Impact of plerixafor use in the mobilization of blood grafts for autologous hematopoietic cell transplantation.

Plerixafor (PLER), a reversible antagonist of the CXC chemokine receptor type 4, has been in clinical use for mobilization of blood grafts for autologous hematopoietic cell transplantation (AHCT) for about 15 years. Initially PLER was investigated in placebo-controlled trials with the granulocyte colony-stimulating factor (G-CSF) filgrastim. It has also been used in combination with chemotherapy plus G-CSF in patients who had failed a previous mobilization attempt or appeared to mobilize poorly with current mobilization (preemptive use). This review summarizes what is known regarding addition of PLER to standard mobilization regimens. PLER increases mobilization of CD34+ cells, decreases the number of apheresis sessions needed to achieve collection targets and increases the proportion of patients who can proceed to AHCT. It appears also to increase the amount of various lymphocyte subsets in the grafts collected. In general, hematologic recovery after AHCT has been comparable to patients mobilized without PLER, although slower platelet recovery has been observed in some studies of patients who mobilize poorly. In phase III studies, long-term outcome has been comparable to patients mobilized without PLER. This also appears to be the case in patients receiving plerixafor for poor or suboptimal mobilization of CD34+ cells. In practice, PLER is safe and has not been shown to increase tumor cell mobilization.

Adverse impact of delay of platelet recovery after autologous hematopoietic cell transplantation for aggressive non-Hodgkin lymphoma and multiple myeloma.

BACKGROUND AIMS: The prognostic impact of platelet recovery after autologous hematopoietic cell transplantation (AHCT) on clinical outcomes remains to be elucidated. We aimed to clarify the impact of platelet recovery on clinical outcomes, risk factors of delayed platelet recovery and the necessary dose of CD34+ cells for prompt platelet recovery in each patient. METHODS: Using a nationwide Japanese registry database, we retrospectively analyzed clinical outcomes of 5222 patients with aggressive non-Hodgkin lymphoma (NHL) or multiple myeloma (MM). RESULTS: At a landmark of 28 days after AHCT, a delay of platelet recovery was observed in 1102 patients (21.1%). Prompt platelet recovery was significantly associated with superior overall survival (hazard ratio [HR] 0.32, P < 0.001), progression-free survival (HR 0.48, P < 0.001) and decreased risks of disease progression (HR 0.66, P < 0.001) and non-relapse/non-progression mortality (HR 0.19, P < 0.001). The adverse impacts of a delay of platelet recovery seemed to be more apparent in NHL. In addition to the dose of CD34+ cells/kg, disease status, performance status and the hematopoietic cell transplant-specific comorbidity index in both diseases were associated with platelet recovery. We then stratified the patients into three risk groups according to these factors. For the purpose of achieving 70% platelet recovery by 28 days in NHL, the low-, intermediate- and high-risk groups needed more than 2.0, 3.0 and 4.0 × 106 CD34+ cells/kg, respectively. In MM, the low-risk group needed approximately 1.5 × 106 CD34+ cells/kg, whereas the intermediate- and high-risk groups required 2.0 and 2.5 × 106 CD34+ cells/kg to achieve about 80% platelet recovery by 28 days. CONCLUSIONS: A delay of platelet recovery after AHCT was associated with inferior survival outcomes.

Autologous hematopoietic cell transplantation versus whole-brain radiotherapy consolidation in primary central nervous system lymphoma: A systematic review and meta-analysis.

The management of newly diagnosed primary central nervous system lymphoma (PCNSL) includes administration of high-dose methotrexate based regimens followed by consolidation therapy to minimize the risk of relapse. However, the best consolidation strategy (autologous hematopoietic cell transplant [auto-HCT] vs. whole-brain radiotherapy [WBRT]) is controversial. Hence, we performed a systematic review and meta-analysis of all randomized controlled trials that compared auto-HCT versus WBRT consolidation for patients with PCNSL after first-line treatment.The primary outcome was overall survival (OS), while the secondary outcomes included progression-free survival (PFS), response rates (overall response rate [ORR] and complete remission [CR]), relapse rate, treatment-related mortality (TRM), and neuropsychological adverse events. We performed a pooled analysis of the single-arm studies that incorporated auto-HCT or WBRT consolidation and evaluated neurocognitive outcomes. Only two studies met the inclusion criteria (n = 240). There was no significant difference in OS (HR = 1.50; 95% CI = 0.95-2.36), PFS (HR = 0.99; 95% CI = 0.44-2.22), ORR (RR = 1.48; 95% CI = 0.90-2.44), CR rate (RR = 1.21; 95% CI = 0.90-1.63), relapse rate (RR = 0.46; 95% CI = 0.05-4.28), and TRM (RR = 5.67; 95% CI = 1.01-31.91). The neuropsychological tests to assess neurocognitive domains were different and inconsistently reported in the two studies and therefore we were unable to perform a meta-analysis but provide a descriptive assessment. Both the studies showed a significant decline in the attention/executive function (based on the trail making test A and trail making test B) in those receiving WBRT compared to auto-HCT. We found 9 single-arm phase II studies that reported data on outcomes associated with either auto-HCT (5 studies) or WBRT (4 studies) consolidation. Of these, two studies (n = 43) reported data on neurocognitive decline following auto-HCT consolidation. Pooled proportion of patients with neurocognitive decline in these studies was 6% (95% CI, 0%-17%) for those receiving auto-HCT and there was no heterogeneity between studies (I2  = 0%). Three studies (n = 122) reported data on neurocognitive decline following WBRT consolidation. Pooled proportion of patients with neurocognitive decline in these studies was 43% (95% CI, 11%-78%) for those receiving WBRT and there was high heterogeneity between studies (I2  = 94%). There was significant heterogeneity between subgroups (p = 0.035). The outcomes were not significantly different in patients with PCNSL receiving auto-HCT or WBRT consolidation therapies, however, there is a higher degree of neurocognitive decline associated with WBRT compared to auto-HCT consolidation. The decision to choose a consolidation strategy needs to be individualized based on age, frailty, and co-morbidities.

The role of additional chemotherapy prior to autologous HCT in patients with relapse/refractory DLBCL in partial remission-A retrospective multicenter study.

OBJECTIVES: To evaluate the role of additional chemotherapy before autologous hematopoietic cell transplantation (HCT) in patients with relapse/refractory diffuse large B-cell lymphoma (DLBCL) who achieve partial remission following first salvage therapy. METHODS: We conducted a multicenter retrospective study of all adult patients with DLBCL who underwent HCT between 2008 and 2020 and achieved partial response (PR) after the first salvage and were either referred directly to HCT (n = 47) or received additional salvage therapy before HCT (n = 22). RESULTS: Post-HCT CR rate and progression-free survival were comparable between the two groups (66% vs. 68%, p = .86 and median not reached vs. 10.2 months [95% confidence interval, CI 7.1-12.3], p = .27, respectively). Median overall survival (OS) and estimated 3-year OS favored patients who were directly referred to HCT (105.8 [95% CI 63-148] months vs. 14.5 [95% CI 0-44] months, p = .035, and 65% [95% CI 51%-75%] vs. 40% [95% CI 21%-53%], p = .035, respectively). In Cox regression model, while International Prognostic Index and primary refractory versus relapse disease did not impact OS, allocation to a second salvage regimen and older age were both associated with inferior survival (hazard ratio [HR] = 2.57 95% CI 1.1-5.8, p = .023 and HR = 1.04 95% CI 0.99-1.2, p = .064, respectively). CONCLUSIONS: Referring patients with chemotherapy-sensitive disease in PR directly to HCT is associated with better OS compared to those receiving additional lines of treatment.

Treatment for relapsed acute promyelocytic leukemia.

The advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has significantly improved the outcomes of acute promyelocytic leukemia (APL); nevertheless, a small fraction of patients still experience relapse. Due to the infrequency of APL relapse coupled with the rapid change in the therapeutic landscape, there are limited available data regarding the treatment of relapsed APL. In this situation, however, ATO-based therapy has been shown to result in high rates of hematological and molecular complete remission (CR). Autologous hematopoietic cell transplantation (HCT) is considered the postremission therapy of choice when patients achieve molecular CR, whereas recent studies have suggested that molecular CR is not prerequisite for the success of autologous HCT. Allogeneic HCT can be reserved for selected patients, i.e., those who cannot achieve CR and those who relapse after autologous HCT, because of high toxicities and the expectation of highly favorable outcomes with autologous HCT during CR. For patients who are ineligible for HCT, prolonged administration of ATRA + ATO would be a viable option. To further refine the therapy for patients with relapsed APL, it is imperative to aggregate clinical data of patients who relapse after the ATRA + ATO frontline therapy within the framework of national and international collaboration.

Successful treatment of metastatic pancreatoblastoma in an adult with autologous hematopoietic cell transplant.

BACKGROUND: Pancreatoblastoma is a rare pediatric malignant neoplasm characterized by its histological resemblance to fetal pancreatic tissue and poor clinical outcomes. Preoperative diagnosis of the neoplasm is difficult due to its rarity, variable clinical presentation, and its lack of distinct laboratory markers. Current mainstay of treatment is surgical resection of the tumor, although a standard of care has not yet been established. METHODS: Data were collected on one patient admitted to the University of Virginia Hospital System. Radiology, hematopoietic cell transplant, and biopsy data were collected according to the best clinical practice. RESULTS: Herein, we describe the case of an adult patient with pancreatoblastoma treated with high-dose chemotherapy and autologous peripheral blood hematopoietic cell transplantation. To the authors' knowledge, this is the first documented successful treatment of pancreatoblastoma using autologous hematopoietic cell transplantation in the United States, and the first successful treatment in an adult patient worldwide. CONCLUSIONS: While it is difficult to draw conclusions based on a single case, we would like to highlight the success of this treatment modality in the management of our patient with a 51-month remission and open further discussion into exploring the use of autologous hematopoietic cell transplantation for pancreatoblastoma. Our patient is currently living 57 months after diagnosis despite the average survival rate being less than 18 months.

Efficacy of proteasome inhibitor-based maintenance following autologous transplantation in multiple myeloma: A systematic review and meta-analysis.

INTRODUCTION: Lenalidomide maintenance, commonly prescribed in the postautologous transplantation (AHCT) setting for multiple myeloma (MM), is associated with development of secondary primary malignancies (SPM). Proteasome inhibitor maintenance (PIM) has also been evaluated in MM. We conduct a systematic review/meta-analysis to assess the efficacy of PIM in MM. METHODS: Performing a comprehensive search of the medical literature using PubMed/Medline and EMBASE on September 11, 2019, we extracted data on clinical outcomes related to benefits (OS, PFS, and depth of hematologic response [DOHR]) and harms (SPM and adverse events). 2144 references were identified; three studies were eligible for inclusion. RESULTS: A total of 1760 patients were included in the analysis; 507 patients received bortezomib and 395 received ixazomib maintenance. Control arms were either placebo (n = 261) or thalidomide (n = 358). PIM did not improve OS (HR 0.88, 95% CI 0.73-1.05, P = .15) but improved PFS (HR 0.77, 95% CI 0.69-0.86, P ≤ .00001) and DOHR (HR 0.88, 95% CI 0.79-0.98, P = .02) compared with control. There were no significant differences between PIM and control regarding SPM (p = NS) and ≥grade 3 peripheral neuropathy (PN) (p = NS). CONCLUSIONS: PIM following AHCT in MM improves PFS and DOHR without an increase in development of SPM or severe PN compared with placebo/thalidomide.

Cost saving, patient centered algorithm for progenitor cell mobilization for autologous hematopoietic cell transplantation.

Administration of plerixafor with granulocyte-colony stimulating factor (G-CSF) mobilizes CD34+ cells much more effectively than G-CSF alone, but cost generally limits plerixafor use to patients at high risk of insufficient CD34+ cell collection based on low peripheral blood (PB) CD34+ counts following 4 days of G-CSF. We analyzed costs associated with administering plerixafor to patients with higher day 4 CD34+ cell counts to decrease apheresis days and explored the use of a fixed split dose of plerixafor instead of weight-based dosing. We analyzed 235 patients with plasma cell disorders or non-Hodgkin's lymphoma who underwent progenitor cell mobilization and autologous hematopoietic cell transplantation (AHCT) between March 2014 and December 2017. Two hundred ten (89%) received G-CSF plus Plerixafor and 25 (11%) received G-CSF alone. Overall, 180 patients (77%) collected in 1 day, 53 (22%) in 2 days and 2 (1%) in 3 days. Based on our data, we present a probabilistic algorithm to identify patients likely to require more than one day of collection using G-CSF alone. CD34+ cell yield, ANC and platelet recovery were not significantly different between fixed and standard dose plerixafor. Plerixafor enabled collection in 1 day and with estimated savings of $5000, compared to patients who did not receive plerixafor and required collection for three days. While collection and processing costs and patient populations vary among institutions, our results suggest re-evaluation of current algorithms.

Propylene Glycol-Free Melphalan versus PG-Melphalan as Conditioning for Autologous Hematopoietic Cell Transplantation for Myeloma.

High-dose melphalan (Mel) conditioning before autologous hematopoietic cell transplantation (autoHCT) is standard of care for patients with transplantation-eligible multiple myeloma. The traditional lyophilized Mel formulation has inadequate solubility and stability after reconstitution, leading to the use of propylene glycol (PG) as a solubilizing agent. A newer PG-free Mel preparation (Evomela) uses beta cyclodextrin captisol as a solubilizing agent and was approved by the United States Food and Drug Administration as a conditioning agent based on a single-phase IIb study showing bioequivalence. We compared the outcomes of consecutive patients with myeloma undergoing autoHCT using the 2 formulations of Mel for conditioning as our center switched from using the older formulation (PG-Mel) to the newer one (PGF-Mel). Of 294 autoHCT recipients, 162 received PG-Mel conditioning and 132 received PGF-Mel conditioning. The PGF-Mel group was older and had a lower average Karnofsky Performance Status score. PGF-Mel was associated with faster neutrophil recovery (median, 12 days versus 13 days; P < .001), fewer grade 3-4 infections within 30 days of autoHCT (1.5% versus 8.0%; P = .048), and a lower 30-day rehospitalization rate (6.8% versus 17.9%; P = .04), as confirmed by propensity-weighted analysis. No significant between-group differences were detected in mucositis, organ toxicity, myeloma response, or 100-day mortality.

Varicella Zoster Virus Infection in Children with Autologous Hematopoietic Cell Transplantation: A Retrospective, Single-Center Study in Korea.

Although long-term antiviral prophylaxis is recommended to prevent varicella zoster virus (VZV) infection in seropositive recipients of allogeneic and autologous (auto-) hematopoietic cell transplantation (HCT), studies of VZV infections in pediatric auto-HCT recipients are rare. This study aimed to investigate the incidence and characteristics of VZV infection in pediatric auto-HCT recipients and explore the risk factors of VZV infection and its effect on survival outcomes. This study included all pediatric patients who underwent auto-HCT at Samsung Medical Center, Seoul, Korea, between January 1998 and December 2013. Before 2006, short-term acyclovir prophylaxis was provided until neutrophil engraftment; thereafter, routine prophylaxis was not provided. Patients who developed either herpes zoster or chickenpox within 2 years from transplantation were identified, and a chart review was performed. A total of 413 recipients and 698 auto-HCTs were included. Sixty-one episodes of VZV infections were identified in 54 patients. Fourteen cases of VZV infection (23%; 14 of 61) occurred within 30 days after auto-HCT. The cumulative incidence of the first episode of VZV infection at 2 years after transplantation was 14% (95% confidence interval [CI], 7.9% to 22.8%) in all recipients and 9% (95% CI, 1.0 to 26.6) in VZV-seronegative patients. Notably, the VZV infection rate increased with age and the VZV infection rate in patients age 15 to 19 years was almost three times higher than in patients age 0 to 4 years (28% versus 10%; P = .003). However, there was no difference in the VZV infection rate between recipients of single auto-HCT and recipients of tandem auto-HCT. Two patients died of disseminated VZV infection. VZV infection is a considerable risk in auto-HCT recipients with or without short-term prophylaxis. Universal antiviral prophylaxis might be considered, particularly in older children, regardless of VZV serologic results. To our knowledge, this is the largest study of VZV infection in pediatric auto-HCT recipients reported to date.

Survivorship after Autologous Hematopoietic Cell Transplantation for Lymphoma and Multiple Myeloma: Late Effects and Quality of Life.

Although autologous hematopoietic cell transplantation (AHCT) is standard therapy for patients with lymphoma and multiple myeloma (MM), few studies have addressed late effects and quality of life (QoL) in long-term survivors after AHCT. Using long-term follow-up (LTFU) annual questionnaires with self-reported outcomes, we surveyed 665 patients who were at ≥5 years after AHCT for the diagnosis of lymphoma or MM. Three-hundred and eighty-nine patients completed the questionnaire (58% response rate) at a median of 11 years (range, 5-30 years) after AHCT. The median patient age was 63 years (range, 22-88 years) in the 268 patients with lymphoma and 69 years (range, 34-84 years) in the 121 patients with multiple myeloma. The most commonly reported medical conditions (>10% incidence) were sexual dysfunction, history of shingles, cataracts, osteoporosis or osteopenia, joint replacement, and skin cancer. Current medication use was more frequent in the patients with MM for infection prevention/treatment (19% for MM versus 5% lymphoma; P < .001), hypertension (41% versus 26%; P = .004), osteoporosis (23% versus 10%; P < .001), and pain (32% versus 11%, P < .001). Treated hypothyroidism was more common in lymphoma patients. In multivariate analysis combining lymphoma and MM, worse physical functioning was associated with older age, shorter interval since AHCT, comorbidities, relapse, and treatment for depression and/or pain. Worse mental functioning was associated with younger age and treatment for anxiety, depression, or pain. In conclusion, AHCT survivors report generally good QoL but many late effects and symptoms that are potentially amenable to intervention.

Surveillance Imaging after Autologous Hematopoietic Cell Transplantation Predicts Survival in Patients with Diffuse Large B Cell Lymphoma.

The utility of surveillance imaging after autologous hematopoietic cell transplantation (AHCT) in relapsed/refractory diffuse large B cell lymphoma (DLBCL) remains unclear. The purpose of this study was to determine whether surveillance imaging predicts survival after AHCT. At the University of Minnesota, serial imaging for early relapse detection has been used prospectively for all consecutive AHCT recipients treated since 2010. The present analysis included 91 AHCT recipients with DLBCL who underwent 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) scan at day +100 post-AHCT. 18F-FDG-PET parameters included the Deauville (D) 5-point scale, peak standardized uptake values (SUVmax), total legion glycolysis (TLG), and total metabolic tumor volume (TMTV). Survival of patients with clinically symptomatic versus asymptomatic radiographically detected relapsed DLBCL after AHCT was compared. Sixty patients experienced relapse; 35% was detected on day +100 surveillance PET scan. 5-year overall survival (OS) by 18F-FDG-PET scan at day +100 post-AHCT was significantly lower in D4 and D5 patients (37%; 95% confidence interval [CI], 14% to 100% versus 25%; 95% CI, 43% to 89%) compared with patients with D1 and D2 (62%; 95% CI, 43% to 89% versus 62%; 95% CI, 46% to 84%). TLG and TMTV were not prognostic. SUVmax at day +100 varied from 1.5 (D1) to 17.9 (D5). In multivariate analysis, only SUVmax was predictive of relapse and OS; mortality increased 1.8-fold with each SUVmax doubling (hazard ratio [HR], 1.8; 95% CI, 1.3 to 2.3; P < .01). At a median follow-up of 3.3 years (range, 1 to 12 years), lymphoma-related mortality was 1.8-fold higher among patients whose relapse was detected clinically (symptomatic) versus radiographically on surveillance scan (HR, 1.8; 95% CI, .9 to 3.4; P = .08). In patients with relapsed/refractory DLBCL, a routine PET imaging at day +100 post-AHCT detects asymptomatic relapse and high SUVmax identifies patients with poor expected survival of less than 1 year. Identifying this high-risk cohort can potentially highlight patients who might benefit from preemptive interventions to prevent or delay relapse.

Effect of Conditioning Regimen Dose Reduction in Obese Patients Undergoing Autologous Hematopoietic Cell Transplantation.

Data are limited on whether to adjust high-dose chemotherapy before autologous hematopoietic cell transplant (autoHCT) in obese patients. This study explores the effects of dose adjustment on the outcomes of obese patients, defined as body mass index (BMI) ≥ 30 kg/m2. Dose adjustment was defined as a reduction in standard dosing ≥20%, based on ideal, reported dosing and actual weights. We included 2 groups of US patients who had received autoHCT between 2008 and 2014. Specifically, we included patients with multiple myeloma (MM, n = 1696) treated with high-dose melphalan and patients with Hodgkin or non-Hodgkin lymphomas (n = 781) who received carmustine, etoposide, cytarabine, and melphalan conditioning. Chemotherapy dose was adjusted in 1324 patients (78%) with MM and 608 patients (78%) with lymphoma. Age, sex, BMI, race, performance score, comorbidity index, and disease features (stage at diagnosis, disease status, and time to transplant) were similar between dose groups. In multivariate analyses for MM, adjusting for melphalan dose and for center effect had no impact on overall survival (P = .894) and treatment-related mortality (TRM) (P = .62), progression (P = .12), and progression-free survival (PFS; P = .178). In multivariate analyses for lymphoma, adjusting chemotherapy doses did not affect survival (P = .176), TRM (P = .802), relapse (P = .633), or PFS (P = .812). No center effect was observed in lymphoma. This study demonstrates that adjusting chemotherapy dose before autoHCT in obese patients with MM and lymphoma does not influence mortality. These results do not support adjusting chemotherapy dose in this population.

Conditional Long-Term Survival after Autologous Hematopoietic Cell Transplantation for Diffuse Large B Cell Lymphoma.

Autologous hematopoietic cell transplantation (AHCT) is standard therapy for patients with chemosensitive, relapsed, diffuse large B cell lymphoma (DLBCL). We performed a retrospective cohort study to delineate subsequent (conditional) and relative survival in 371 adult patients with DLBCL who underwent AHCT between 2000 and 2014 and had survived for 1, 2, 3, or 5 years after transplant. The probability of overall survival at 10 years after AHCT was 62%, 71%, 77%, and 86%, respectively, for the 4 cohorts, whereas that of progression-free survival (PFS) was 55%, 65%, 72%, and 81%, respectively. The respective cumulative incidence of nonrelapse mortality (NRM) at 10 years after transplantation was 13%, 12%, 11%, and 8%, respectively. In multivariable analysis, older age was associated with greater mortality risk among all but 5-year survivors; relapse within the landmark time was associated with greater mortality risk in all groups. Older age and relapse within the landmark time were associated with worse PFS in all groups. Standardized mortality ratio (SMR) was significantly higher than an age-, gender-, and race-matched general population, with the magnitude of SMR decreasing as the landmark time increased (4.0 for 1-year, 3.0 for 2-year, 2.4 for 3-year, and 1.8 for 5-year survivors). Our study provides information on long-term survival and prognosis that will assist in counseling patients with DLBCL who have received AHCT. Survival improves with longer time in remission post-transplant, although patients continue to remain at risk for NRM, underscoring the need for continued vigilance and prevention of late complications.

Autologous Hematopoietic Cell Transplantation for Treatment-Refractory Relapsing Multiple Sclerosis: Position Statement from the American Society for Blood and Marrow Transplantation.

Multiple sclerosis (MS) is a chronic, disabling, immune-mediated, demyelinating and degenerative disease of the central nervous system. Approved disease-modifying therapies may be incompletely effective in some patients with highly active relapsing disease and high risk of disability. The use of immunoablative or myeloablative therapy followed by autologous hematopoietic cell transplantation (AHCT) has been investigated in retrospective studies, clinical trials, and meta-analyses/systematic reviews as an approach to address this unmet clinical need. On behalf of the American Society for Blood and Bone Marrow Transplantation (ASBMT), a panel of experts in AHCT and MS convened to review available evidence and make recommendations on MS as an indication for AHCT. A review of recent literature identified 8 retrospective studies, 8 clinical trials, and 3 meta-analyses/systematic reviews. In aggregate, these studies indicate that AHCT is an efficacious and safe treatment for active relapsing forms of MS to prevent clinical relapse, magnetic resonance imaging-detectable lesion activity, and worsening disability and to reverse disability without unexpected adverse events. Based on the available evidence, the ASBMT recommends that treatment-refractory relapsing MS with high risk of future disability be considered a "standard of care, clinical evidence available" indication for AHCT. Collaboration of neurologists with expertise in treating MS and transplantation physicians with experience performing AHCT for autoimmune disease is crucial for ensuring appropriate patient selection and optimizing transplantation procedures to improve patient outcomes. Transplantation centers in the United States and Canada are strongly encouraged to report baseline and outcomes data on patients receiving AHCT for multiple sclerosis to the Center for International Blood and Marrow Transplant Research.

Thrombotic Microangiopathy Following Pediatric Autologous Hematopoietic Cell Transplantation: A Report of Significant End-Organ Dysfunction in Eculizumab-Treated Survivors.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a known complication of autologous hematopoietic cell transplantation (aHCT), particularly in children with neuroblastoma. We describe a pediatric single-institution experience of TA-TMA after aHCT. Data were abstracted from the medical record of patients who underwent aHCT between January 1, 2008, and July 1, 2018, at Boston Children's Hospital. TA-TMA was diagnosed using either the International Working Group criteria or the "probable TA-TMA criteria" of Cho et al. Overall, 318 aHCTs were performed in 243 patients. Nine patients (3.7%) were diagnosed with TA-TMA. TA-TMA occurred most frequently in children with neuroblastoma (n = 7; 78%), all of whom were conditioned with carboplatin, etoposide, and melphalan. The median age at aHCT in children who developed TA-TMA was 3 years, 5 months (range, 18 months to 25 years). TMA was diagnosed at a median of 35 days (range, 8 to 106 days) after stem cell infusion. On a retrospective chart review using the same criteria used by the provider, patients met criteria a median of 5 days before the clinical diagnosis (range, 0 to 58 days). Eight patients had renal involvement at presentation, including nephrotic range proteinuria and severe hypertension, requiring from 2 to 6 antihypertensive medications. Two patients presented with multiorgan failure. Six patients were treated with eculizumab a median of 0 days after TA-TMA diagnosis (range, 0 to 11 days). On retrospective review, patients were treated a median of 18 days (range, 0 to 58 days) after meeting criteria for TA-TMA. Before initiation of therapy, 4 of 6 patients checked for serum complement levels had normal values, 1 had elevated CH50 and 1 had elevated sC59-b and CH50. All patients had CH50 levels within the target range (≤3 CAE) after induction therapy. Two patients (33%) had no response to eculizumab and died of multiorgan failure. The other 4 had both a hematologic response with transfusion independence (median, 6.5 weeks; range, 4 to 9 weeks) and renal response, defined as resolution of nephrotic range proteinuria (median, 21 weeks; range, 13 to 25 weeks). Among the eculizumab-treated survivors, 2 patients remained on prolonged eculizumab therapy, and one had recurrence of TA-TMA after discontinuation of eculizumab. All 4 eculizumab treated survivors have persistent organ dysfunction. Three children were treated with supportive care only; 2 died of relapsed cancer, and the third is alive with stage 2 chronic kidney disease. The median duration of follow-up after TA-TMA diagnosis was 2.5 years (range, 9 months to 4 years). The 1-year overall survival was 78% (SE = 14%). However, regardless of treatment, no survivors had complete normalization of function in all organs. Three children with normal serum CH50 and sc5b-9 levels responded to eculizumab. This report highlights the importance of maintaining a high suspicion for TA-TMA after aHCT. Further study is warranted to identify individual risk factors for TMA after aHCT, predict the response to eculizumab, and capture long-term sequelae in survivors.

Transplantation.

Mature T-cell non-Hodgkin lymphomas (T-cell NHL) are a heterogeneous group of lymphoid malignancies including NK/T-cell lymphomas. Hematopoietic cell transplantation (HCT) is an important component of the management of T-cell NHL; however, the optimal timing and type of transplant for each different subtype is an ongoing debate. For the purpose of this chapter, PTCL will be classified as (1) systemic PTCL that includes nodal as well as non-nodal histologies in PTCL (2) CTCL-or cutaneous T-cell lymphomas that arise primarily in the skin and (3) NK/T-cell lymphomas both nasal and extranasal types. It is difficult to do any large trials in PTCL as they are rare diseases with variable clinical and biological characteristics and most patients are not transplant eligible due to various reasons including poor disease control. There are no randomized trials in transplant for PTCL but there is an experience based on retrospective as well as some well-designed prospective trials that have helped outline the role of HSCT in the treatment paradigm of PTCL. High-dose therapy and autologous HCT is recommended in first complete remission for most systemic (non-cutaneous) nodal subtypes, or peripheral T-cell lymphomas (PTCL). Autologous HCT can provide long-term remission for relapsed PTCL but is ineffective for refractory/chemoresistant disease. Allogeneic stem cell transplantation harnesses the graft-versus-lymphoma effect, providing long-term remission for relapsed PTCL. AlloHCT is also being used successfully to provide long-term disease control for advanced cutaneous T-cell lymphoma (CTCL). The use of transplant in NK/T-cell lymphoma is increasingly being recommended in the relapsed setting only as there are more effective treatments available for the upfront setting in limited stage disease.

Early infectious complications after autologous hematopoietic cell transplantation for multiple myeloma.

BACKGROUND: The spectrum of infectious complications in autologous hematopoietic cell transplant recipients (AHCT) with multiple myeloma has not been well described in the recent era of novel agent induction and improved supportive care. METHODS: We conducted a retrospective cohort study of 413 adult myeloma AHCT recipients at our institution from 2007-2016 to describe the cumulative incidence and risk factors for various infections and FN occurring within the first 100 days after AHCT. Additionally, landmark analysis was done among 404 patients who survived at least 100 days after transplant admission to estimate the association of infections with subsequent non-relapse mortality (NRM), overall survival (OS), and relapse-free survival (RFS). RESULTS: Cumulative incidences (95% CI) of infection events by day 100 were: FN 43% (38-48), any infection 21% (17-25), bacterial 17% (14-21), viral 4% (3-7) and fungal 1% (0.5-3), central line-associated blood stream infection 3% (2-6), and Clostridium difficile colitis 6% (4-8). Patients with infection had a longer initial transplant hospitalization (median 17 vs 16 days, P < 0.01), more readmissions (31% vs 8%, P < 0.01), and spent more days in hospital in first 100 days (median 18 vs 16 days, P < 0.01). A 100-day mortality was low and similar between groups (2% vs 1%, P = 0.28). In landmark analysis of 404 100-day survivors, OS was worse among patients with early infections (hazard ratio 1.54 [1.03-2.30], P = 0.03), although there was no difference in NRM and RFS. CONCLUSIONS: Notwithstanding advances in supportive care, early infectious complications remain a relevant source of morbidity and require attention in myeloma AHCT recipients.

GENESIS: Phase III trial evaluating BL-8040 + G-CSF to mobilize hematopoietic cells for autologous transplant in myeloma.

Effective hematopoietic cell transplantation relies upon collecting adequate numbers of CD34+ hematopoietic stem cells, typically from peripheral blood. A minimum of ≥2 × 106 CD34+ cells/kg are necessary, while transplants of ≥5-6 × 106 CD34+ cells/kg are associated with improved hematopoietic recovery. Granulocyte colony stimulating factor (G-CSF) remains the gold standard for hematopoietic stem cell mobilization. However, in randomized trials for autologous-hematopoietic cell transplantation in multiple myeloma, approximately 45% of patients remain unable to optimally mobilize with G-CSF alone despite multiple injections and apheresis days. Therefore, reducing mobilization failures remains an unmet need. The study objective is to evaluate the superiority of one dose of BL-8040 plus G-CSF over placebo plus G-CSF to mobilize ≥6.0 × 106 CD34+ cells/kg in up to two apheresis days. ClinicalTrials.gov: NCT03246529.