Jeremy Pantin

Effect of high-dose plerixafor on CD34+ cell mobilization in healthy stem cell donors: results of a randomized crossover trial

Hematopoietic stem cells can be mobilized from healthy donors using single-agent plerixafor without granulocyte colony-stimulating factor and, following allogeneic transplantation, can result in sustained donor-derived hematopoiesis. However, when a single dose of plerixafor is administered at a conventional 240 μg/kg dose, approximately one-third of donors will fail to mobilize the minimally acceptable dose of CD34+ cells needed for allogeneic transplantation. We conducted an open-label, randomized trial to assess the safety and activity of high-dose (480 μg/kg) plerixafor in CD34+ cell mobilization in healthy donors. Subjects were randomly assigned to receive either a high dose or a conventional dose (240 μg/kg) of plerixafor, given as a single subcutaneous injection, in a two-sequence, two-period, crossover design. Each treatment period was separated by a 2-week minimum washout period. The primary endpoint was the peak CD34+ count in the blood, with secondary endpoints of CD34+ cell area under the curve (AUC), CD34+ count at 24 hours, and time to peak CD34+ following the administration of plerixafor. We randomized 23 subjects to the two treatment sequences and 20 subjects received both doses of plerixafor. Peak CD34+ count in the blood was significantly increased (mean 32.2 versus 27.8 cells/μL, P=0.0009) and CD34+ cell AUC over 24 hours was significantly increased (mean 553 versus 446 h cells/μL, P<0.0001) following the administration of the 480 μg/kg dose of plerixafor compared with the 240 μg/kg dose. Remarkably, of seven subjects who mobilized poorly (peak CD34+ ≤20 cells/μL) after the 240 μg/kg dose of plerixafor, six achieved higher peak CD34+ cell numbers and all achieved higher CD34+ AUC over 24 hours after the 480 μg/kg dose. No grade 3 or worse drug-related adverse events were observed. This study establishes that high-dose plerixafor can be safely administered in healthy donors and mobilizes greater numbers of CD34+ cells than conventional-dose plerixafor, which may improve CD34+ graft yields and reduce the number of apheresis procedures needed to collect sufficient stem cells for allogeneic transplantation. (ClinicalTrials.gov, identifier: NCT00322127)

Conditioning with rabbit versus horse ATG dramatically alters clinical outcomes in identical twins with severe aplastic anemia transplanted with the same allogeneic donor

Severe aplastic anemia (SAA) is a rare disorder leading to bone marrow failure, which if left untreated, is invariably fatal. Conventional therapies with immunosuppressive therapy or allogeneic hematopoietic stem cell transplantation (HSCT) are highly effective. HSCT can offer a greater outcome in younger patients who have an available HLA match-related donor. Recent studies showing the addition of antithymocyte globulin (ATG) to the conditioning regimen improves engraftment and reduces the risk of graft-versus-host disease (GVHD).There are currently two ATG preparations in the USA, equine (or horse) and rabbit ATG. These agents are pharmacologically distinct, having significant differences in their pharmacokinetics and in vivo immunosuppressive effects [N Engl J Med 365(5):430–438, 2011]. Here, we report a case of two monozygotic twins with constitutional SAA that evolved to myelodysplastic syndrome (MDS) who both underwent allogeneic peripheral blood stem cell transplantation (PBSC) from the same single HLA antigen mismatched sibling donor with the only difference in the transplant regimen being the type of ATG used in the preparative regimen; one twin received horse ATG and the other received rabbit ATG during conditioning. This report emphasizes that dramatic differences in donor T cell chimerism and clinical outcomes including GVHD can occur as a consequence of the type of ATG that is utilized in the transplant conditioning regimen. These differences highlight that these agents should not be considered interchangeable drugs when used in this setting.

Allogeneic transplantation using CD34+selected peripheral blood progenitor cells combined with non-mobilized donor T cells for refractory severe aplastic anaemia

Allogeneic haematopoietic stem cell transplantation is curative for severe aplastic anaemia (SAA) unresponsive to immunosuppressive therapy. To reduce chronic graft‐versus‐host disease (GVHD), which occurs more frequently after peripheral blood stem cell (PBSC) transplantation compared to bone‐marrow transplantation (BMT), and to prevent graft rejection, we developed a novel partial T‐cell depleted transplant that infuses high numbers of granulocyte colony‐stimulating factor‐mobilized CD34+ selected PBSCs combined with a BMT‐equivalent dose of non‐mobilized donor T‐cells. Fifteen patients with refractory SAA received cyclophosphamide, anti‐thymocyte globulin and fludarabine conditioning, and were transplanted with a median 8 × 106 CD34+ cells/kg and 2 × 107 non‐mobilized CD3+ T‐cells/kg from human leucocyte antigen‐matched sibling donors. All achieved sustained engraftment with only two developing acute and two developing chronic GVHD. With a 3·5‐year median follow‐up, 86% of patients survived and were transfusion‐independent. When compared to a retrospective cohort of 56 bone‐marrow failure patients that received the identical transplant preparative regimen and GVHD prophylaxis with the exception that the allograft contained unmanipulated PBSCs, partial T‐cell depleted transplant recipients had delayed donor T‐cell chimerism and relative reduction of 75% in the incidence of acute grade II‐IV GVHD (13% vs. 52%; P = 0·010) and of 82% in chronic GVHD (13% vs. 72%; P = 0·0004). In multivariate analysis, partial T‐cell depleted transplants remained significantly associated with a reduced risk of GVHD. In conclusion, for patients with refractory SAA, this novel transplant strategy achieves excellent engraftment and survival when compared to unmanipulated PBSC transplants and dramatically reduces the incidence of both acute and chronic GVHD.

Administration of anti-thymocyte globulin: A comparison of two protocols

Antithymocyte globulin (ATG) can be utilized in allogeneic hematopoietic cell transplantation (allo-HCT) conditioning regimens to reduce the risk of GVHD. Although the overall goal of ATG is immunosuppressive in nature, infusion of foreign proteins from the rabbit or equine source can lead to an initial immune response and subsequent infusion reaction symptoms (fever, chills, hypertension and tachycardia) frequently occur. Despite the high incidence of these reactions, strategies for optimal administration of ATG and management of these infusion reaction symptoms are not well documented in the literature. Product labeling recommends premedications (corticosteroid, acetaminophen, antihistamine-1) and suggests a 6-h initial administration time and at least 4 h for administration of subsequent infusions. However, aside from premedication and slowing the infusion rate, recommendations are not made regarding the prevention and management of ATG-related infusion reactions. Complications of ATG administration can result in numerous deleterious effects. There is the potential need for additional medications as supportive care to ameliorate uncomfortable symptoms, increased nursing time, waste of expired ATG, need for additional ATG to complete the regimen and potential for incomplete administration of the prescribed dose. Furthermore, the cost of nursing time, symptom management including initiation of empiric antibiotics and wasted ATG drug product could be substantial. There is a clear need to investigate optimum administration methods. In view of these issues, we evaluated two sequential ATG administration protocols at our institution with approval from the local Institutional Review Board. All patients (n= 28) who received rabbit-derived ATG during conditioning for allo-HCT at our institution from 2010 to 2013 were reviewed. In November 2012, rates of ATG infusion reactions prompted a revision of institutional guidelines for ATG administration via consensus of physician, nursing and pharmacy staff. To overcome the high incidence of infusion reactions that had often required interruption of ATG and a significant amount of nursing and provider time, often in the evening hours, the consensus was to set the ATG infusion rate without titration. This was based on our anecdotal experience where those patients who experienced an ATG reaction often tolerated the rest of the ATG when given at a set rate over several hours without further titration. The institutional historical administration protocol, herein defined as protocol A, administered rabbit-derived ATG 2mg/kg on days − 4, − 3 and − 2 and titrated over at least 4 h. The revised administration protocol, herein defined as protocol B, extended the administration of ATG as follows: 1 mg/kg days − 5 and − 2 and 2mg/kg days − 4 and − 3 at a fixed rate over 20 h. All patients were premedicated with methylprednisolone 60mg i.v. and diphenhydramine 50mg p.o. on both protocols, but patients on protocol B additionally received diphenhydramine 25mg p.o. three times a day and famotidine 20 mg p.o. twice a day during ATG administration. All patients received the following prophylaxis: ursodiol for sinusoidal obstructive syndrome, tacrolimus and MTX for GVHD, as well as levofloxacin, acyclovir and either fluconazole or voriconazole for infections. No patient received a test dose of ATG. Administration and clinical outcomes were retrospectively compared between patients treated on each administration protocol (n= 14 each). Administration outcomes included the number of infusion interruptions, administration of additional corticosteroids, amount of additional ATG needed and the number of patients unable to complete the regimen. Clinical outcomes included data on GVHD and infections including the number and type of microbiologically defined infections and number of patients with escalation to empiric antibacterial and/or treatment dose antifungal. With regard to demographics, patients treated on protocol A had a median age of 49 years (range 24–64 years), 57% male, 79% Caucasian, 71% 10/10 HLA match and 93% received fludarabine +BU, whereas 7% received BU+CY conditioning regimen. Patients on protocol B had a median age of 52 years (range 32–67 years), 64% male, 93% Caucasian, 93% 10/10 HLA match and 79% received fludarabine+BU, whereas 14% received BU+CY and 7% fludarabine+CY conditioning regimen. Conditioning regimens were as follows: fludarabine i.v. 30 mg/m and BU i.v. 130mg/m (target area under the curve (AUC) 4800 μmol/L) once daily days − 6 through − 3; BU 0.8 mg/kg i.v. q6h (target AUC 1200 μmol/L) days − 7 through − 4 and CY 60mg/kg i.v. days − 3 and − 2; fludarabine i.v. 30 mg/m days − 7 through − 4 and CY 60mg/kg i.v. days − 3 and − 2. Over the course of ATG administration, the infusion was interrupted 12 times for 14 patients treated on protocol A and 7 times for 14 patients on protocol B. When each dose of ATG was treated independently, the number of times the infusion was interrupted over the course of ATG administration was not significantly different between protocols (28.6% vs 12.5%, P= 0.0696; Fisher’s exact). The number of times additional steroids were administered for ATG infusion reaction management was significantly more frequent in protocol A vs B (P= 0.0001; Fisher’s exact) (Table 1). No clear association between protocols was found with respect to the number of patients experiencing fever, rigors, tachycardia and/or alterations in blood pressure on each ATG day (data not shown). Although the percent of patients experiencing fever, rigors or tachycardia appeared to be lower for protocol B on the first 2 days of ATG, this was not consistent for alterations in blood pressure or for the third day. For each ATG infusion day the mean heart rates did not appear to be different between groups. In both groups, 3/14 (21%) had the ATG infusion interrupted due to infusion reaction symptoms and were not able to receive the full dose on the prescribed day. For patients on protocol A, the amount administered on an additional day to complete the regimen ranged 11–33% of the total ATG dose vs 2.5–11% for patients on protocol B. Given dose rounding policies at many institutions, a difference between ordered and administered of o5–10% may be considered clinically irrelevant. Notably, two of the three patients in protocol B had the make-up dose added to the last scheduled day of ATG; this allowed for less additional steroid premedication and a reduction in nursing administration time for make-up doses for patients treated on protocol B. Bone Marrow Transplantation (2014) 49, 1535–1537

Impact of fluoroquinolone prophylaxis on infectious-related outcomes after hematopoietic cell transplantation

Background Patients immediately post-hematopoietic cell transplantation are at high risk for bacteremia. Judicious prophylactic antimicrobial utilization must balance anticipated benefits (reduction infections) versus risk (bacterial resistance, Clostridium difficile). Objective To compare infectious outcomes (primary: incidence bacteremia; secondary: febrile neutropenia, C. difficile, susceptibility of bacteremia, time to discharge and 30-day mortality) between hematopoietic cell transplantation who received fluoroquinolone prophylaxis to those who did not. Methods A local institutional review board-approved retrospective study was conducted on all hematopoietic cell transplantation patients (nu2009=u2009171) comparing those who received fluoroquinolone prophylaxis (nu2009=u2009105) to those who did not (nu2009=u200966). Data included infectious outcomes and mortality for the first 30 days post-hematopoietic cell transplantation. Chi-squared was performed for categorical variables (GraphPad Software Inc., 2015). Secondary analysis compared outcomes within autologous and allogeneic sub-groups. Results Bacteremia was significantly lower for the overall cohort receiving fluoroquinolone (median duration eight days) versus those without fluoroquinolone (15.2% vs. 31.8%; Pu2009<u20090.01). No difference was seen in C. difficile infection (Pu2009=u20090.81) or 30-day mortality (2.9% vs. 4.5%; Pu2009=u20090.67). In the autologous sub-group (nu2009=u2009115), bacteremia was significantly lower in the fluoroquinolone cohort (8.5% vs. 27.3%; Pu2009=u20090.0069), while no differences were seen in C. difficile infection (Pu2009=u20091) or 30-day mortality (Pu2009=u20091). In the allogeneic sub-group (nu2009=u200956), there was no difference between those with and without fluoroquinolone in bacteremia (29.4% vs. 40.9%; Pu2009=u20090.4) or C. difficile (Pu2009=u20090.72); however, there was a trend toward improved 30-day mortality (2.9% vs. 9.1%; Pu2009=u20090.55). Conclusions Fluoroquinolone prophylaxis reduces incidence of bacteremia in autologous hematopoietic cell transplantation without increasing C. difficile after hematopoietic cell transplantation.

Acute Kidney Injury in Hematopoietic Cell Transplantation Patients Receiving Vancomycin and Piperacillin/Tazobactam Versus Vancomycin and Cefepime

Empiric antimicrobials are frequently utilized in the pre-engraftment phase after hematopoietic cell transplantation (HCT). Recent evidence suggests an increased risk of acute kidney injury (AKI) from combination of vancomycin with piperacillin/tazobactam; however, this has not specifically been evaluated in the HCT population. A single-center, retrospective review was conducted from 2011 to 2017 on 110 autologous and 60 allogeneic HCT patients with the primary objective of comparing incidence of AKI for those who received vancomycin with piperacillin/tazobactam versus vancomycin with cefepime in the pre-engraftment phase. Demographics and outcomes were compared for all patients who received vancomycin with piperacillin/tazobactam versus vancomycin with cefepime as well as within the autologous and allogeneic subgroups. The primary endpoint of incidence of AKI, defined as increase in serum creatinine by .3u2009mg/dL oru2009>50% from baseline (whichever was larger), was significantly higher for those who received vancomycin with piperacillin/tazobactam versus cefepime for the overall cohort (68% versus 27%; Pu2009<u2009.001) resulting in an odds ratio (OR) of 5.16 (95% confidence interval [CI], 2.5 to 10.5) when adjusting for hypotension. Results were similar within the autologous (59% versus 22%; Pu2009<u2009.001; OR, 4.63; 95% CI, 1.85 to 11.6) and allogeneic (79% versus 39%; P=u2009.0021; OR, 5.41; 95% CI, 1.60 to 18.3) subgroups. Within the overall cohort between those who received vancomycin with piperacillin/tazobactam versus cefepime the time to onset of AKI was more commonly within 48 hours of concomitant antimicrobial use (53% versus 26%; P=u2009.012), whereas resolution of AKI by discharge date was not different (39% versus 26%; P=u2009.23). No difference in percentage of patients requiring at least 1 session of dialysis, duration of hospital stay, or 30-day mortality was found between overall cohorts. Further studies of HCT patients are warranted to fully elucidate the risk of various combination antimicrobial regimens on renal outcomes.

Treatment of refractory anemia with ring sideroblasts associated with marked thrombocytosis with lenalidomide in a patient testing negative for 5q deletion and JAK2 V617F and MPL W515K/L mutations

Refractory anemia with ring sideroblasts associated with marked thrombocytosis (RARS-T) is a hematologic malignancy that often results in transfusion dependency and a hypercoagulable state. This rare disease currently lacks formal guidelines for treatment; however, various case reports have demonstrated efficacy in the use of lenalidomide. This immunomodulatory drug has shown promise in patients with 5q deletions, with reports of achieving transfusion independence and normalization of platelet counts. Herein we present the case of a 68-year-old African American woman with RARS-T who tested negative for 5q deletion and JAK2 V617F and MPL W515K/L mutations. Her treatment with lenalidomide therapy resulted in a five-year durable complete clinical response.