Hematopoietic Cell Transplantation, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology

Hematopoietic cell transplantation (HCT) involves the infusion of hematopoietic progenitor cells into patients with hematologic disorders with the goal of re-establishing normal hematopoietic and immune function. HCT is classified as autologous or allogeneic based on the origin of hematopoietic cells. Autologous HCT uses the patient's own cells while allogeneic HCT uses hematopoietic cells from a human leukocyte antigen-compatible donor. Allogeneic HCT is a potentially curative treatment option for patients with certain types of hematologic malignancies, and autologous HCT is primarily used to support patients undergoing high-dose chemotherapy. Advances in HCT methods and supportive care in recent decades have led to improved survival after HCT; however, disease relapse and posttransplant complications still commonly occur in both autologous and allogeneic HCT recipients. Allogeneic HCT recipients may also develop acute and/or chronic graft-versus-host disease (GVHD), which results in immune-mediated cellular injury of several organs. The NCCN Guidelines for Hematopoietic Cell Transplantation focus on recommendations for pretransplant recipient evaluation and the management of GVHD in adult patients with malignant disease.

Characterization of collaborative practice agreements held by hematopoietic stem cell transplant pharmacists.

BACKGROUND: Current workforce shortages within the hematopoietic stem cell transplant field necessitate capitalizing on the role of oncology-trained pharmacists. Working within an agreed-upon protocol, pharmacists are able to expand patient care delivery through optimal medication therapy management. METHODS: An electronic survey was developed by the Advocacy & Policy Working Committee of the American Society for Blood and Marrow Transplantation Pharmacy Special Interest Group and distributed to pharmacists involved in the care of hematopoietic stem cell transplant patients. The primary objective was to assess the current state of collaborative practice agreements in the hematopoietic stem cell transplant setting. RESULTS: Forty-eight responses representing 41 institutions were returned. Respondents were mostly female (67%) and practiced in the adult setting (83%). Reponses represented a range of practice experience in hematopoietic stem cell transplant with the majority of the hematopoietic stem cell transplant positions (83%) funded by the department of pharmacy at an academic medical center. Of the 48 responses, 22 (46%) respondents reported having collaborative practice agreements in place; 10 (21%) respondents did not currently have collaborative practice agreements, but were planning to implement them; and 16 (33%) respondents did not have collaborative practice agreements at their institution. Clinical activities performed under a collaborative practice agreement included medication selection and dosing modifications, therapeutic drug monitoring, supportive care management, and management of comorbid conditions and chronic diseases. The most commonly cited barrier to establishing collaborative practice agreements was the inability to secure reimbursement for services provided. No respondents reported a negative impact on job satisfaction. CONCLUSIONS: The results of this survey provide the pharmacy community with a robust understanding of the current landscape of hematopoietic stem cell transplant pharmacy collaborative practice agreements.

IL-2 promotes early Treg reconstitution after allogeneic hematopoietic cell transplantation.

Graft-versus-host disease (GvHD) remains a major cause of transplant-related mortality. Interleukin-2 (IL-2) plus sirolimus (SIR) synergistically reduces acute GvHD in rodents and promotes regulatory T cells. This phase II trial tested the hypothesis that IL-2 would facilitate STAT5 phosphorylation in donor T cells, expand regulatory T cells, and ameliorate GvHD. Between 16th April 2014 and 19th December 2015, 20 patients received IL-2 (200,000 IU/m2 thrice weekly, days 0 to +90) with SIR (5-14 ng/mL) and tacrolimus (TAC) (3-7 ng/mL) after HLA-matched related or unrelated allogeneic hematopoietic cell transplantation (HCT). The study was designed to capture an increase in regulatory T cells from 16.0% to more than 23.2% at day +30. IL-2/SIR/TAC significantly increased regulatory T cells at day +30 compared to our published data with SIR/TAC (23.8% vs. 16.0%, P=0.0016; 0.052 k/uL vs. 0.037 k/uL, P=0.0163), achieving the primary study end point. However, adding IL-2 to SIR/TAC led to a fall in regulatory T cells by day +90 and did not reduce acute or chronic GvHD. Patients who discontinued IL-2 before day +100 showed a suggested trend toward less grade II-IV acute GvHD (16.7% vs. 50%, P=0.1475). We surmise that the reported accumulation of IL-2 receptors in circulation over time may neutralize IL-2, lead to progressive loss of regulatory T cells, and offset its clinical efficacy. The amount of phospho-STAT3+ CD4+ T cells correlated with donor T-cell activation and acute GvHD incidence despite early T-cell STAT5 phosphorylation by IL-2. Optimizing IL-2 dosing and overcoming cytokine sequestration by soluble IL-2 receptor may sustain lasting regulatory T cells after transplantation. However, an approach to target STAT3 is needed to enhance GvHD prevention. (clinicaltrials.gov identifier: 01927120).

Retrospective comparison of filgrastim plus plerixafor to other regimens for remobilization after primary mobilization failure: clinical and economic outcomes.

We performed a retrospective analysis to evaluate clinical and economic outcomes in patients receiving remobilization therapy after primary mobilization failure. Our primary endpoint was to compare filgrastim plus plerixafor to other regimens in their ability to collect a target cell dose of at least 2 million CD34+ cells/kg (cumulative). Of 96 consecutive patients who failed their primary mobilization therapy and in whom a second mobilization was attempted, remobilization consisted of filgrastim plus plerixafor (n = 38), filgrastim with or without sargramostim (n = 43), or chemotherapy plus filgrastim (n = 15), 84% of filgrastim/plerixafor patients were able to collect at least 2 million CD34+ cells/kg from both mobilizations, compared to 60% of patients mobilized with chemotherapy/filgrastim and 79% of the filgrastim ± sargramostim patients (P = 0.17). However, when combined with cells collected from the first mobilization, 53% of filgrastim/plerixafor patients reached the target of 2 million CD34+ cells in one apheresis, compared to 20% of those receiving chemotherapy/filgrastim and 28% of those receiving filgrastim ± sargramostim (P = 0.02). Resource utilization, mobilization drug costs, clinical care costs, and total costs were significantly different. We conclude that while filgrastim/plerixafor is the most efficient remobilization strategy, those clinical benefits may not translate into lower cost, especially when multiple days of plerixafor administration are required.

ATG prevents severe acute graft-versus-host disease in mismatched unrelated donor hematopoietic cell transplantation.

Severe acute graft-versus-host disease (aGVHD) remains a major source of morbidity and mortality following mismatched unrelated donor hematopoietic cell transplantation (HCT). Through a retrospective analysis, we investigated the efficacy of GVHD prophylaxis with rabbit anti-thymocyte globulin (ATG) 7.5 mg/kg (1 mg/kg given on day -3, then 3.25 mg/kg/day on days -2 and -1 before stem cell infusion) followed by standard tacrolimus plus methotrexate in a consecutive series of 45 HLA partially matched unrelated donor HCT recipients. The cumulative incidence of grade III-IV aGVHD was 11% by 100 days (95% confidence interval [CI] 5%-25%). Moderate to severe chronic GVHD (per NIH consensus criteria) was 19% (95% CI 10%-36%) at 1 year, and 28% (95% CI 16%-48%) at 2 years. With a median follow-up time for surviving patients of 12 months (range: 5-39 months), overall survival was 55% (95% CI 39%-71%) at 1 year, and 45% (95% CI 27%-63%) at 2 years. Nonrelapse mortality was 11% (95% CI 5%-25%) by 100 days post-HCT, 26% (95% CI 16%-44%) by 1 year, and 30% (95% CI 18%-50%) by 2 years. The cumulative incidence of primary disease relapse was 23% (95% CI 13%-41%) at 1 year, and 33% (95% CI 20%-56%) by 2 years after HCT. Cytomegalovirus (CMV) infection or reactivation varied according to recipient and donor CMV serostatus. Epstein-Barr Virus (EBV) reactivation occurred in 54% (95% CI 40%-71%) of patients. Preemptive rituximab therapy was administered for EBV reactivation, however, posttransplant lymphoproliferative disorder was diagnosed in 5 (11%) cases, and was fatal in 1. A regimen of ATG 7.5 mg/kg total ending on day -1 effectively decreased the occurrence of grade III-IV aGVHD and severe chronic GVHD.

Severe hypoalbuminemia at day 90 predicts worse nonrelapse mortality and overall survival after allogeneic hematopoietic stem cell transplantation for acute myelogenous leukemia and myelodysplastic syndrome.

Because patients who undergo allogeneic hematopoietic cell transplantation (allo-HCT) remain in the vicinity of the transplant center for approximately 90 days posttransplantation, identifying prognostic factors to determine those at immediate higher risk of mortality is essential. A normal serum albumin level generally denotes healthiness. We evaluated the prognostic significance of day 90 hypoalbuminemia (and other clinical, pharmacologic, and laboratory variables) in 163 patients, median age 48 years (range, 19-69 years), who underwent allo-HCT for acute myelogenous leukemia (n = 124) or myelodysplastic syndrome (n = 39). Day 90 hypoalbuminemia (serum albumin <3.0 g/dL) was associated with worse nonrelapse mortality (NRM) and poor overall survival (OS). The estimated 1- and 2-year cumulative incidence rates of NRM were 48% and 52%, respectively, and the corresponding OS rates were 7% and 3%. Serum albumin level <3.0 g/dL and Karnofsky score <80 at day 90 were strong independent predictors of worse NRM and OS in multivariate analysis. These results support day 90 hypoalbuminemia as an adverse prognostic marker for NRM and OS after allo-HCT for acute myelogenous leukemia and myelodysplastic syndrome.

Clotrimazole troches induce supratherapeutic blood levels of sirolimus and tacrolimus in an allogeneic hematopoietic cell-transplant recipient resulting in acute kidney injury.

Allogeneic hematopoietic cell transplantation is a potential curative treatment option for various malignant and nonmalignant hematologic disorders. Patients undergoing an allogeneic hematopoietic cell transplant are prescribed immune-suppressant therapies to facilitate hematopoietic donor-cell engraftment and prevent graft-versus-host disease. Drug-drug interactions may occur, owing to exposure to complex multidrug regimens with narrow therapeutic windows and high toxicity profiles. Here, we describe a unique case of a 65-year-old man with poor-risk acute myeloid leukemia who underwent a matched-sibling hematopoietic cell allograft. Sirolimus and tacrolimus were used for graft-versus-host disease prophylaxis. He developed oral thrush requiring treatment with clotrimazole troches, which subsequently resulted in serious renal toxicity attributed to supratherapeutic levels of sirolimus and tacrolimus. Patient renal function improved after temporarily holding both immune suppressants, and administering phenytoin to help induce sirolimus and tacrolimus metabolism. This case highlights sudden and serious toxicities that resulted from clotrimazole-sirolimus and clotrimazole-tacrolimus drug-drug interactions, even when administered topically.

Pentostatin as rescue therapy for glucocorticoid-refractory acute and chronic graft-versus-host disease.

BACKGROUND: Despite scientific advances in hematopoietic cell allografting, glucocorticoid-refractory acute (aGVHD) and chronic graft-versus-host disease (cGVHD) represent major sources of transplant-related morbidity and mortality. We aimed to characterize the activity of pentostatin as rescue therapy for refractory GVHD. MATERIAL/METHODS: In a retrospective analysis, we examined the activity of pentostatin as rescue therapy of glucocorticoid-refractory acute and chronic GVHD. RESULTS: In 12 patients with advanced (overall aGVHD grade III/IV in 8/12) refractory aGVHD, overall response (ORR) was achieved in 6/12, and complete remission (CR) of aGVHD in 4/12 allowing additional rescue immunosuppressive agents. Median overall survival (OS) was 1.4 months (95% CI: 0.26-2.4). Causes of death included refractory aGVHD and infection. In 18 patients with refractory cGVHD (12/18 with severe cGVHD), pentostatin induced CR in 1/18, and partial response (PR) in 9/18. Activity was observed in all affected organs. The median decrease in glucocorticoid therapy over 24 months after pentostatin initiation for refractory cGVHD was 38% (range=0-100%). Median OS was 5 months (95% CI: 1.6 - NR). CONCLUSIONS: Allowing for the utilization of additional immune suppressive agents, this series suggests the activity of pentostatin as rescue therapy of refractory GVHD.