RICE is salvage therapy for treating CD20+non-Hodgkin lymphoma (NHL). It is combined with G-CSF to collect autologous peripheral blood stem cells (aPBSC). Little data exists, though, on the combination of G-CSF and Plerixafor after RICE in mobilizing adequate number of CD34 cells and the product’s immune content. We report on the results of twenty CD20+ NHL patients after RICE, G-CSF and Plerixafor were given to collect aPBSC. The median number of cells collected was 12.92 × 106 CD34 cells/kg (range 5.44-83.76). Plerixafor toxicity included diarrhea (n = 5) and injection-site irritation (n = 1). Seventeen patients collected; fifteen patients did so in one session. Two patients with CLL/Richter or transformed follicular had positive-flow products. Addition of Plerixafor to G-CSF increased by 2.6-9 folds the number of blood CD34 cells. Sixteen patients went to ASCT, with a median of 7.29 × 106 CD34 cells/kg infused. The median engraftment time post-ASCT for neutrophils was 12 (range 10-19), for platelets ≥20K 11 (range 0-19) and ≥50K 16.5 (range 11-42) days. There were no graft failures. In APBSC product, there was no evidence of NK or LAK lytic activity (n = 10), only LAK activity (n = 4) and both LAK and NK activity (n = 2). Blood NK activity was common on day +28 post-ASCT. There was no significant correlation between apheresis product and the number of blood immune cells post- ASCT or relapse. Addition of Plerixafor to RICE/G-CSF is well tolerated. The majority of patients collected aPBSC in one session.

1Department ofMedicine, Massachusetts General Hospital, Boston, Massachusetts, USA 2Department of LaboratoryMedicine and Pathology, Seattle,Washington, USA 3Department of Pathology, City of HopeMedical Center, Duarte, California, USA 4Division of Hematology, University ofWashington, Seattle,Washington, USA 5Division of Rheumatology, University ofWashington, Seattle,Washington, USA 6FredHutchinson Cancer Center, Seattle,Washington, USA

During the Coronavirus disease 2019 pandemic, cryopreservation of allogeneic donor stem cell products ensured the availability of products at the start of conditioning for hematopoietic cell transplantation (HCT). Following recommendations from unrelated donor registries, including the National Marrow Donor Program, many centers began to cryopreserve related donor peripheral blood stem cell (PBSC) products. Throughout this process, several centers have published outcomes with cryopreserved versus fresh products, some with conflicting results. Even though cryopreservation was initially considered only a temporary measure driven by the pandemic, potential advantages include greater flexibility of transplantation timing. However, concerns about detrimental effects of cryopreservation, including increased risk of graft rejection, relapse, and consequent mortality, remained. The primary objective of the present study was to describe our center's experience comparing outcomes following PBSC transplantation with cryopreserved versus fresh grafts. This was an observational case study with a retrospective review comparing cryopreserved grafts (n = 213) to a recent historical cohort (controls) using fresh grafts (n = 167). In multivariable analyses, the adjusted hazard ratio (HR) for fresh versus cryopreserved grafts was 1.20 (95% confidence interval [CI], .79 to 1.82; P = .40) for overall mortality, .99 (95% CI, .55 to 1.77; P = .98) for nonrelapse mortality, and .94 (95% CI, .60 to 1.48; P = .80) for relapse. The adjusted HR for platelet engraftment was 1.31 (95% CI, 1.05 to 1.63; P = .02) and the odds ratio of grade III-IV acute GVHD was 1.75 (95% CI, 1.01 to 3.04; P = .05) with fresh grafts compared to cryopreserved grafts. There was no demonstrable difference in the risk of chronic GHVD. Although longer-term follow-up is needed, these data provide preliminary reassurance that in the event of another pandemic or should the logistical need arise in individual patients, cryopreservation of PBSC products is a reasonably safe alternative.

A major barrier for proceeding to autologous stem cell transplantation (ASCT) is an inability to mobilize and collect an adequate number of peripheral blood (PB) stem cells (PBSC) for the transplant graft. Plerixafor added to granulocyte colony stimulating factor (G-CSF) alone, without prior chemotherapy, significantly improves the mobilization of autologous PBSC in patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). However, the efficacy of plerixafor and the best timing to give the drug to poorly mobilizing patients with very low PB CD34+ cell counts after salvage chemotherapy and G-CSF are not well defined. We hypothesized that PBSC mobilization and collection might be improved in heavily treated patients who mobilized very poorly after salvage chemotherapy and G-CSF by alternating the days of plerixafor administration and leukapheresis. A day of rest between plerixafor doses, while continuing G-CSF, could allow time for some replenishment of the marrow stem/progenitor cell pool before the next mobilization. A retrospective review of collection results in poorly mobilizing patients at our center was undertaken. Three cohorts were identified: those who got every-other-day plerixafor and leukapheresis, those who got sequential plerixafor and leukapheresis and those who got risk adapted plerixafor. Overall, 69% of patients with NHL and MM with PB CD34+ cell counts <5/µL after salvage chemotherapy and G-CSF were ultimately able to collect adequate CD34+ cells to support ASCT using daily plerixafor and leukapheresis. On the alternating plerixafor and leukapheresis schedule, all 17 patients achieved the cumulative CD34+ cell product goals required for ASCT. This positive observation after salvage chemotherapy and G-CSF led to the incorporation at our center of an alternate-day schedule of plerixafor and leukapheresis into our real-time risk adapted strategy for poor mobilizers. © 2023 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Pre-harvest autologous blood collection from bone marrow (BM) donors is performed to meet potential post-operative transfusion needs. This study examines the impact of autologous blood transfusion on BM donor's health and safety. The study included first-time unrelated BM donors from the United States whose BM harvest was facilitated by the National Marrow Donor Program (NMDP) centers between 2006 and 2017. Examination of 7024 BM donors revealed that 60% received at least one unit of autologous blood. The donors who received autologous blood were older, had lower hemoglobin pre-harvest, underwent longer duration of anesthesia, and higher volume BM harvest. Only donors who underwent high-volume BM harvest, defined as a BM harvest volume >27% of donor's blood volume, benefited from autologous transfusion. After a high-volume BM harvest, autologous blood transfusion was shown to decrease grade 2 to 4 collection-associated toxicities within 48 h of BM donation (p = 0.010) and shorten the time to donor-reported "complete" recovery from donation-associated symptoms (p < 0.001). Therefore, autologous transfusion could be avoided as support of marrow donation in the majority of unrelated BM donors and should be limited to cases where the planned BM harvest volume is expected to exceed 27% of donor's blood volume.

The incidence and risk factors for severe adverse events (SAEs) in related donors (RD) of hematopoietic cell transplants is unknown. The Related Donor Safe study is a prospective observational cohort of 1680 RDs and represents an opportunity to examine characteristics of SAEs in RDs. In this cohort, we found that SAEs were reported in a total 12 (0.71%) RDs. Of these, 5 SAEs occurred in bone marrow donors (5/404, 1.24%), and 7 (7/1276, 0.55%) were in donors of peripheral blood stem cells. All of the SAEs were considered to be related (definite, probable, or possible) to the donation process. There were no donor fatalities. Of the 12 RDs who experienced an SAE, 10 were either overweight or obese. Five of the 12 RDs had predonation medical conditions that would have resulted in either possible or definite ineligibility for donation were they being assessed as unrelated donors. These SAE data will be useful in the counseling of prospective RDs before planned donation and may be helpful in identifying donors who should be considered medically unsuitable for donation.

The porphyrias are a family of metabolic disorders caused by defects in the activity of one of the enzymes in the heme biosynthetic pathway. Acute intermittent porphyria (AIP), caused by autosomal dominant mutations in the gene encoding hydroxymethylbilane synthase, can lead to hepatocyte overaccumulation and systemic distribution of the proximal porphyrin precursors, 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). ALA and PBG are toxic to neurons and extrahepatic tissue and cause the neurovisceral clinical manifestations of AIP. Management of AIP includes awareness and avoidance of triggering factors, infusions of hemin for severe acute attacks, and, if indicated for chronic suppressive therapy, maintenance treatment with hemin or givosiran, a small interfering RNA molecule that antagonizes ALA synthase 1 transcripts. Erythropoietic protoporphyria (EPP) is most commonly caused by autosomal recessive mutations in the gene encoding ferrochelatase (FECH), the heme pathway terminal enzyme. FECH deficiency leads to erythrocyte overaccumulation and high plasma levels of lipophilic protoporphyrins that photoactivate in the skin, causing burning pain and erythema. Protoporphyrins excreted in the bile can cause gallstones, cholestasis, fibrosis, and ultimately liver failure. Management of EPP includes skin protection and afamelanotide, an α-melanocyte stimulating hormone analog that increases melanin pigment and reduces photoactivation. Liver transplantation may be necessary for severe EPP-induced liver complications. Because AIP and EPP arise from defects in the heme biosynthetic pathway, hematologists are often consulted to evaluate and manage suspected or proven porphyrias. A working knowledge of these disorders increases our confidence and effectiveness as consultants and medical providers.

Multiple investigations have documented the health-related quality-of-life (HRQoL) and donation-related experiences of unrelated donors (URDs), but similar investigations of the related donor (RD) experience have been less common. The central goal of this study was to longitudinally examine and compare HRQoL of RD and URD hematopoietic stem cell (HSC) donors from predonation through 1 year postdonation. This prospective investigation included adult HSC donors ages 18 to 60 years who donated bone marrow or peripheral blood stem cells at one of 48 geographically diverse US transplant/donor centers and completed HRQoL interviews at predonation and 4 weeks and 1 year postdonation. At predonation, related donors were less ambivalent about donation (t = -3.30; P = .001), more satisfied with their decision to donate (t = 2.65; P = .009), and more likely to define themselves as donors (t = 2.94; P = .004) than were URDs. However, related donors were more concerned about the use of needles (odds ratio [OR] = 2.19; P = .012), about who would pay for the procedure (OR = 2.80; P = .011), and the possibility that they would feel responsible if the transplant failed (t = 2.31; P = .022). Shortly postdonation, related donors were more likely to report donation-related pain (t = 2.50; P = .013) and lightheadedness (OR = 3.63; P = .028). At 1 year postdonation, related donors were less likely to be fully recovered from donation (OR = 0.10; P = .010) and more likely to report a longer recovery period following donation (t = 2.57; P = .011), although this latter finding was primarily due to the percentage of related versus unrelated donors not fully recovered at 1 year postdonation (10% versus 1%). Taken together, these findings suggest that current related donor management practices may be sufficient in preparing related donors for the psychological aspects of donation but that there may be more to do in terms of calibrating the description of donation-related experiences and recovery time to the related donor group (i.e., descriptions of donation experiences based on unrelated donation may not provide best estimates of experience for this group). (C) 2020 Published by Elsevier Inc. on behalf of the American Society for Transplantation and Cellular Therapy

See article on page 2360–2369, in this issue

Unlike unrelated donor registries, transplant centers lack uniform approaches to related donor assessment and deferral. To test whether related donors are at increased risk for donation-related toxicities, we conducted a prospective observational trial of 11,942 related and unrelated donors aged 18–60 years. Bone marrow (BM) was collected at 37 transplant and 78 National Marrow Donor Program centers, and peripheral blood stem cells (PBSC) were collected at 42 transplant and 87 unrelated donor centers in North America. Possible presence of medical comorbidities was verified prior to donation, and standardized pain and toxicity measures were assessed pre-donation, peri-donation, and one year following. Multivariate analyses showed similar experiences for BM collection in related and unrelated donors; however, related stem cell donors had increased risk of moderate [odds ratios (ORs) 1.42; P

The development of reduced-intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RDs) of peripheral blood stem cells (PBSCs). The effects of age on donation efficacy, toxicity, and long-term recovery in RDs are poorly understood. To address this we analyzed hematologic variables, pain, donation-related symptoms, and recovery in 1211 PBSC RDs aged 18 to 79 enrolled in the Related Donor Safety Study. RDs aged > 60 had a lower median CD34+ level before apheresis compared with younger RDs (age > 60, 59 × 106/L; age 41 to 60, 81 × 106/L; age 18 to 40, 121 × 106/L; P < .001). This resulted in older donors undergoing more apheresis procedures (49% versus 30% ≥ 2 collections, P < .001) and higher collection volumes (52% versus 32% > 24 L, P < .001), leading to high percentages of donors aged > 60 with postcollection thrombocytopenia <50 × 109/L (26% and 57% after 2 and 3days of collection, respectively). RDs aged 18 to 40 had a higher risk of grades 2 to 4 pain and symptoms pericollection, but donors over age 40 had more persistent pain at 1, 6, and 12 months (odds ratio [OR], 1.7; P = 0.02) and a higher rate of nonrecovery to predonation levels (OR, 1.7; P = .01). Donors reporting comorbidities increased significantly with age, and those with comorbidities that would have led to deferral by National Marrow Donor Program unrelated donor standards had an increased risk for persistent grades 2 to 4 pain (OR, 2.41; P < .001) and failure to recover to predonation baseline for other symptoms (OR, 2.34; P = .004). This information should be used in counseling RDs regarding risk and can assist in developing practice approaches aimed at improving the RD experience for high-risk individuals.

BACKGROUNDThe clinical and procedural parameters that affect the optimal collection of lymphocytes for the production of chimeric antigen receptor (CAR) T cells remain undefined but are increasingly important, as commercial products are now available. We evaluated determinants of low lymphocyte collection efficiency (CE) and the rate of successful CAR T‐cell manufacture in middle‐aged and older adults with advanced B‐cell malignancies.STUDY DESIGNS AND METHODSMononuclear cell collections using two apheresis platforms (COBE Spectra and Spectra Optia, Terumo BCT) from patients participating in a CD19‐directed CAR T‐cell therapy trial were reviewed. Patient‐ and disease‐specific factors, peripheral blood counts, apheresis parameters, and product cell counts were analyzed to determine effects on lymphocyte CE.RESULTSNinety‐two apheresis events from patients with acute lymphocytic leukemia (ALL) (n = 28), chronic lymphocytic leukemia (n = 18), and non‐Hodgkin lymphoma (n = 46) were available for analysis. Forty‐one collections (45%) had a lymphocyte CE of <40%. On multivariable analysis, age (every 10‐year increase, odds ratio [OR] = 1.51; p = 0.034), disease type (chronic lymphocytic leukemia vs. ALL, OR = 0.24; p = 0.052; non‐Hodgkin lymphoma vs. ALL, OR = 0.20; p = 0.009) and precollection platelets (every 10 × 103/μL increase, OR = 1.07; p = 0.005) were appreciably associated with a lymphocyte CE of <40%. No major apheresis complications occurred.CONCLUSIONSLymphocyte collection at our center was well tolerated and 100% successful in manufacturing CD19‐directed CAR T cells from adult patients with B‐cell malignancies despite low CE in some patients. A diagnosis of ALL, advancing age, and higher preapheresis platelet counts were observed to be associated with low CE.

The Choosing Wisely campaign has stimulated clinicians to think about the appropriateness of various tests and procedures, compelling physicians to make smarter, safer and more effective choices for high quality patient care and to reduce healthcare cost. The American Society for Apheresis (ASFA) strives to advance apheresis medicine through education, evidence-based practice, research and advocacy. To complement these shared missions, ASFA created a working group, consisting of representatives from the various ASFA committees, to produce recommendations for apheresis medicine that reflect the Choosing Wisely guiding principles. A diverse group of ASFA physician and allied health members reviewed, rated and ranked 9 original draft proposals. Additional revisions and refinements were made prior to external review and adoption of five final recommendations by the ASFA Board of Directors. The ASFA Choosing Wisely recommendations encourage apheresis practitioners, patients and donors to discuss and prioritize best clinical practices that avoid harm and waste while optimizing clinical benefit.

Although donation of bone marrow (BM) or peripheral blood stem cells (PBSCs) from children to family members undergoing allogeneic transplantation are well-established procedures, studies detailing levels of pain, symptoms, and long-term recovery are lacking. To address this lack, we prospectively enrolled 294 donors age <18 years at 25 pediatric transplantation centers in North America, assessing them predonation, peridonation, and at 1 month, 6 months, and 1 year postdonation. We noted that 71% of children reported pain and 59% reported other symptoms peridonation, with resolution to 14% and 12% at 1 month postdonation. Both older age (age 13 to 17 years versus younger) and female sex were associated with higher levels of pain peridonation, with the highest rates in older females (57% with grade 2-4 pain and 17% with grade 3-4 pain). Multivariate analyses showed a 4-fold increase in risk for older females compared with males age <13 years (P <.001). At 1 year, 11% of 13- to 17-year-old females reported grade 2-4 pain, compared with 3% of males age 13 to 17 years, 0% of females age <13 years, and 1% of males age <13 years (P = .01). Males and females age 13 to 17 years failed to return to predonation pain levels at 1 year 22% and 23% of the time, respectively, compared with 3% and 10% in males and females age <13 years (P = .002). Our data show that females age 13 to 17 years are at increased risk of grade 2-4 pain at 1 year and >20% of females and males age 13 to 17 years do not return to baseline pain levels by 1 year after BM donation. Studies aimed at decreasing symptoms and improving recovery in older children are warranted.

Background: The development of reduced intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RD) of PBSC. The effects of age on donation efficacy, toxicity, and long-term recovery in RD are poorly understood. Methods: We analyzed hematologic variables, pain, donation-related symptoms and recovery in 1211 related PBSC donors aged 18-79 enrolled in the Related Donor Safety Study (RDSafe). Results: RD >60 had a lower median CD34 level pre-apheresis compared to younger RD (age >60, 59x106/L; age 41-60, 81x106/L; age 18-40, 121x106/L; p 24L, p 60 with post-collection thrombocytopenia <50x109/L (26% and 57% after 2 and 3 days of collection, respectively). RD age 18-40 had a higher risk of grade 2-4 pain and symptoms peri-collection, burrt donors above age 40 had more persistent pain at 1, 6, and 12 months (OR1.7, p=0.02) and a higher rate of non-recovery to pre-donation levels (OR 1.7, p=0.01). Donors reporting comorbidities increased significantly with age, and those with comorbidities that would have led to deferral by NMDP unrelated donor standards had an increased risk for persistent grade 2-4 pain (OR=2.41, p<0.001) and failure to recover to pre-donation baseline for other symptoms (OR=2.34, p=0.004). Conclusion: This information should be used in counseling RD regarding risk and can assist in developing practice approaches aimed at improving the RD experience for high-risk individuals. Funding Statement: This study was funded by R01 HL085707 through the NHLBI. Additional funding for MAP was provided by 2UG1HL069254 (NHLBI/NCI) and the Johnny Crisstopher Children’s Charitable Foundation St. Baldrick’s Consortium Grant. Conflict of Interests: None of the authors has any conflict of interest to declare. Ethical Approval Statement: If approved for donation, RD were approached for consent for this IRB approved study if they were willing and able to complete symptom reviews at 1, 6 and 12 months after donation administered by the CIBMTR Survey Research Group.

Transfusion practices for bone marrow harvests: a survey analysis from the AABB Bone Marrow Quality Improvement Initiative Working Group

Hematopoietic cell transplantation (HCT) provides potentially curative treatment for patients with myelofibrosis (MF). HCT outcomes are associated with the Dynamic International Prognostic Scoring System (DIPSS) risk scores. In the present study we analyzed results in 233 patients to determine if the DIPSS plus classification, which adds cytogenetics, thrombocytopenia, and RBC transfusion dependence as risk factors, would better predict post-HCT outcomes than the original DIPSS. Multivariate analysis showed that each risk parameter incorporated into the DIPPS plus model contributed to its predictive power of overall mortality, relapse-free survival, and nonrelapse mortality. The 5-year overall survival (OS), relapse, and treatment-related mortality (TRM) rates for patients with low/intermediate-1 risk MF were 78%, 5%, and 20%, respectively. The 5-year OS, relapse, and TRM rates for patients with high-risk MF were 35%, 28%, and 40%, respectively. The HCT-specific comorbidity index of 3 or greater was associated with higher nonrelapse and overall mortality and reduced relapse-free survival. The relapse incidence was significantly increased in older patients (HR, 3.02; P = .0007). With a median follow-up of 8 years 124 patients (53%) were surviving. The components of the DIPSS plus classification still have prognostic relevance after adjustment by the DIPSS classification. This information should enhance our ability to advise patients when making decisions regarding timing of transplant. (C) 2017 American Society for Blood and Marrow Transplantation.

The increasing number of older adults with blood-related disorders and the introduction of reduced intensity conditioning regimens has led to increases in hematopoietic stem cell (HSC) transplantation among older adults and a corresponding increase in the age of siblings who donate HSCs to these patients. Data regarding the donation-related experiences of older donors are lacking. The Related Donor Safety Study aimed to examine/compare health-related quality of life (HRQoL) of older versus younger HSC donors. Sixty peripheral blood stem cell (PBSC) donors ages 18 to 60 years and 104 PBSC donors age >60 years completed validated questionnaires before donation and 4 weeks and 1 year after donation. Before donation, older donors had poorer general physical health (t = 3.27; P=.001) but better mental health (t = 2.11; P<.05). There were no age differences in multiple other donation-related factors. At 4 weeks after donation, there were no group differences in general physical/mental health, but older donors were less likely to report donation-related pain (t=-2.26; P<.05) and concerns (t=-3.38; P=.001). At both 4 weeks and 1 year after donation, there were no significant differences in the percentage of each age group feeling physically back to normal or in the number of days it took donors to feel completely well. There was no evidence that increasing age within the older donor group was associated with poorer donation-related HRQoL. Taken together, these data support the current practice of HSC donation by sibling donors above age 60, providing no evidence of worsening HRQoL up to 1 year after donation in individuals up to age 76. (C) 2017 American Society for Blood and Marrow Transplantation.