Graft failure occurred in 13% of the evaluable patients (9 of 66). All but one of these patients experienced bone marrow recovery with a median time to neutrophil engraftment of 15 days and platelet engraftment of 28 days. For all patients, the cumulative incidence of treatment-related mortality (TRM) was found to be 15% with a re- lapse rate of 51% at 1 year. The 2-year overall survival (OS) was 36% and event-free survival (EFS) was 26%. The development of acute GVHD occurred in 34% of patients at grades 2–4 with 6% of patients at grades 3–4. The only important difference identified between the different Cy dosing groups was a trend toward decreased development of chronic GVHD in the two-dose Cy group (5% versus 25%;HR = 0.21; 95% CI: 0.04–1.01; p = .05).6 For adult patients with high-risk malignancies, this trial proved haploidentical HSCTs as a viable option with fairly low GVHD rates utilizing posttransplant Cy on days +3 and +4. Further investigation is needed.
A larger confirmatory trial conducted by Munchel and colleagues studied 210 patients with advanced hematological malignancies who received nonmyeloablative haploidentical HSCTs with posttransplant Cy as GVHD prophylaxis. Patients received the following preparatory regimen: Cy 14.5 mg/ kg/day on days -6 to -5, fludarabine 30 mg/m2/ day on days -6 to -2, and 2 Gy of TBI on day -1. Grafts were bone marrow product with no manipulation to remove T cells. GVHD pro- phylaxis consisted of Cy 50 mg/ kg/day on days +3 and +4, MMF 15 mg/ kg orally three times per day on days +5 to +35, and tacrolimus targeting 5–15 ng/mL from days +5 to +180. Only 204 of the 210 patients included were evaluable for engraftment data. Thirteen percent of patients failed to engraft but nearly all had autologous reconstitution. The median time to neutrophil recovery was 15 days and 24 days for platelets. Acute GVHD occurred in 27% of patients as grade 2–4 and 5% as grade 3–4. The chronic GVHD incidence was low at 13%. The overall incidence of relapse mortality was 55% and nonrelapse mortality (NRM) was 18%. Patients experienced a 3-year OS of 41% and EFS of 32%. An interesting result was discovered with regard to HLA-antigen disparity among donors and recipients. This trial showed a trend toward improved EFS with increasing disparity with a 20% reduction in the risk of an event (death or relapse) for each increment of HLA mismatch (HR = 0.80; 95% CI: 0.66–0.96; p = .02).7 This larger trial provides additional support for the use of posttransplant Cy to prevent GVHD in haploidentical HSCTs.
The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) conducted two parallel phase 2 clinical trials to study the reproducibility and applicability of the already published results with the goal of generating future phase 3 randomized controlled trials. BMT CTN 0604 evaluated the efficacy of double umbilical cord blood (dUCB) transplantation, while 0603 studied the efficacy of haploidentical bone marrow transplantation after reduced-intensity conditioning. Patients eligible for either trial needed to have advanced or high- risk leukemia or lymphoma. The conditioning regimen for the dUCB transplants included fludarabine 40 mg/m2/day on days -6 to -2, Cy 50 mg/ kg on day -5, and 2 Gy of TBI on day -1. GVHD prophylaxis included MMF given every 8 hours beginning on day -3 until day +30 or 7 days after engraftment (whichever was later) and cyclosporine dosed to achieve trough levels of 200–400 ng/mL until day +100 in the absence of GVHD. Patients undergoing haploidentical HSCTs received fludarabine 30 mg/m2/day on days -6 to -2, Cy 14.5 mg/ kg on days -6 and -5, and 2 Gy of TBI on day -1. GVHD prophylaxis for this regimen included Cy 50 mg/ kg on days + 3 and +4, MMF three times per day on days +5 to +35, and tacrolimus dosed to achieve a target trough level of 5–10 ng/mL with the goal of discontinuation by day+180. Patients undergoing dUCB transplantation had a median time to neutrophil recovery of 15 days and 38 days for platelet recovery. Ten percent of patients experienced primary graft failure. After haploidentical bone marrow transplant, the median time to neutrophil recovery was 16 days and 26 days to platelet recovery. There was only one case (2%) of primary graft failure in this group. Acute GVHD occurred in 40% of patients at grade 2–4 and 21% of patients at grade 3–4 after dUCB transplant. In the haploidentical transplant group, acute GVHD occurred in 32% of patients at grade 2–4 and 0% of patients at grade 3–4. The cumulative incidence of chronic GVHD in dUCB transplant patients was 25% at 1 year and 13% for haploidentical HSCT patients. The 1-year cumulative incidence of NRM was 24% in dUCB transplant patients and relapse/progression of 31%. The 6-month sur- vival for this group was 74% with a 1-year probability of progression- free survival (PFS) of 46% and OS of 54%. For the haploidentical transplant group the 1-year cumulative incidence of NRM was 7% and relapse/progression was 45%. For this group the 6-month survival was determined to be 84% and 1-year probability of PFS was 48% and OS of 62%.8,9 This trial reproduced results similar to those seen in previous clinical trials. The outcomes of these studies are comparable to high- risk patients transplanted with blood or marrow from matched unrelated donors after reduced intensity conditioning, confirming the utility of alternative donor transplants with unique GVHD prevention strategies. This study led to the development of the BMT CTN Trial 1101 to compare dUCB and haploidentical transplants in a larger phase 3 randomized trial that is still ongoing.9
Use of Peripheral Blood Stem Cells as a Donor Source
Recently clinical trials have evaluated the use of peripheral blood stem cells as a graft source instead of bone marrow when utilizing haploidentical HSCTs with posttransplant Cy. The use of peripheral blood stem cells (PBSC) has been linked to a higher incidence of chronic GVHD but a decreased risk of relapse, leading to improved OS and EFS.2 In the study by Solomon and colleagues, patients were deemed to be at high risk for relapse after nonmyeloablative haploidentical HSCT, therefore a myeloablative conditioning regimen was used. Twenty patients with hematologic malignancies were included in the study and received busulfan-based conditioning followed by T cell– replete peripheral blood stem cells from haploidentical donors. The first five patients received fludarabine 30 mg/m2/day on days -7 to -2, IV busulfan 130 mg/m2/day on days -7 to -4, and Cy 14.5 mg/ kg/day on days -3 and -2. This regimen resulted in a notable amount of mucositis requiring dose reductions to the conditioning regimen for the following 15 patients to fludarabine 25 mg/m2/day on days -6 to -2, IV busulfan 110 mg/m2/day on days -7 to -4, and Cy 14.5 mg/ kg/day on days -3 and -2. Posttransplant immunosuppression included Cy 50 mg/ kg/day on days +3 and +4 and, starting on day +5, MMF 15 mg/ kg three times per day, and continued until day +35, and tacrolimus with a goal level of 5–15 ng/mL continued until day +180. All 20 patients on the study experienced donor engraftment with a median time to neutrophil recovery of 16 days and 27 days for platelet recovery. The overall incidence of acute GVHD was 30% for grades 2–4 and 10% for grades 3–4. At a 20-month median follow-up time, the incidence of chronic GVHD was 35% (5% severe). There was 10% NRM at both 100 days and 1 year in this study. The 1-year estimate for OS was 69%, 50% for EFS, and 40% for relapse.10 This study highlights the promising outcomes of utilizing a myeloablative conditioning regimen with PBSC as a donor source.
To further elucidate the impact graft source has on haploidentical HSCT, additional retrospective analyses have been conducted. Ci- urea and colleagues completed a retrospective analysis of 65 consecutive haploidentical HSCTs for patients with hematologic malignancies. Patients received either T cell–replete peripheral blood stem cell transplants (n = 32) or T cell–deplete bone marrow transplants (n= 33), both following the same conditioning regimen. The preparative regimen contained melphalan 140 mg/m2 on day -8, fludarabine 40 mg/m2/day on days -6 to -3, and thiotepa 10 mg/ kg on day -7. For the bone marrow group, GVHD prophylaxis contained rabbit anti-thymocyte globulin (ATG) dosed at 1.5 mg/ kg/day on days -6 to -3. The PBSC group received Cy 50 mg/ kg/day on days +3 and +4, with MMF starting on day +5 to +35 and tacrolimus continuing for at least 4 months posttransplant. For the last 11 patients in the PBSC group, MMF was continued until day +100 as a result of several initial patients developing acute GVHD. Neutrophil engraftment occurred in 94% of the PBSC patients and 81% of the bone marrow patients (p = .10). Within 100 days, the cumulative incidence of acute GVHD grade 2–4 was 20% versus 11% (p = .20) and grade 3–4 5% versus 9% (p = .59) in the T cell–replete arm compared with the T cell–deplete arm, respec- tively. The rate of chronic GVHD was 7% in the T cell–replete arm and 18% in the T cell–deplete arm (p = .03). The 1-year OS rate was 64% versus 30% (p = .02) and PFS rate was 50% versus 21% (p = .02) in the T cell–replete arm compared with the T cell–deplete arm. The 1-year NRM rates were significantly improved in the T cell–replete arm at 16% versus 42% in the deplete arm (p = .02).11
Castagna also conducted a study comparing PBSC (n = 23) and bone marrow (n = 46) donor products for haploidentical HSCT, yet this time both products were T cell replete. Patients underwent a non- myeloablative conditioning regimen including Cy 14.5 mg/ kg/day on days -6 to -5, fludarabine 30 mg/m2/day on days -6 to -2, and 2 Gy of TBI on day -1. The GVHD prophylactic regimen administered was Cy 50 mg/ kg/day on days +3 and +4 and, starting on day +5, MMF at 15 mg/ kg three times per day until day +35 and tacrolimus adjusted to maintain trough levels 10–20 ng/mL or cyclosporine adjusted to maintain levels between 100–200 ng/mL tapered by day +180. Patients re- ceiving PBSC were given prophylaxis with cyclosporine, and patients receiving bone marrow were administered either tacrolimus (n = 34) or cyclosporine (n = 12). For the entire study population, the median time to neutrophil recovery was 20 days and 29 days for platelet recovery. Grade 2–4 acute GVHD occurred in 25% of patients receiving bone marrow (BM) and 33% of those receiving PBSC (p = .43). The cumulative incidence of grades 3–4 acute GVHD was 14% and 3% in the PBSC and BM arms, respectively (p = .10). The incidence of chronic GVHD was 13% regardless of stem cell source (p = .21). The 2-year OS estimate was 68% and PFS was 62%. The 2-year overall NRM was 18%; 22% for BM source and 12% for PBSC source (p = .96).12 Several studies have analyzed the use of PBSC as a source for haploidentical HSCTs, showing that it is an alternative to bone marrow product.
Matched Related and Unrelated Transplant
With the role of posttransplant Cy established in haploidentical HSCT with either PBSC or BM as a source, the use of Cy in the post- transplant setting was further evaluated in matched related and unrelated HSCTs. Patients with advanced hematologic malignancies who received matched related (n = 78) or unrelated (n = 39) donor trans- plants were included in this analysis by Lunzik and colleagues. The conditioning regimen utilized was myeloablative with busulfan 4 mg/ kg/day orally or 3.2 mg/ kg/day IV given in four daily divided doses for 4 consecutive days, followed by admistering Cy 50 mg/ kg IV for 2 days. Busulfan doses were adjusted to achieve a target area under the curve (AUC) of 800–1400 µmol/ L x min. Grafts were T cell–replete bone marrow product. GVHD prophylaxis was single-agent Cy given at a dose of 50 mg/ kg/day on days +3 and +4 after trans- plant. Neutrophils recovered in a time of 23 days for related grafts and 25 days for unrelated grafts. Platelet recovery occurred in a median of 31 days for related donors and 34 days for unrelated donors. At 100 days posttransplant the cumulative incidence of grade 2–4 acute GVHD was 43% and of grade 3–4 was 10%. There was not a significant difference in grade 2–4 acute GVHD between related and unrelated donors (42% versus 46%; HR = 0.87; 95% CI: 0.50–1.54; p = .64). The cumulative incidence of chronic GVHD for all patients was 10% with a median follow-up time of 26.3 months. The cumulative incidence of chronic GVHD at 2 years was not significantly different be- tween related and unrelated donors (9% versus 11%; HR = 0.83; 95% CI: 0.25–2.88; p = .79). The 2-year cumulative incidence of relapse was 44%. This was not significantly different when analyzed by donor type (HR = 1.4; 95% CI: 0.78–2.60; p = .25). For related donor grafts the median follow-up on trial was 29 months and 24 months for unrelated donor grafts for surviving recipients. The OS and EFS also did not significantly differ by donor type (OS HR = 0.85; 95% CI: 0.49–1.50; p= .58; EFS HR = 1.12; 95% CI: 0.68–1.86; p = .65). The OS was found to be 36% at 1 year and 55% at 2 years. The 1-year EFS was 48% and at 2 years was 39%.13 This trial revealed promising results for posttransplant Cy use in matched related and unrelated donors.
An additional multi-institutional trial utilized a myeloablative conditioning regimen of IV busulfan targeted to AUC and fludarabine at 40 mg/m2/day on days -5 to -2 in patients with high-risk hematologic malignancies undergoing HLA-matched related and unrelated BM transplants. GVHD prophylaxis consisted of single-agent posttransplant Cy given on days +3 and +4 at a dose of 50 mg/ kg/day. A total of 92 patients were transplanted during this analysis with 45 patients receiving related donor grafts and 47 patients receiving unrelated do- nor grafts. The median time to neutrophil engraftment was 21 days and platelet engraftment was 24 days. Grade 2–4 acute GVHD occurred in 51% of patients, with grade 3–4 in 15%. The cumulative incidence of chronic GVHD was 14% at 2 years. Approximately one-third of all patients (35%) never required additional immunosuppressive medication. NRM was 9% at day 100 and 16% at 1 year. OS was 67% at 2 years, and EFS was 62%.14 This study also supports the efficacy of posttransplant Cy for myeloablative related and unrelated matched donor transplant.
A clinical trial in matched sibling and unrelated donor transplants compared posttransplant Cy with tacrolimus and minidose methotrexate as GVHD prevention. Patients on the study arm (n = 49) received reduced-intensity conditioning with fludarabine at 40 mg/m2 followed by IV busulfan targeting an AUC of 4,000 µmol/ L x min on days -6 to -3. Patients receiving an unrelated donor graft also were given ATG on days -3 to -1 (total dose 4 mg/ kg). Posttransplant Cy was given at a dose of 50 mg/ kg/day on days +3 and +4. In the control arm (n = 133) patients received the same reduced-intensity conditioning regimen of fludarabine with melphalan. GVHD prophylaxis for this arm included tacrolimus plus mini-MTX (10 mg/m2 on day +1, then 5 mg/m2 on days +3, +6, +11). Unrelated donor transplants also received anti-thymocyte globulin (ATG) in the control arm. A computer- generated algorithm identified matched controls for 37 of the study patients. More than half (59%) of patients in both arms had unrelated donors and required additional immunosuppression during conditioning with ATG. More patients in the posttransplant Cy arm received bone marrow product than in the control arm (70% versus 48%). The cumulative incidence of acute GVHD grade 2–4 occurred in 46% of the posttransplant Cy arm and 19% in the control arm (HR, 2.8; 95% CI, 1.1-6.7; p = .02). The incidence of acute GVHD grades 3–4 was 14% in the study arm and 0% in the control arm (p = .02). For chronic GVHD, the cumulative incidence was 14% versus 21% in the study arm compared with the control arm, respectively (HR = 0.8; 95% CI: 0.2-2.6; p = .7). The OS, PFS, and NRM at 2 years were not significantly different between the groups with results of 26% versus 46% (HR = 1.8; 95% CI: 0.9-3.3; p = .08), 22% vs 33% (HR = 1.3; 95% CI: 0.7–2.3; p = .4), and 36% versus 16% (HR = 2.4; 95% CI: 0.8–6.7; p = .1) for the posttransplant Cy arm compared with the control arm, respectively.15
Building on the results of the data for single-agent Cy posttransplant in matched related and unrelated donors, a trial by Solomon and col- leagues evaluated a CNI-free GVHD prevention strategy. Patients were given a reduced-intensity conditioning regimen consisting of fludarabine 30 mg/m2/day on days -9 to -6, IV busulfan 130 mg/m2/ day on days -5 to -4, and Cy 14.5 mg/ kg/day on days -3 and -2 fol- lowed by administration of an unmanipulated peripheral blood stem cell graft on day 0. Immunosuppression consisted of Cy 50 mg/ kg/ day on days +3 and +4, then sirolimus began on day +5 and was discontinued day +90 to +100 without tapering in the absence of GVHD. Twenty-six patients with high-risk hematologic malignancies were treated in this trial. Seventeen patients had matched sibling donors, and the remaining nine patients had matched unrelated donors. All patients engrafted with a median time for neutrophil recovery of 15 days and 30 days for platelets. Acute GVHD grades 2–4 occurred in 46% of patients and 15% in grades 3–4. Thirty-one percent of patients experienced chronic GVHD. The 1-year cumulative incidence of NRM was 4%. Two-year estimated OS was 71%, EFS 64%, relapse 32%, and NRM 13% at a 20-month median follow-up period for surviving patients.16
The results of this trial are promising, with a very low rate of NRM and an impressive 2-year OS.
Posttransplant Cy is a safe and effective alternative to standard immunosuppression strategies. Cy administered early after HSCT leads to suppression of GVHD and graft rejection without compromising immune reconstitution. It has been utilized as a GVHD prevention strategy in HSCTs from bone marrow or peripheral blood as well as with vari- ous conditioning regimens and donor sources. Patients included in these studies had related, unrelated, matched, and mismatched donors, high- lighting the versatility of posttransplant Cy. The BMT-CTN continues to explore this method of immunosuppression and has an ongoing trial, BMT CTN 1203, that is comparing novel approaches for GVHD prevention to contemporary controls in patients undergoing related or un- related reduced-intensity conditioning transplants. In one arm of this tri- al, patients will receive posttransplant Cy at 50 mg/kg on days +3 and +4 followed by tacrolimus and MMF.9 The results of this large multicenter trial are anticipated to confirm the data from the completed studies on using posttransplant Cy. Posttransplant Cy should continue to be evaluated as an immunosuppression option given its comparably low rates of acute and chronic GVHD and minimal side effects.
1. Pasquini MC, Wang Z. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR summary slides, 2013. www.cibmtr.org. Accessed January 15, 2015.
2. Rezvani AR, Storb RF. Prevention of graft-vs.-host disease. Expert Opin Pharmacother. 2012;13(12):1737-1750.
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American Society of Hematology 2014 Annual Meeting Highlights
Connie Cheng, PharmD
Hematology/Oncology Clinical Pharmacist
The 56th American Society of Hematology Annual Meeting took place in San Francisco, CA, December 6–9, 2014. There were more than 20,000 attendees from across the world. In addition, more than 4,000 abstracts and six plenary sessions were presented. This report reviews key oral abstracts and plenary presentations regarding pharmacologic treatment of acute and chronic leukemia, myelodysplastic syndrome, and mantle cell lymphoma.
Abstract 0164: A Final Report: Phase I/ II Study of Sequential Azacitidine and Lenalidomide in Patients with Higher-Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)
Azacitidine is a hypomethylating agent used as first-line treatment of higher-risk myelodysplastic syndrome (MDS) and in patients with acute myeloid leukemia (AML) who are unfit to receive induction chemotherapy. Furthermore, lenalidomide is increasingly studied in combination with azacitidine in patients with MDS and AML. A phase 1/2 study evaluated sequential azacitidine (75 mg/m2 days 1–5) and lenalidomide in 88 patients with high-risk MDS and AML, including 23 patients with AML (>30% blasts). Lenalidomide was administered starting on day 6 per 28-day cycle. Following myelosuppression and infections observed with repeated cycles in the first 20 phase-2 subjects, the optimal lenalidomide dose was determined to be 25 mg on days 6–10. Rapid responses were obtained within median of two cycles. The overall response rate (ORR) was 35% with median overall survival (OS) of 33 weeks (range 1–172). Among the 40 patients ad- ministered the optimal lenalidomide dose, ORR was 55% with median OS duration of 75 weeks. Among 31 patients who responded to treatment, 42% of them proceeded to stem cell transplant. Therefore, this combination dose schedule was determined to be effective for patients with high-risk MDS and AML.
Acute Myeloid Leukemia
Abstract 0006: Sorafenib Versus Placebo in Addition to Standard Therapy in Younger Patients with Newly Diagnosed Acute Myeloid Leukemia (AML): Results from 267 Patients Treated in the Randomized Placebo- Controlled SAL-SORAML Trial
In vitro data and nonrandomized clinical studies have suggested that sorafenib as a multikinase inhibitor may be effective in the treatment of AML. This abstract was presented at the plenary session, which highlighted the results of the SORAML trial, a double-blind, placebo- controlled study that evaluated sorafenib in addition to standard induction and consolidation treatment in 267 AML patients who were 18–60 years old. All patients received two cycles of induction with daunorubicin 60 mg/m2 days 3–5 and cytarabine 100 mg/m2 days 1–7 followed by three cycles of consolidation with cytarabine 3 g/m2 twice daily on days 1, 3, 5. Allogeneic stem cell transplantation was scheduled for all intermediate and high-risk patients. Patients were randomized to receive either sorafenib (800 mg/day) or placebo in addition to standard treatment. The primary endpoint, median event-free survival (EFS), was 9.2 versus 20.5 months in favor of sorafenib. Further- more, there was a significant difference in 3-year relapse-free survival, which was 38% in the placebo arm and 56% with sorafenib. No differences in 3-year OS were reported, 56% in placebo arm and 63% with sorafenib, respectively. Similar EFS rates were observed among 46 FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD)- positive patients. Notably there was a higher incidence of fever, bleeding events, and hand-foot syndrome observed in sorafenib-treated patients.
Acute Promyelocytic Leukemia
Abstract 0012: Improved Outcome with ATRA-Arsenic Trioxide Compared to the ATRA-Chemotherapy in Non- High-Risk Acute Promyelocytic Leukemia (APL): Updated Results of the Italian-German APL0406 Trial on the Extended Final Series
Recently the randomized intergroup acute promyelocytic leukemia (APL) 0406 trial revealed the effectiveness of ATRA and arsenic tri- oxide (ATO) in combination compared with ATRA with chemotherapy for treatment of low-intermediate risk APL as defined by white blood cell count (WBC) <10x109/ L (Lo-CoCo et al., NEJM 2013). Patients in the ATRA-ATO arm received ATO 0.15 mg/ kg and ATRA 45 mg/m2/day until complete remission (CR), then ATO 5 days/week, 4 weeks on and 4 weeks off, for a total of four courses and ATRA 2 weeks on and 2 weeks off for a total of seven courses. The primary study objective was EFS at 2 years. Follow-up results of an extended cohort of 254 additional patients demonstrated the 2-year EFS was 98% versus 84.9% in favor of ATRA-ATO. Furthermore, the ATRA- ATO arm was associated with superior 2-year OS (99.1% versus 94.4%) and 2-year cumulative incidence of relapse rates (1.1% versus 9.4%), and CR was achieved in every patient who received ATRA-ATO. This data further confirm the survival benefit of ATRA with ATO versus chemotherapy in the non-high-risk setting.
Acute Lymphoblastic Leukemia
Abstract 0379: BLAST: A Confirmatory, Single-Arm, Phase 2 Study of Blinatumomab, a Bispecific T-Cell Engager (BiTE) Antibody Construct, in Patients with Minimal Residual Disease B-Precursor Acute Lymphoblastic Leukemia (ALL)
Minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL) refers to the presence of leukemic cells below the threshold of detection by conventional morphologic methods despite achieving complete hematologic remission. Patients with persistent/recur- rent MRD following induction therapy are at a higher risk of relapse. A phase 2 study evaluated 116 adult patients with MRD-positive (> 10-3) B-precursor ALL who received blinatumomab after achieving hematologic complete remission, including 35% who were treated in second or later remission. The monoclonal antibody is a bispecific T cell engager that redirects CD3-positive T cells to CD19 target cells to ultimately cause lytic destruction of CD19-positive B cells.
Notably patients with Philadelphia chromosome, central nervous sys- tem (CNS) involvement or extramedullary disease, or previous allogeneic stem cell transplant were excluded. Blinatumomab 15 µg/m²/ day was intravenously administered as continuous infusion for 4 weeks per 6-week cycle. Responders received up to four cycles of treatment or underwent stem cell transplant after completion of at least one cycle. Patients with hematologic relapse discontinued treatment. The primary study endpoint was rate of complete MRD response, which was achieved in 78% of patients after one cycle of treatment and 80% across all cycles. The most common adverse events observed (≥20%) included pyrexia (88%), headache (38%), tremor (29%), chills (25%), fatigue (24%), nausea (22%), and vomiting (22%). Serious adverse events that occurred in ≥5% of patients included pyrexia (15%), tremors (7%), aphasia (5%), encephalopathy (5%), and overdose (5%). Therefore, blinatumomab has the potential to improve patient out- comes, especially in those with MRD-positive ALL following intensive therapy, including second-line treatment.
Chronic Myeloid Leukemia
Abstract 0152: Final Study Results of the Phase 3 Dasatinib Versus Imatinib in Newly Diagnosed Chronic Myeloid Leukemia (CML-CP) Trial (DASISION)
The recent 3-year follow-up results of the DASISION trial, a randomized phase 3 study, demonstrated improved efficacy and faster response at 3 months with dasatinib 100 mg daily (n = 259) versus imatinib 400 mg daily (n = 260) in treatment-naïve chronic-phase chronic myeloid leukemia (CML-CP) patients (Jabbour et al., Blood. 2014). Since then, the final 5-year analysis of DASISION has been completed. The primary endpoint was confirmed complete cytogenetic response (cCCyR). At the end of the study period, 61% of dasatinibtreated patients and 63% of the imatinib group were still receiving therapy. The rate of cCCyR by 5 years was 83% with dasatinib versus 78% with imatinib and increased rates of major molecular response (BCR-ABL ≤ 0.1%) were observed with dasatinib (76% versus 64%) by 5 years. Time to cCCyR (HR = 1.46; 95% CI: 1.20–1.77) and major molecular response (HR = 1.54; 95% CI: 1.25–1.89) were faster with dasatinib. There were no differences in 5-year, progression-free survival (PFS) and OS rates between both treatment arms. Although no new or unexpected safety events were identified in either treatment arm at 5 years, the total incidence of pleural effusion increased each year among the dasatinib group (29% overall). A majority of pleural effusion events were grade 1–2 (91%), and the median time to first grade 1–2 pleural effusion was 114 weeks (range: 4–299 weeks). Only 20% of dasatinib-treated patients who experienced a pleural effusion discontinued treatment. At 5 years, dasatinib 100 mg once daily has demonstrated superior outcomes compared with imatinib 400 mg once daily as initial therapy for CML, and the 5-year follow-up data confirm dasatinib should remain the standard of care in this setting.
Chronic Lymphocytic Leukemia
Abstract 0019: Frontline Chemoimmunotherapy with Fludarabine, Cyclophosphamide, and Rituximab (FCR) Shows Superior Efficacy in Comparison to Bendamustine and Rituximab (BR) in Previously Untreated and Physically Fit Patients with Advanced Chronic Lymphocytic Leukemia (CLL): Final Analysis of an International Randomized Study of the German CLL Study Group (CLL10 Study)
Among physically fit advanced chronic lymphocytic leukemia (CLL) patients with low comorbidity burden, fludarabine, cyclophosphamide, and rituximab (FCR) is considered the standard frontline regimen.
The CLL10 study is a phase 3 study that compared bendamustine and rituximab (BR) with FCR in the frontline setting among 547 evaluable fit patients without del(17p) and who had a cumulative illness rating scale (CIRS) score <6 and creatinine clearance >70 ml/min. Patients were randomized to receive six courses of FCR (n = 274; fludarabine 25 mg/m2 days 1–3, cyclophosphamide 250 mg/m2 days 1–3, rituximab 375 mg/m2 day 0 at first cycle and 500 mg/m2 day 1 all subsequent cycles every 28 days) or BR (n =273; bendamustine 90 mg/m² days 1–2, rituximab 375 mg/m2 day 0 at first cycle and 500 mg/m2 day 1 all sub- sequent cycles every 28 days). The median CIRS score was 2 and a significantly higher proportion of patients 70 years or older was included in the BR arm (22% versus 14%, p = .020). The ORR in both arms was 97.8%. The CR rate was 40.7% in favor of FCR compared to 31.5% with BR. Median PFS was 53.7 months in the FCR arm, which was significantly higher than 43.2 months in the BR arm (HR = 1.589; 95% CI:1.25–2.079). Interestingly, among patients with unmutated IGHV status, median time to progression was 43.9 months after FCR compared with 34.0 months after BR (p = .015). Physically fit subgroups (CIRS max 3, only one CIRS item, age <65 years) benefited most from FCR therapy. On the other hand, no differences in PFS were observed be- tween both treatment arms in patients 65 years or older, CIRS 4–6 or >1 CIRS item. No difference in 3-year OS was observed between the two treatment groups (90.6% for FCR versus 92.2% for BR). There was a higher incidence of severe neutropenia observed in the FCR arm (87.7% versus 67.8%, p < .001), but no significant difference in the incidence of anemia (14.2% versus 12.0%; p = .46) or thrombocytopenia (22.4% versus 16.5%; p = .096) was found. Severe infections occurred more frequently (39.8% versus 25.4%, p = .001) in the FCR arm, especially in older patients (48.4% versus 26.8%; p = .001). Treatment-related mortality was 3.9% (FCR) and 2.1% (BR), respectively. The final analysis of the CLL10 study demonstrates that FCR results in higher CR rates and longer PFS, especially in very fit CLL patients. How- ever, BR should be considered as an alternative regimen in elderly fit patients or those with previous infections because increased toxicities were seen in older patients, which may have led to similar efficacy results between both arms.
Mantle Cell Lymphoma
Abstract 0149: Phase II Trial of R-CHOP Plus Bortezomib Induction Therapy Followed by Bortezomib Maintenance for Previously Untreated Mantle Cell Lymphoma: SWOG 0601
Currently there is no optimal induction regimen established for treat- ment of mantle cell lymphoma (MCL). Bortezomib, which is a 26S proteasome inhibitor, has been demonstrated to be active as mono- therapy for treatment of MCL, and preclinical data suggest that synergism may be exerted by combination with other cytotoxic agents. Given that maintenance rituximab administration following rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) was associated with a survival benefit, the SWOG cancer re- search cooperative group conducted a phase 2 study (S0601) to evaluate the safety and efficacy of combining bortezomib with R-CHOP for induction, followed by bortezomib maintenance for 2 years among 65 treatment-naïve adult patients with stage 3, 4, or bulky stage 2 MCL. Induction therapy included six cycles of R-CHOP (375 mg/m2 rituximab, 750 mg/m2 cyclophosphamide, 50 mg/m2 doxorubicin, 1.4 mg/m2 vincristine on day 1 and 100 mg prednisone daily for 5 days) plus bortezomib 1.3 mg/m2 on days 1 and 4 of every 21 day cycle. Patients achieving at least stable disease after induction were eligible for bortezomib maintenance therapy 1.3 mg/m2 days on 1, 4, 8, and 11 every 3 months for eight cycles. The primary endpoint was 2-year PFS rate. The 2-year PFS was 62% and 2-year OS was 85%. At 5 years the PFS was 28% and OS was 66%. Based on prior studies, the historical 2-year PFS rate for R-CHOP alone in this population is 30%. The Mantle Cell Lymphoma International Prognostic Index (MIPI) scores were significantly associated with outcome, with a 2-year PFS of 72%, 61%, and 25% for low-, intermediate-, and high-risk MIPI groups, respectively. Forty-eight percent of patients experienced grade 4 hematologic toxicities during induction therapy and 38.5% grade 3 nonhematologic and 6% grade 4 nonhematologic toxicities. During maintenance therapy, 13% of patients experienced grade 3 nonhematologic toxicities. Grade 3 peripheral neuropathy was experienced by 8% of patients during induction and 2% of patients during maintenance bortezomib, but grade 4 neuropathy was not reported. Combination R-CHOP with bortezomib followed by maintenance bortezomib appears to improve outcomes compared with historical data of R-CHOP alone, which suggests the addition of bortezomib to induction chemotherapy or maintenance should be further evaluated in a larger prospective study.
Highlights from the JADPRO Live at APSHO 2014 Conference
Megan Brafford, PharmD BCOP
Clinical Oncology Pharmacy Specialist
Baptist Health Lexington Lexington, KY
The second annual Journal of the Advanced Practitioner in Oncology (JADPRO) Live conference was held in Orlando, FL, October 29– November 2, 2014. This meeting was held in conjunction with the first annual Advanced Practitioner Society for Hematology and Oncology (APSHO) meeting. The theme of this year’s meeting was “Transition Oncology Practice” and focused on advanced practitioners and physicians coming together to discuss current treatment options and advances in the care of cancer patients, describe key legislative changes essential to the advanced practitioner, and identify means to improve collaboration—all with an ultimate goal of decreasing adverse events and improving patient outcomes. The first day of the 4-day conference consisted of multiple workshops, including writing for publication, decoding genetics, establishing a collaborative practice, interpreting an electrocardiogram (EKG) and pathology report, and a hands-on skills workshop reviewing bone marrow aspiration, lumbar puncture, Ommaya reservoir placement, punch biopsy, and suturing.
The remaining 3 days included more than 20 educational sessions on didactic, interactive, evidence-based content targeted to advanced practitioners in oncology including nurse practitioners, physician assistants, clinical nurse specialists, other advanced-degree nurses, hematology/oncology nurses, pharmacists, and physicians. Each presentation reviewed best practices involving a multidisciplinary setting.
The didactic grand round presentations were fantastic overviews of the disease states, diagnostics, identification of risk factors, and management options with both current and future treatment options. Each presentation included at least two speakers from different roles within the multidisciplinary team. The grand round presentations included effective strategies that practitioners could implement in their own institutions and clinics. The topics included non-Hodgkin lymphoma, chronic myelogenous leukemia, prostate cancer, breast cancer, basal cell carcinoma, chronic lymphocytic leukemia, gynecologic malignancies, and lung cancer.
One of the panel presentations, “Genetic and BRCA Mutations,” ad- dressed the controversies and challenges in genetic testing for breast cancer, including the social and ethical implications of testing for genetic mutations in this patient population. “Treatment and Disease- Related Cardiotoxicity in the Oncology Setting” provided the tools needed to apply the principles of risk analysis, prevention, early identification of signs and symptoms, and individualized treatment planning for cancer patients at risk of developing disease or treatment-related cardiac events. Cardiovascular disease is the second leading cause of death in cancer survivors, which explains the need for cardiologists and oncologists to collaborate throughout and after chemotherapy treatment. The presentation focused on the main medications that can result in cardiotoxicity, including anthracyclines, QTc prolongation medications, and tyrosine kinase inhibitors. Exciting new cancer therapies are being discovered; however, to maximize their potential, cardiac toxicities need to be identified and addressed upfront.
The program “Avoiding Common Drug Interactions and Reactions” not only reviewed the most frequent drug interactions and clinical impact in oncology and hematology, but also helped the audience develop ideas on how to create protocols to identify and minimize the risk of drug interactions by improving collaboration between all members of the healthcare team. At this program and throughout the entire conference, attendees received both quality education and practical resources that can be engaged and utilized in cancer centers through- out the country.
An additional program with pharmacy-related topics included “New Hematology/Oncology Drug Updates,” which was a great review of pharmacology and indications of every new oncology/ hematology drug approved in 2014. Recommendations for monitoring and management of toxicities also were addressed. This presentation emphasized the impact of each of these medications on advanced practitioners and explained how to utilize each medication in clinical practice.
Another highlight was the keynote presentation, “A Funny Thing Happened on My Way to Chemotherapy,” by Dan Shapiro, PhD. Presented in first-person stories illustrating the complexity of front-line medicine, his talk emphasized the importance of connecting to others in the face of challenging regimens.
JADPRO Live at APSHO 2014 provided practitioners the opportunity to network with a multidisciplinary team and work together to better serve our patients. More information about joining APSHO and JADPRO Live can be found at www.jadprolive.com.
Recalls and Safety Alerts from the FDA
Lindsay Hladnik, PharmD BCOP
Clinicial Pharmacist, Hematologic Malignancies/SCT Barnes-Jewish Hospital
St. Louis, MO
Creative Compounds Recall in Oregon and Washington
Oregon Compounding Centers, Inc. has issued a voluntary recall of certain unexpired sterile products in Oregon and Washington due to issues with sterility assurance. This is a precautionary measure being taken by the company following a recent inspection. There have been no reports of adverse events or product contamination to date. Recalled products are labeled with the Creative Compounds name, have a lot number, and were made from July 1, 2014, through September 22, 2014. For a full list of recalled products and affected lot numbers, refer to the following website: www.fda.gov/Safety/ Recalls/ucm418324.htm.
Serious and fatal infections, including sepsis, pneumonia, and viral reactivation (including hepatitis B and Epstein-Barr viruses), have been reported with romidepsin. Patients with disease involvement of the bone marrow and those who have received prior treatment with monoclonal antibodies directed against lymphocyte antigens maybe at greater risk of developing life-threatening infections. Infections may occur during treatment and within 30 days after treatment. In a clinical trial that included patients with relapsed or refractory extra- nodal NK/ T-cell lymphoma, Epstein-Barr viral reactivation leading to liver failure was reported. In clinical trials that included peripheral T cell lymphoma (PTCL) patients, hepatitis B reactivation was reported in 1% of the population. Consider monitoring for hepatitis B reactivation and administering antiviral prophylaxis in patients with evidence of prior hepatitis B infection. www.fda.gov/Safety/MedWatch/SafetyInformation/ucm360070.htm
Updates have been made to the “Warnings and Precautions” section of the product labeling to include the risk of dehydration and renal failure, which can be fatal. Patients with nausea, vomiting, diarrhea, asthenia, anorexia, preexisting compromised renal function, or those receiving concomitant nephrotoxic agents are at higher risk. Dehydration should be corrected and prevented. In addition, therapy should be interrupted and dehydration corrected if grade 2 or higher dehydration occurs. Treatment may be restarted after the patient is rehydrated and precipitating factors have been controlled or corrected.
There is a risk of Stevens-Johnson syndrome and toxic epidermal necrolysis with capecitabine, which can be fatal. In patients who experience severe mucocutaneous reactions from capecitabine, therapy should be permanently discontinued. www.fda.gov/Safety/MedWatch/SafetyInformation/ucm422806.htm
Goserelin Acetate Implant (Zoladex) and Leuprolide Acetate (Eligard)
Updated warnings and precautions include the potential for androgen deprivation therapy to prolong the QT/QTc interval. Risks versus benefits should be considered in patients with congestive heart fail ure, congenital long QT syndrome, frequent electrolyte abnormalities, or taking concomitant medications known to prolong the QT interval. Correct electrolyte abnormalities and consider periodic monitoring of electrocardiograms and electrolytes. www.fda.gov/Safety/MedWatch/SafetyInformation/ucm182245.htm www.fda.gov/Safety/MedWatch/SafetyInformation/ucm232194.htm