Prevention of Cytomegalovirus Reactivation in Haploidentical Stem Cell Transplantation.

Cytomegalovirus (CMV) infection can increase the morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Because of a higher degree of immunosuppression, haploidentical transplant recipients may be at an increased risk of viral infections, particularly CMV. We retrospectively analyzed 86 haploidentical HCT recipients at our institution to determine whether a more intensified antiviral strategy would reduce the incidence of CMV reactivation compared with a traditional antiviral prophylaxis regimen. According to practice changes over time in antiviral prophylaxis at our institution, patients were divided into the following 3 groups: hybrid (n = 15), traditional (n = 26), and intermediate dose (n = 45). The hybrid group received valganciclovir from admission to day -2 followed by standard-dose valacyclovir. The traditional group received standard-dose valacyclovir starting on day -1. The intermediate-dose group received ganciclovir from admission through day -2, followed by intermediate-dose valacyclovir. The hybrid and intermediate-dose groups were combined into an intensified group for further analysis. We found the cumulative incidence (CI) of CMV reactivation within 100 days post-HCT was higher for patients receiving the traditional strategy compared with the hybrid and intermediate-dose strategy groups (81% versus 53% versus 71%, respectively; P = .08) and was significantly higher when the traditional group was compared against the intensified group (81% versus 67%, respectively; P = .032). Median time to CMV reactivation was also shorter in the traditional group versus the intensified group (31 versus 41 days, respectively). Moreover, the CI of CMV disease by day 100 was significantly worse for patients receiving the traditional prophylaxis strategy among the 3 groups (8% traditional versus 0% hybrid versus 0% intermediate dose; P = .032). Renal toxicity did not differ between the traditional and intensified group. In conclusion, an intensified approach to prevention of CMV reactivation was associated with lower incidence of CMV reactivation and less CMV disease without increased toxicity. Because the most benefit was observed in the intensified group, further studies are needed to assess which antiviral intervention is the most beneficial on lowering the rates of CMV viremia and disease.

Post-transplantation cyclophosphamide versus conventional graft-versus-host disease prophylaxis in mismatched unrelated donor haematopoietic cell transplantation.

Post-transplantation cyclophosphamide (PTCy) is an effective strategy to prevent graft-versus-host disease (GVHD) after haploidentical haematopoietic cell transplantation (HCT). We determined the efficacy of PTCy-based GVHD prophylaxis in human leucocyte antigen (HLA)-mismatched unrelated donor (MMUD) HCT. We analysed 113 adult patients with high-risk haematological malignancies who underwent one-antigen MMUD transplantation between 2009 and 2013. Of these, 41 patients received PTCy, tacrolimus and mycophenolate mofetil (MMF) for GVHD prophylaxis; 72 patients received conventional prophylaxis with anti-thymocyte globulin, tacrolimus and methotrexate. Graft source was primarily bone marrow (83% PTCy vs. 63% conventional group). Incidence of grade II-IV (37% vs. 36%, P = 0·8) and grade III-IV (17% vs. 12%, P = 0·5) acute GVHD was similar at day 100. However, the incidence of grade II-IV acute GVHD by day 30 was significantly lower in the PTCy group (0% vs. 15%, P = 0·01). Median time to neutrophil (18 days vs. 12 days, P < 0·001) and platelet (25·5 days vs. 18 days, P = 0·05) engraftment was prolonged in PTCy group. Rates of graft failure, chronic GVHD, 2-year non-relapse mortality, relapse, progression-free survival or overall survival were similar. Our results demonstrate that PTCy, tacrolimus and MMF for GVHD prophylaxis is safe and produced similar results as conventional prophylaxis in patients with one antigen HLA-MMUD HCT.

Possible amlodipine-induced hepatotoxicity after stem cell transplant.

OBJECTIVE: To report the occurrence of hepatotoxicity in a patient initiated on amlodipine. A review of other reports of amlodipine hepatotoxicity is also provided. CASE SUMMARY: A 34-year-old patient was admitted for worsening gastrointestinal graft versus host disease 100 days after an allogeneic stem cell transplant and treated with high-dose systemic steroids. Amlodipine was started for steroid-induced hypertension; 11 days after its initiation, alanine aminotransferase and aspartate aminotransferase peaked at 630 and 421 IU/L, respectively. Total bilirubin and alkaline phosphatase remained normal. A liver biopsy interpreted the liver injury as being possibly drug induced. Amlodipine, the most recently added medication, was discontinued, and transaminases trended down to normal within 2 weeks. DISCUSSION: Allogeneic stem cell transplant patients are often prescribed many medications that carry the risk of hepatotoxicity. Amlodipine, ondansetron, and tacrolimus all have literature support for hepatotoxicity. Amlodipine, however, was the only agent for which initiation and discontinuation followed the acute rise and fall of liver transaminases. An objective causality assessment for liver toxicity, the RUCAM, revealed that the elevation in transaminases was "possible" drug toxicity caused by amlodipine. The package insert and other case reports of amlodipine hepatotoxicity suggest that it can occur both in the acute and chronic setting, and the injury is characterized as either cholestatic or hepatocellular. CONCLUSION: Amlodipine is a commonly used agent in allogeneic stem cell transplant patients. As the first published case in a hematopoietic stem cell transplantation patient, it brings to light a rare, yet important, event of which clinicians should be aware when caring for patients on this agent.

Tacrolimus-associated posterior reversible encephalopathy syndrome in hematopoietic allogeneic stem cell transplantation.

Tacrolimus-associated posterior reversible encephalopathy syndrome (PRES) is a potential complication of allogeneic stem cell transplant (SCT). Due to the paucity of information on the management of PRES in SCT patients receiving tacrolimus, more information is needed on trends associated with the incidence of PRES and to characterize its management. A retrospective review was conducted of patients receiving tacrolimus for prevention of graft versus host disease (GVHD) after allogeneic SCT who developed PRES from September 2008 to July 2011. Nineteen patients were identified. Altered mental status, seizures, and visual abnormalities were experienced by 78.9%, 52.6%, and 31.5% of the patients, respectively, at time of PRES onset. Compared with baseline, patients with PRES were likely to have an increase in mean arterial pressure (P < 0.0001) and serum creatinine. Elevated tacrolimus levels and hypomagnesemia were not observed with PRES onset. Tacrolimus was managed in three general strategy groups: not held, held then continued, and switched to another agent. Survival was defined as survival to discharge from PRES hospitalization. When tacrolimus was not held, held then continued, or switched to another agent, 40% (2 of 5), 40% (4/10), and 50% (2/4) survived to discharge, respectively. PRES was associated with high blood pressure and adequate blood pressure control should be part of its management. No management strategy pertaining to tacrolimus usage appeared more beneficial over another.

Cancer immunotherapy: sipuleucel-T and beyond.

In April 2010, sipuleucel-T became the first anticancer vaccine approved by the United States Food and Drug Administration. Different from the traditional chemotherapy agents that produce widespread cytotoxicity to kill tumor cells, anticancer vaccines and immunotherapies focus on empowering the immune system to overcome the tumor. The immune system consists of innate and adaptive components. The CD4(+) and CD8(+) T cells are the most crucial components of the adaptive arm of the immune system that act to mediate antitumor responses. However, T-cell responses are regulated by intrinsic and extrinsic mechanisms, which may interfere with effective antitumor responses. Many anticancer immunotherapies use tumor-associated antigens as vaccines in order to stimulate an immune response against tumor cells. Sipuleucel-T is composed of autologous mononuclear cells incubated with a fusion protein consisting of a common prostate cancer antigen (prostatic acid phosphatase) linked to an adjuvant (granulocyte-macrophage colony-stimulating factor). It is postulated that when the vaccine is infused into the patient, the activated antigen-presenting cells displaying the fusion protein will induce an immune response against the tumor antigen. In a recent randomized, double-blind, placebo-controlled, phase III clinical trial, sipuleucel-T significantly improved median overall survival by 4.1 months in men with metastatic castration-resistant prostate cancer compared with placebo. Although overall survival was improved, none of the three phase III clinical trials found a significant difference in time to disease progression. This, along with cost and logistic issues, has led to an active discussion. Although sipuleucel-T was studied in the metastatic setting, its ideal place in therapy is unknown, and clinical trials are being conducted in patients at different stages of disease and in combination with radiation therapy, antiandrogen therapy, and chemotherapy. Various other anticancer vaccines and immunotherapies for other tumor types are currently under investigation and in clinical trials. These immunotherapies were formulated to incorporate tumor-associated antigens aimed at stimulating effector T-cell responses or to block regulatory mechanisms that suppress the function of effector T cells. Additional studies will determine how these therapies can best improve clinical outcomes in patients with cancer.