Search

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.

Pretransplant respiratory virus infections (RVIs) have been shown to negatively affect hematopoietic cell transplantation (HCT) outcomes. The impact of and need for delay of HCT for pretransplant infection with human rhinovirus (HRV) or endemic human coronavirus (HCoV; 229E, OC43, NL63, and HKU1) remain controversial. We analyzed the impact of symptomatic RVI within ≤90 days before HCT on overall mortality, posttransplant lower respiratory tract disease (LRD), and days alive and out of hospital (DAOH) by day 100 post-HCT in multivariable models. Among 1,643 adult HCT recipients (58% allogeneic recipients), 704 (43%) were tested for RVI before HCT, and 307 (44%) tested positive. HRV was most commonly detected (56%). Forty-five (15%) of 307 HCT recipients had LRD with the same virus early after HCT. Pretransplant upper respiratory tract infection (URI) with influenza, respiratory syncytial virus, adenovirus, human metapneumovirus, parainfluenza virus, HRV, or endemic HCoV was not associated with increased overall mortality or fewer DAOH. However, in allogeneic recipients who received myeloablative conditioning, LRD due to any respiratory virus, including HRV alone, was associated with increased overall mortality (adjusted hazard ratio, 10.8 [95% confidence interval, 3.29-35.1] for HRV and 3.21 [95% confidence interval, 1.15-9.01] for all other viruses). HRV LRD was also associated with fewer DAOH. Thus, the presence of LRD due to common respiratory viruses, including HRV, before myeloablative allogeneic HCT was associated with increased mortality and hospitalization. Pretransplant URI due to HRV and endemic HCoV was not associated with these outcomes. Improved management strategies for pretransplant LRD are warranted.

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with various plasma cell neoplasms, including multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates/changes specific to the treatment of patients with multiple myeloma in the 2022 version of the guidelines.

Background CMV reactivation is occasionally detected during the work-up for hematopoietic cell transplantation (HCT) but its natural history and significance on posttransplant CMV risk is unknown. Methods CMV seropositive 1st HCT allograft recipients in the preemptive therapy era (2010-17) were analyzed. CMV PCR testing was routinely performed before and after HCT. Cumulative incidences of CMV reactivation after HCT were calculated at multiple PCR thresholds by pre-HCT viral loads (peak: < or >150 IU/mL; last prior to HCT positive vs positive to negative). Treatment of pre-HCT reactivation was recommended for viral loads >50 IU/mL. Multivariable Cox proportional hazard models were used to determine the association of pre-transplant CMV reactivation on post-HCT CMV reactivation at different PCR thresholds. Results Among 1536 patients (median age 50 y, range 0.1-81), 155 (10%), 53 (3.5%) and 24 (1.6%) had pre-HCT reactivation in the month before HCT at any level, >150 IU/mL, and >500 IU/mL, respectively. Pre-transplant CMV reactivation was associated with a higher risk of post-HCT CMV reactivation at all examined PCR thresholds and with CMV disease after transplantation in cumulative incidence (Figure 1) and multivariable analyses (Figure 2A). Patients who had CMV DNA detected that subsequently became negative before HCT (with or without treatment) had a lower risk than those who proceeded to HCT with viremia (Figure 2B). Cumulative Incidence of CMV Infection and Disease Multivariable Cox Regression Conclusion CMV reactivation occurs pre-HCT in ∼10% of CMV seropositive HCT candidates and is a risk factor for post-HCT CMV events at all severity levels, placing a HCT recipient in a high-risk category. Thus, pre-HCT PCR testing and antiviral treatment as well as the use of optimized posttransplant antiviral or immunotherapy prevention strategies are recommended. Disclosures Joshua A. Hill, MD, Allovir: Advisor/Consultant|Allovir: Grant/Research Support|Covance/CSL: Advisor/Consultant|CRISPR: Advisor/Consultant|Deverra: Grant/Research Support|Gilead: Grant/Research Support|Karius: Advisor/Consultant|Karius: Grant/Research Support|Merck: Grant/Research Support|Octapharma: Advisor/Consultant|OptumHealth: Advisor/Consultant|Oxford Immunotec: Grant/Research Support|Pfizer: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Advisor/Consultant Leona Holmberg, MD, PhD, Bristol Myers Squibb: Grant/Research Support|Janssen: Grant/Research Support|Merck: Grant/Research Support|Millennium-Takada: Grant/Research Support|Sanofi: Grant/Research Support|Seattle Genetics: Grant/Research Support|Up to Date: Royalty Alpana Waghmare, MD, Allovir: Grant/Research Support|Ansun Biopharma: Grant/Research Support|Devarra Therapeutics: DSMB|Kyorin Pharmaceutical: Advisor/Consultant|Pfizer: Grant/Research Support|Vir/GSK: Grant/Research Support Alexander L. Greninger, MD, PhD, Abbott: Contract Testing|Cepheid: Contract Testing|Gilead: Grant/Research Support|Gilead: Contract Testing|Hologic: Contract Testing|Merck: Grant/Research Support|Novavax: Contract Testing|Pfizer: Contract Testing Mary Flowers, MD, Incyte Corp.: Grant/Research Support|Janssen: Honoraria|Johnson & Johnson: Honoraria|Novartis: Honoraria|Pharmacyclics, Inc.: Grant/Research Support Geoffrey Hill, M.D., FRACP, FRCPA, Applied Molecular Transport: Grant/Research Support|Compass Therapeutics: Grant/Research Support|Generon Corporation: Advisor/Consultant|Heat Biologics: Grant/Research Support|iTeos Therapeutics: Advisor/Consultant|iTeos Therapeutics: Grant/Research Support|Laevoroc Oncology: Grant/Research Support|NapaJen Pharma: Advisor/Consultant|Neoleukin Therapeutics: Advisor/Consultant|Serplus Technology: Grant/Research Support|Syndax Pharmaceuticals: Grant/Research Support Michael J. Boeckh, MD PhD, Allovir: Advisor/Consultant|Amazon: Grant/Research Support|Ansun Biopharma: Grant/Research Support|EvrysBio: Advisor/Consultant|Gates Ventures: Grant/Research Support|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|GlaxoSmithKline: Advisor/Consultant|GlaxoSmithKline: Grant/Research Support|Helocyte: Advisor/Consultant|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Kyorin Pharmaceuticals: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Moderna: Advisor/Consultant|Moderna: Grant/Research Support|Regeneron: Grant/Research Support|ReViral: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Grant/Research Support|Vir Biotechnology: Advisor/Consultant|Vir Biotechnology: Grant/Research Support.

The role of maintenance therapy after high-dose chemotherapy and first autologous transplantation in multiple myeloma (MM) is well established. We explored the effect of maintenance therapy on outcomes after salvage second autologous hematopoietic cell transplant (AHCT2) using the Center for International Blood and Marrow Transplant Research registry. Outcomes of interest included non-relapse mortality (NRM), relapse/progression (REL), progression-free and overall survival (PFS, OS). Of 522 patients who underwent AHCT2 between 2010 and 2018, 342 received maintenance therapy and 180 did not. Maintenance regimens included lenalidomide (42%), pomalidomide (13%), and bortezomib (13%). Median follow up was 58 months in the maintenance group and 61.5 months in the no-maintenance group. Univariate analysis showed superior outcomes at 5 years in maintenance compared to the no-maintenance group: NRM 2 (0.7-3.9)% vs 9.9 (5.9-14.9)%, (p < 0.01), REL 70.2 (64.4-75.8)% vs 80.3 (73.6-86.3)% (p < 0.01), PFS 27.8 (22.4-33.5)% vs. 9.8 (5.5-15.2)% (p < 0.01), and OS 54 (47.5-60.5)% vs 30.9 (23.2-39.2)% (p < 0.01), respectively. Use of maintenance therapy retained its association with improved outcomes in multivariate analysis. There was no difference in second cancers in the two groups (p = 0.39). We conclude that maintenance after AHCT2 is associated with improved 5-year outcomes.

Relapsed or refractory primary CNS lymphoma (rrPCNSL) is a rare and challenging malignancy for which better evidence is needed to guide management. We present a retrospective cohort of 66 consecutive patients with rrPCNSL treated at the University of Washington between 2000 and 2020. Immunosuppressed and secondary CNS lymphoma patients were excluded. During a median follow-up of 40.5 months from initial diagnosis, median OS for relapsed disease was 14.1 (0.2–88.5) months and median PFS was 11.0 (0.2–73.9) months. At diagnosis (r2 = 0.85, p

Radiation is the most effective treatment for localized lymphoma, but treatment of multifocal disease is limited by toxicity. Radioimmunotherapy (RIT) delivers tumoricidal radiation to multifocal sites, further augmenting response by dose-escalation. This phase II trial evaluated high-dose RIT and chemotherapy prior to autologous stem-cell transplant (ASCT) for high-risk, relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). The primary endpoint was progression free survival (PFS). Secondary endpoints were overall survival (OS), toxicity, and tolerability. Patients age

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.

Multiple studies have documented that racial/ethnic minority patients are less likely to undergo hematopoietic cell transplantation (HCT) in the United States (US), and if they do, they often have worse outcomes. No studies to our knowledge have compared the outcomes of English-speakers to non-English speakers undergoing HCT in the US. To test our hypothesis that non-English speakers have worse outcomes than English speakers after HCT, all transplants performed between 2015 and 2019 at Fred Hutchinson Cancer Research Center in Seattle, WA, USA were analyzed. Cox proportional hazards models were used to test our hypothesis, adjusting for significant clinical covariates. Out of 2051 patients, 106 (5%) were documented to be non-English speakers. Mortality for non-English speakers was not different than English speakers (adjusted HR 1.02, 95% CI 0.63-1.63, p = 0.95). When the analysis was limited to the allogeneic population, the results were similar to the total population (adjusted HR 1.10, 0.64-1.88, p = 0.73). The risk of grade II-IV acute graft-versus-host disease (GVHD) was higher in the non-English speaking subset: adjusted OR 2.01, 95% CI, 1.02-3.98, p = 0.04. These data suggest that non-English speakers have similar survival compared to English speakers following HCT although they have more acute GVHD.

Purpose: External-beam radiation is the single most effective therapy for localized lymphoma. However, toxicity limits its use for multifocal disease. We evaluated CD45 as a therapeutic target for an antibody–radionuclide conjugate (ARC) for the treatment of lymphoma based on its ubiquitous expression, infrequent antigen loss or blockade, and the ability to target minimal disease based on panhematopoietic expression. Patients and Methods: We performed a phase I trial of escalating doses of single-agent CD45-targeted ARC based on per-patient dosimetry using the BC8 antibody labeled with iodine-131 (131I) followed by autologous stem cell support in adults with relapsed, refractory, or high-risk B-cell non-Hodgkin lymphoma (B-NHL), T-cell NHL (T-NHL), or Hodgkin lymphoma. The primary objective was to estimate the maximum tolerated radiation absorbed dose. Results: Sixteen patients were enrolled: 7 patients had B-NHL, 6 had Hodgkin lymphoma, and 3 had T-NHL. Median number of prior therapies was three (range: 2–12). Absorbed doses up to 32 Gy to liver were delivered. No dose-limiting toxicities occurred. Nonhematologic toxicity was infrequent and manageable. Objective responses were seen across histologies. Fourteen patients had measurable disease at enrollment, 57% of whom achieved complete remission (CR), including all 3 with T-NHL. Three patients with B-NHL treated among the highest dose levels (26–32 Gy) remain in CR without subsequent therapy 35–41 months later. Conclusions: CD45-targeted ARC therapy is well-tolerated at doses up to at least 32 Gy to the liver. Objective responses and long-term remissions were observed in patients with relapsed/refractory lymphoma. These data validate continued evaluation of anti-CD45 ARCs in lymphoma.

Malignancy relapse is the most common cause of treatment failure among recipients of hematopoietic cell transplantation (HCT). Conditioning dose intensity can reduce disease relapse but is offset by toxicities. Improvements in radiotherapy techniques and supportive care may translate to better outcomes with higher irradiation doses in the modern era. This study compares outcomes of recipients of increasing doses of high-dose total body irradiation (TBI) divided into intermediate high dose (IH; 13-13.75 Gy) and high dose (HD; 14 Gy) with standard dose (SD; 12 Gy) with cyclophosphamide. A total of 2721 patients ages 18 to 60 years with hematologic malignancies receiving HCT from 2001 to 2013 were included. Cumulative incidences of nonrelapse mortality (NRM) at 5 years were 28% (95% confidence interval [CI], 25% to 30%), 32% (95% CI, 29% to 36%), and 34% (95% CI, 28% to 39%) for SD, IH, and HD, respectively (P = .02). Patients receiving IH-TBI had a 25% higher risk of NRM compared with those receiving SD-TBI (12 Gy) (P = .007). Corresponding cumulative incidences of relapse were 36% (95% CI, 34% to 38%), 32% (95% CI, 29% to 36%), and 26% (95% Cl, 21% to 31%; P = .001). Hazard ratios for mortality compared with SD were 1.06 (95% CI,.94 to 1.19; P = .36) for IH and .89 (95% CI,.76 to 1.05; P = .17) for HD. The study demonstrates that despite improvements in supportive care, myeloablative conditioning using higher doses of TBI (with cyclophosphamide) leads to worse NRM and offers no survival benefit over SD, despite reducing disease relapse. (C) 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

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/m(2). 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. (C) 2018 American Society for Blood and Marrow Transplantation.

IMPORTANCE: Primary central nervous system lymphoma (PCNSL) requires induction and consolidation to achieve potential cure. High-dose therapy and autologous hematopoietic cell transplant (AHCT) is an accepted and effective consolidation strategy for PCNSL, but no consensus exists on the optimal conditioning regimens. OBJECTIVE: To assess the outcomes in patients with PCNSL undergoing AHCT with the 3 most commonly used conditioning regimens: thiotepa/busulfan/cyclophosphamide (TBC), thiotepa/carmustine (TT-BCNU), and carmustine/etoposide/cytarabine/melphalan (BEAM). DESIGN, SETTING, AND PARTICIPANTS: This observational cohort study used registry data from the Center for International Blood and Marrow Transplant Research registry. The Center is a working group of more than 380 transplantation centers worldwide that contributed detailed data on HCT to a statistical center at the Medical College of Wisconsin, Milwaukee. The participant data were from 603 adult patients with PCNSL who underwent AHCT as initial, or subsequent, consolidation between January 2010 and December 2018. Patients were excluded if they had a non-Hodgkin lymphoma subtype other than diffuse large B-cell lymphoma, systemic non-Hodgkin lymphoma, or HIV; received an uncommon conditioning regimen; or were not in partial remission or complete remission prior to AHCT. Statistical analysis was performed from July 5, 2020, to March 1, 2021. INTERVENTIONS: Patients received 1 of 3 conditioning regimens: TBC (n = 263), TT-BCNU (n = 275), and BEAM (n = 65). MAIN OUTCOMES AND MEASURES: The primary outcome was progression-free survival. Secondary outcomes included hematopoietic recovery, incidence of relapse, nonrelapse mortality, and overall survival. RESULTS: Of 603 patients, the mean age was 57 (range, 19-77) years and 318 (53%) were male. The 3-year adjusted progression-free survival rates were higher in the TBC cohort (75%) and TT-BCNU cohort (76%) compared with the BEAM cohort (58%) (P = .03) owing to a higher relapse risk in the BEAM cohort (hazard ratio [HR], 4.34; 95% CI, 2.45-7.70; P

Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. This manuscript discusses the management of patients with solitary plasmacytoma, smoldering multiple myeloma, and newly diagnosed multiple myeloma.

Primary plasma cell leukemia (pPCL) is an aggressive plasma cell disorder with a guarded prognosis. The diagnosis is confirmed when peripheral blood plasma cells (PCs) exceed 20% of white blood cells or 2000/μL. Emerging data demonstrates that patients with lower levels of circulating (PCs) have the same adverse prognosis, challenging the clinical disease definition, but supporting the adverse impact of circulating PCs. The cornerstone of treatment consists of combination therapy incorporating a proteasome inhibitor, an immunomodulatory agent, steroids, and/or anthracyclines and alkylators as part of more-intensive chemotherapy, followed by consolidative autologous hematopoietic cell transplantation in eligible patients and then maintenance therapy. Monoclonal antibodies are also currently being evaluated in this setting with a strong rationale for their use based on their activity in multiple myeloma (MM). Due to limited therapeutic studies specifically evaluating pPCL, patients with pPCL should be considered for clinical trials. In contrast to MM, the outcomes of patients with pPCL have only modestly improved with novel therapies, and secondary PCL arising from MM in particular is associated with a dismal outlook. Newer drug combinations, immunotherapy, and cellular therapy are under investigation, and these approaches hopefully will demonstrate efficacy to improve the prognosis of pPCL.

Autologous hematopoietic cell transplantation (AHCT) is a standard of care for several subtypes of high-risk lymphoma, but durable remissions are not achieved in the majority of patients. Intensified conditioning using CD45-targeted antibody-radionuclide conjugate (ARC) preceding AHCT may improve outcomes in lymphoma by permitting the delivery of curative doses of radiation to disease sites while minimizing toxicity. We performed sequential phase I trials of escalating doses of yttrium-90 (90Y)-labeled anti-CD45 antibody with or without BEAM (carmustine, etoposide, cytarabine, melphalan) chemotherapy followed by AHCT in adults with relapsed/refractory or high-risk B cell non-Hodgkin lymphoma (NHL), T cell NHL (T-NHL), or Hodgkin lymphoma (HL). Twenty-one patients were enrolled (16 NHL, 4 HL, 1 T-NHL). Nineteen patients received BEAM concurrently. No dose-limiting toxicities were observed; therefore, the maximum tolerated dose is estimated to be ≥34 Gy to the liver. Nonhematologic toxicities and engraftment kinetics were similar to standard myeloablative AHCT. Late myeloid malignancies and 100-day nonrelapse deaths were not observed. At a median follow-up of 5 years, the estimates of progression-free and overall survival of 19 patients were 37% and 68%, respectively. Two patients did not receive BEAM; one had stable disease and the other progressive disease post-transplant. The combination of 90Y-anti-CD45 with BEAM and AHCT was feasible and tolerable in patients with relapsed and refractory lymphoma. The use of anti-CD45 ARC as an adjunct to hematopoietic cell transplantation regimens or in combination with novel therapies/immunotherapies should be further explored based on these and other data.

To improve disease control without increasing the toxicity of a reduced-intensity allogeneic hematopoietic cell transplantation (HCT) in multiple myeloma (MM), a phase I trial was performed using an antibody-radionuclide conjugate targeting CD45 (90Y-DOTA-BC8) as conditioning. 90Y-DOTA-BC8 was combined with fludarabine and low-dose TBI followed by allogeneic HCT in patients with MM and ≥1 adverse risk characteristic at diagnosis, relapse after autologous transplant, or plasma cell leukemia (PCL). The primary objective was to estimate the maximum tolerated radiation absorbed dose. Fourteen patients were treated (one with PCL, nine failed prior autologous HCT, and nine with ≥1 adverse cytogenetics). Absorbed doses up to 32 Gy to liver were delivered. No dose-limiting toxicities occurred. Non-hematologic toxicities were manageable and included primarily gastrointestinal (43%) and metabolic/electrolyte disturbances (36%). Treatment-related mortality at 100 days was 0%. At a median follow-up of 5 years, the overall survival was 71% (median not reached) and the progression-free survival was 41% (median 40.9 months). The incorporation of CD45-targeted radioimmunotherapy (RIT) into a reduced-intensity allogeneic HCT is well-tolerated and may induce long-term remissions among patients with poor-risk MM, supporting further development of RIT-augmented conditioning regimens for HCT.

Background US hematopoietic cell transplantation (HCT) recipients have a low prevalence of latent tuberculosis infection (LTBI), but if latently infected they are at risk for progression to active tuberculosis. At our center, all HCT recipients underwent LTBI testing pretransplant by tuberculin skin testing (TST) until 2013 when we implemented a targeted screening program. Our objective was to assess the utility of our screening program that incorporated a pretransplant LTBI questionnaire to target TST and QuantiFERON TB Gold (QFT) testing. Methods We performed a retrospective cohort study of HCT recipients undergoing first transplant from 2014 to 2016. Patients with positive, indeterminate, and a subset with negative QFT results underwent electronic medical record (EMR) review to assess TST results and risk factors for LTBI. Results Among 1290 eligible recipients, 457 (35%) had at least 1 risk factor for LTBI on the pretransplant questionnaire; nonwhites were more likely to undergo LTBI testing (P, Hematopoietic cell transplantation in the United States has a low population prevalence for latent tuberculosis infection. A pretransplant latent tuberculosis (LTBI) questionnaire allowed for an approximate 65% reduction in LTBI testing when compared with universal screening., Visual Abstract Visual Abstract

The outcomes of patients with primary plasma cell leukemia (pPCL) after undergoing hematopoietic cell transplantation (HCT) in the novel agent era are unknown. We report outcomes of 348 patients with pPCL receiving autologous (auto-) HCT (n = 277) and allogeneic (allo-) HCT (n = 71) between 2008 and 2015. Median age was 60 years and 56 years for auto- and allo-HCT respectively. For auto-HCT, the 4-year outcomes were: non-relapse mortality (NRM) 7% (4-11%), relapse (REL) 76% (69-82%), progression-free survival (PFS) 17% (13-23%), and overall survival (OS) 28% (22-35%). Karnofsky performance status (KPS) > 90 and ≥very good partial response (VGPR) predicted superior OS in multi-variate analysis for auto-HCT. For allo-HCT, the 4-year outcomes were: NRM 12% (5-21%), REL 69% (56-81%), PFS 19% (10-31%), and OS 31% (19-44%). Compared with prior CIBMTR pPCL patients (1995-2006), inferior survival was noted in the current cohort (3-year OS, 39% vs. 38% in allo-HCT, and 62% vs. 35% in auto-HCT) respectively. However, we noted an increased HCT utilization, from 12% (7-21%) in 1995 to 46% (34-64%) in 2009 using SEER data (available till 2009). Despite modern induction translating to higher proportion receiving HCT, the outcomes remain poor in pPCL patients, mainly derived by high relapse rates post-HCT.

Background Bendamustine is a chemotherapeutic agent that has shown broad activity in patients with lymphoid malignancies. It contains both alkylating and nucleoside analog moieties, and thus, is not commonly used for stem cell mobilization due to concerns that it may adversely affect stem cell collection. Here we describe the lymphoma subset of a prospective, non-randomized phase II study of bendamustine, etoposide, and dexamethasone (BED) as a mobilization agent for lymphoid malignancies. Methods This subset analysis includes diffuse large B-cell lymphoma (N=3), follicular lymphoma (N=1), primary mediastinal B-cell lymphoma (N=1), and NK/T-cell lymphoma (N=1). Patients received bendamustine (120 mg/m2 IV d 1, 2), etoposide (200 mg/m2 IV d 1-3), and dexamethasone (40 mg PO d 1-4) followed by filgrastim (10 mcg/kg/d sc. through collection). Results We successfully collected stem cells from all patients, with a median of 7.9×106/kg of body weight (range, 4.4 to 17.3×106/kg) over a median of 1.5 days (range, 1 to 3) of apheresis. All patients who received transplants were engrafted using kinetics that were comparable to those of other mobilization regimens. Three non-hematologic significant adverse events were observed in one patient, and included bacterial sepsis (grade 3), tumor lysis syndrome (grade 3), and disease progression (grade 5). Conclusion For non-Hodgkin lymphoma, mobilization with bendamustine is safe and effective.

Background Bortezomib has been incorporated into thalidomide and dexamethasone provided with cisplatin, doxorubicin, cyclophosphamide, and etoposide (PACE) as an intensive regimen before autologous stem-cell transplantation for multiple myeloma (MM). We examined MM patients at our center who received chemomobilization with a regimen that substituted carfilzomib and lenalidomide for bortezomib and thalidomide (KRD-PACE). Patients and Methods This was a retrospective study of 27 MM patients who received KRD-PACE for chemomobilization. Our analysis included patients who had circulating plasma cells (CPCs) by flow cytometry, ≥ 10% bone marrow plasma cells (BMPC), a monoclonal protein ≥ 1 g/dL, or an involved serum free light chain ≥ 10 mg/dL. Results The most common indication for KRD-PACE was BMPC ≥ 10% in 16 patients (60%), followed by CPCs in 11 (41%). The median (range) age was 61 (35-69) years, and the median (range) BMPC before treatment was 10% (5%-47%). The overall response rate was 43%, and a median (range) of 20.24 (8.08-69.88) × 106 CD34+ cells/kg were collected. CPC clearance rate was 50%, and the median reduction in BMPC was 75%. Two patients had sinus bradycardia and 5 (19%) had neutropenic fever. Conclusion KRD-PACE is an effective therapy to mobilize peripheral blood stem cells in MM patients with residual disease burden. This regimen was successful at clearing CPCs and reducing BMPC burden, with an overall response rate of 43%. Despite theoretical concern regarding the combination of 3 cardiotoxic agents, we observed a low frequency of cardiac issues.

Circulating plasma cells (CPCs) have been detected in patients with multiple myeloma (MM) at various stages of disease and associated with worse outcomes. Little data exist regarding the impact of CPCs at the time of autologous peripheral blood stem cell (PBSC) collection on outcomes, and the impact of maintenance therapy after autologous stem cell transplantation (ASCT) on prognosis in patients with CPC-containing collections. All patients with MM who underwent first ASCT at Fred Hutchinson Cancer Research Center from 2012 to 2015 and had evaluation for CPCs at the time of PBSC collection were included in our analysis. Seven-color flow cytometry was used to detect the presence of CPCs. Kaplan-Meier estimates were used to generate overall survival (OS) and progression-free survival (PFS) rates from the time of ASCT. A multivariate analysis, including receipt of maintenance therapy post-ASCT, high-risk cytogenetics, and international staging system (ISS) stage, was included in a Cox proportional hazards regression model for associations with OS and PFS. We identified 227 patients with MM who underwent ASCT; of these, 144 (63.4%) patients had routine assessment of CPCs at the time of PBSC collection. One hundred seventeen (81.3%) patients did not have CPCs and 27 (18.8%) did have CPCs. The presence of CPCs was highly associated with poorer PFS (P = .031 by log-rank analysis), but did not affect OS. The median PFS for those patients without CPCs was 39.4 months (95% confidence interval [CI], 31.1 to not reached), while the median PFS for those patients with CPCs was 16.5 months (95% CI, 13.7 to not reached). A subgroup analysis of patients achieving very good partial response (VGPR) or better at time of collection, showed the median PFS for patients without CPCs was 38.3 months (95% CI, 29 to not reached), as compared with those patients with CPCs, where it was only 16.5 months (95% CI, 12 months to not reached; P = .02). There was no statistically significant difference in PFS or OS among those patients achieving partial response at the time of collection. In a Cox proportional hazards model, adjusting for post-ASCT maintenance therapy, high-risk cytogenetics, and ISS stage at time of initial diagnosis, there was a 43% higher risk of progression or death among the patients with CPCs (P = .04). The presence of CPCs at the time of autologous PBSC collection is a negative prognostic factor for risk of early relapse or death despite the advent of novel agents and maintenance strategies. The impact of CPCs was most significant among patients achieving a VGPR or better at time of collection. The presence of CPCs denotes a unique group of high-risk MM patients for whom alternative treatment strategies are needed to overcome resistance to current standard therapies.

The application of allogeneic hematopoietic cell transplantation (allo-HCT) in non-Hodgkin lymphoma (NHL) patients ≥65 years in the United States is limited by lack of Medicare coverage for this indication. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we report allo-HCT outcomes of NHL patients aged ≥65 years (older cohort; n = 446) compared with a cohort of younger NHL patients aged 55-64 years (n = 1183). We identified 1629 NHL patients undergoing a first reduced-intensity conditioning (RIC) or nonmyeloablative conditioning allo-HCT from 2008 to 2015 in the United States. Cord blood or haploidentical transplants were excluded. The median age was 68 years (range 65-77) for the older cohort vs 60 years (range 55-64) in the younger cohort. The 4-year adjusted probabilities of nonrelapse mortality (NRM), relapse/progression (R/P), progression-free survival (PFS), and overall survival (OS) of the younger and older groups were 24% vs 30% (P = .03), 41% vs 42% (P = .82), 37% vs 31% (P = .03), and 51% vs 46% (P = .07), respectively. Using multivariate analysis, compared with the younger group, the older cohort was associated with increased NRM, but there was no difference between the 2 cohorts in terms of R/P, PFS, or OS. The most common cause of death was disease relapse in both groups. In NHL patients eligible for allo-HCT, there was no difference in OS between the 2 cohorts. Age alone should not determine allo-HCT eligibility in NHL, and Medicare should expand allo-HCT coverage to older adults.

Autologous stem cell transplant (ASCT) consolidation has become a standard approach for patients with mantle cell lymphoma (MCL), yet there is little consensus on the role of total body irradiation (TBI) as part of high-dose transplantation conditioning. We analyzed 75 consecutive patients with MCL who underwent ASCT at our institution between 2001 and 2011 with either TBI-based (n = 43) or carmustine, etoposide, cytarabine, melphalan (BEAM; n = 32) high-dose conditioning. Most patients (97%) had chemosensitive disease and underwent transplantation in first remission (89%). On univariate analysis, TBI conditioning was associated with a trend toward improved PFS (hazard ratio [HR], .53; 95% confidence interval [CI], .28-1.00; P = .052) and similar OS (HR, .59; 95% CI, .26-1.35; P = .21), with a median follow-up of 6.3 years in the TBI group and 6.6 years in the BEAM group. The 5-year PFS was 66% in the TBI group versus 52% in the BEAM group; OS was 82% versus 68%, respectively. However, on multivariate analysis, TBI-based conditioning was not significantly associated with PFS (HR, .57; 95% CI .24-1.34; P = .20), after controlling for age, disease status at ASCT, and receipt of post-transplantation rituximab maintenance. Likewise, early toxicity, nonrelapse mortality, and secondary malignancies were similar in the 2 groups. Our data suggest that both TBI and BEAM-based conditioning regimens remain viable conditioning options for patients with MCL undergoing ASCT.

Correspondence: Donor body mass index does not predict graft versus host disease following hematopoietic cell transplantation

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, evaluation, treatment, including supportive-care, and follow-up for patients with myeloma. These NCCN Guidelines Insights highlight the important updates/changes specific to the myeloma therapy options in the 2018 version of the NCCN Guidelines.

In a prior phase 2 study, personalized cancer vaccination with autologous dendritic cells (DCs) fused with primary MM tumor cells (DC/MM fusions) induced the expansion of circulating MM-reactive lymphocytes and was associated with conversion to complete response (CR) post-autoHCT in the absence of maintenance therapy. 1 We now present a multicenter randomized phase II study that examined the efficacy of DC/MM fusion vaccination with lenalidomide maintenance therapy after autoHCT, compared with lenalidomide maintenance alone. The study offered a first-of-its-kind academic collaborative effort of personalized cell therapy using an open-source format, site-specific production, and centralized product characterization/release criteria verification. Under the aegis of the BMT CTN (CTN 1401), 203 patients enrolled from 18 participating centers. Sixty-three patients dropped out of the study from enrollment to randomization for an overall dropout rate of 31%, concordant with the expected rate of 30% pre-specified in the protocol. Among the 140 patients, 68 were randomized to the vaccine arm, 37 to the lenalidomide/GM-CSF arm, and 35 to the lenalidomide alone arm. Ninety-one (65.0%) patients had high-risk MM. A collaborative process was established for the standardization of vaccine manufacturing including tumor cell harvest and cryopreservation, DC generation from leukapheresis collection, creation and quantification of the DC/tumor fusion vaccine, and the process of characterizing each cellular product. Of the 140 patients who underwent tumor collection, the median percentage of plasma cells in bone marrow aspirate differential was 45%. Mean CD86 expression and viability of the DC preparations were 80.6% and 79.3%, respectively. The mean fusion efficiency of the DC/MM product, as determined by co-expression of standard DC (CD86) and MM (CD38) markers, was 47.9%. Mean fusion cell viability was 78.6%. Vaccine was successfully generated for 63/68 patients (93%) assigned to the vaccine arm of the study. Thirty-six of the 68 (52.9%) evaluable patients on the vaccine arm (80% confidence interval 44.5%, 61.3%) and 34 of the 68 (50.0%) of the non-vaccine arms (80% confidence interval 41.6%, 58.4%) achieved CR/sCR at 1-year post-transplant (p=0.3). Of the patients not achieving CR at time of randomization post-transplant, conversion to CR at 1-year was 34.8% for the vaccine arm and 27.3% for the non-vaccine arm (p=0.4). sCR/CR/VGPR at 1-year was achieved by 85.3% and 77.8% of patients on the vaccine and non-vaccine arms, respectively (p=0.2). The rates of post-transplant grade 3-4 toxicities were 76.5%, 62.5% for the vaccine, and non-vaccine arms, respectively (p=0.07). There were no grade 5 toxicities in any of the cohorts. The overall grade 2-3 infection rate was 22.9% (23.5% on the vaccine arm, 13.5% on the lenalidomide/GM-CSF arm, and 31.4% on the lenalidomide alone arm). Quantification of circulating MM-reactive T cells was performed for an initial cohort of 20 patients who completed 1-year post-transplant assessments. Patients in the vaccine arm demonstrated a significant expansion of MM-reactive CD8 cells, representing 2.9%, 3.5%, and 15.9% of the lymphocyte population prior to post-transplant maintenance, following 1 cycle of lenalidomide and following 3 vaccinations at 1-year post-transplant, respectively (Figure). In contrast, there was no increase in MM-specific CD8 T cells in the control arm with levels of 1.1, 2.0. and 0.6, respectively. Single-cell transcriptomic analysis performed on the peripheral T-cell repertoire of 14 patients from the vaccine arm at serial time points demonstrated progressive expansion of dominant CD8, CD4, and NKT cell clones with an activated phenotype. Vaccination was associated with the recovery of T-cell clonal diversity. This multicenter trial demonstrated successful site-specific production. DC/MM fusion vaccination with lenalidomide maintenance after autoHCT did not result in a significant increase in CR rates at 1-year but was associated with measurable anti-MM immune reactivity for which the impact on response duration will require longer term follow-up. 1. Rosenblatt, J. et al. Vaccination with dendritic cell/tumor fusions following autologous stem cell transplant induces immunologic and clinical responses in multiple myeloma patients. Clin. Cancer Res. 19, 3640-3648 (2013) Figure 1 Figure 1. Disclosures Shah: CareDx: Consultancy; GSK: Consultancy; Teneobio: Research Funding; Kite: Consultancy; Nektar: Research Funding; Poseida: Research Funding; Oncopeptides: Consultancy; Bluebird Bio: Research Funding; CSL Behring: Consultancy; Indapta Therapeutics: Consultancy; Janssen: Research Funding; Sanofi: Consultancy; Sutro Biopharma: Research Funding; Precision Biosciences: Research Funding; BMS/Celgene: Research Funding; Karyopharm: Consultancy; Amgen: Consultancy. Stroopinsky: The Blackstone Group: Consultancy. Anderson: Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees. Devine: Magenta Therapeutics: Current Employment, Research Funding; Tmunity: Current Employment, Research Funding; Johnsonand Johnson: Consultancy, Research Funding; Orca Bio: Consultancy, Research Funding; Be the Match: Current Employment; Sanofi: Consultancy, Research Funding; Vor Bio: Research Funding; Kiadis: Consultancy, Research Funding. Holmberg: Sanofi: Research Funding; Millennium-Takeda: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Merck: Research Funding; Janssen: Research Funding; Up-To-Date: Patents & Royalties. Johnson: Miltenyi Biotec: Research Funding. Lazarus: Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees. Malek: Janssen: Other: Advisory board ; Medpacto Inc.: Research Funding; Takeda: Honoraria; BMS: Honoraria, Research Funding; Amgen: Honoraria; Cumberland Inc.: Research Funding; Bluespark Inc.: Research Funding; Sanofi: Other: Advisory Board. McCarthy: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Juno: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. McKenna: Qihan Bio: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Other: all manufacturing of cell therapy products for clinical trials; Intima: Other: all manufacturing of cell therapy products for clinical trials; Gamida: Other: all manufacturing of cell therapy products for clinical trials; Magenta: Other: all manufacturing of cell therapy products for clinical trials. Munshi: Takeda: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Amgen: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Abbvie: Consultancy; Adaptive Biotechnology: Consultancy; Legend: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy. Nooka: Janssen Oncology: Consultancy, Research Funding; Adaptive technologies: Consultancy; Sanofi: Consultancy; GlaxoSmithKline: Consultancy, Other: Travel expenses; Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Research Funding; Oncopeptides: Consultancy; Karyopharm Therapeutics: Consultancy. Soiffer: Jazz Pharmaceuticals, USA: Consultancy; Precision Biosciences, USA: Consultancy; Juno Therapeutics, USA: Other: Data Safety Monitoring Board; Kiadis, Netherlands: Membership on an entity's Board of Directors or advisory committees; Rheos Therapeutics, USA: Consultancy; Gilead, USA: Other: Career Development Award Committee; NMPD - Be the Match, USA: Membership on an entity's Board of Directors or advisory committees; Jasper: Consultancy; Takeda: Consultancy. Uhl: Grifols: Consultancy, Speakers Bureau; Abbott: Consultancy, Speakers Bureau; UpToDate: Patents & Royalties. Young: Amgen: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company. Rosenblatt: Attivare Therapeutics: Consultancy; Bristol-Myers Squibb: Research Funding; Parexel: Consultancy; Wolters Kluwer Health: Consultancy, Patents & Royalties; Imaging Endpoints: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Waller: Verastem Oncology: Consultancy, Research Funding; Cambium Oncology: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Pasquini: GlaxoSmithKline: Research Funding; Kite Pharma: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Avigan: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Consultancy, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Partner Tx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Aviv MedTech Ltd: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Parexcel: Consultancy; Takeda: Consultancy; Sanofi: Consultancy. OffLabel Disclosure: Dendritic Cell/Tumor Fusion Vaccine and GM-CSF

Background: T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory immune checkpoint receptor expressed on subsets of T cells and NK cells. In multiple myeloma (MM), TIGIT expression increases as the disease progresses and correlates with defective T cell effector functions. Higher TIGIT expression was observed in MM bone marrow CD8+ T cells in mice and patients compared to other immune checkpoint inhibitors, including PD-1, TIM-3, LAG-3, or CTLA-4 (Guillerey, C. et al, Blood 2018; Minnie, S. A. et al . Blood 2018). EOS884448/GSK4428859A (EOS-448) is a potent and highly selective fully human antagonist IgG1 antibody targeting TIGIT. Preclinically, anti-TIGIT Ab elicits superior anti-tumor immune responses compared to anti-PD1 mAbs (Guillerey, C. et al, Blood 2018). In murine Vk*Myc MM models, Fc-enabled a-TIGIT Ab elicits effective control of MM disease progression after autologous stem-cell transplant (ASCT), while Fc-disabled version is inactive. Anti-tumor activity is seen with monotherapy after ASCT at high T cell doses and provides significant synergistic activity when combined with an Immunomodulatory imide drug (IMiD) if T cell doses are suboptimal (Minnie, S. A. et al, Abstract submitted ASH 2021). Iberdomide (also known as CC-220) is a novel potent cereblon (CRBN) E3 ligase modulatory compound (CELMoD) that regulates multiple transcription factors within immune cells (Gandhi, A. K. et al . Brit J Haematol 2014). Iberdomide has shown notable clinical activity and acceptable tolerability in heavily pre-treated patients with relapsed or refractory multiple myeloma (RRMM), including those refractory to prior IMiDs (Lonial, S. et al. J Clin Oncol 2019). Given the dominant role of TIGIT in the immune suppression associated with MM, we hypothesize that TIGIT represents an ideal checkpoint to target clinically. EOS-448 alone or the synergistic combination of EOS-448 with iberdomide may provide a therapeutic opportunity to amplify myeloma-specific T-cell anti-tumor responses in difficult to treat RRMM patients previously exposed to IMiD, proteasome inhibitors (PIs) and anti-CD38. Methods: This phase I/II, open-label, multicenter, dose-escalation/expansion study will assess the safety, tolerability and preliminary activity of EOS-448 as monotherapy and in combination with iberdomide with or without dexamethasone in up to 158 adults with RRMM, who have progressed after prior treatments with IMiDs, PI and anti-CD38. EOS-448 will be infused intravenously on Day 1 of 28-day cycles. In Part 1, the safety and tolerability of EOS-448 as monotherapy and in combination with iberdomide with or without dexamethasone will be assessed in cohorts of up to 18 participants to identify the maximum tolerated dose and recommended phase II dose (RP2D) in each of the 3 treatment arms. In Part 2, the safety and anti-cancer activity of the RP2D will be assessed in up to 102 RRMM participants. Primary endpoints are treatment emergent adverse events, laboratory abnormalities, dose-limiting toxicities and clinical activity according to the International Myeloma Working Group (IMWG) Uniform Response Criteria. Secondary endpoints include overall response rates, duration of response, PK, and antidrug antibodies. Exploratory biomarkers including study treatment-mediated pharmacodynamic (PD) effects, PK-PD correlations, and correlative analyses of predictive and PD measurements with response, toxicity, and resistance will be investigated. Minimal residual disease (MRD) status with therapy will also be assessed as clinically indicated. The study is planned to open in November 2021 in North America and Europe. Disclosures Moreau: Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Celgene BMS: Honoraria; Oncopeptides: Honoraria. Holmberg: Janssen: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Sanofi: Research Funding; Millennium-Takeda: Research Funding; Bristol Myers Squibb: Research Funding; Up-To-Date: Patents & Royalties. Meuleman: iTeos Therapeutics: Consultancy. Graham: iTeos Therapeutics: Current Employment. De Henau: iTeos Therapeutics: Current Employment, Current equity holder in publicly-traded company; Bristol-Meyer-Squibb: Current equity holder in publicly-traded company. Driessens: iTeos Therapeutics: Current Employment, Current equity holder in publicly-traded company. McGrath: iTeos Therapeutics: Current Employment, Current equity holder in publicly-traded company; Norgine: Other: Spouse Current Employment. Lager: iTeos Therapeutics: Current Employment, Current equity holder in publicly-traded company. Hill: NeoLeukin Therapeutics: Consultancy; Applied Molecular Transport: Research Funding; Syndax Pharmaceuticals: Research Funding; NapaJen Pharma: Consultancy; iTeos Therapeutics: Consultancy, Research Funding; Compass Therapeutics: Research Funding; Generon Corporation: Consultancy; Roche: Research Funding.

Since the introduction of lenalidomide into induction therapy for multiple myeloma (MM), there have been conflicting reports about its impact on autologous peripheral blood stem cell (PBSC) mobilization. We evaluated the impact of previous lenalidomide exposure in a large cohort of patients with MM undergoing mobilization and collection at a tertiary stem cell transplantation center. We hypothesized that collection of PBSCs is feasible even with a prolonged duration of previous lenalidomide therapy. We examined patients with MM who attempted stem cell mobilization and collection, seen at our center between January 2012 and July 2015. The patients were categorized into 3 groups for analysis: (1) patients with previous receipt of >6 cycles lenalidomide, (2) patients with previous receipt of ≤6 cycles of lenalidomide, and (3) patients without previous lenalidomide exposure. We compared collection yields and days of apheresis among the 3 groups using linear regression analysis. We identified 297 patients with MM who underwent mobilization of PBSCs. Of these, 35 had received >6 cycles of lenalidomide (median, 8 cycles; range, 7 to 25 cycles), 156 had received ≤6 cycles of lenalidomide (median, 4 cycles; range, 1 to 6 cycles), and 106 had received no lenalidomide. Prior lenalidomide exposure did not have a statistically significant impact on the absolute number of CD34+ cells collected or on the duration of collection based on a multivariate linear regression analysis for association between receipt of >6 cycles of lenalidomide. In this retrospective analysis of MM patients undergoing autologous PBSC transplantation, we show that the duration of previous lenalidomide exposure does not impact the total number of PBSCs collected or the number of days of apheresis. These data suggest that longer courses of induction therapy with lenalidomide-containing regimens to achieve a maximum response can be safe without impairing the ability to collect PBSCs, and that limiting lenalidomide use before mobilization does not appear warranted in all cases.

Duration of initial disease response remains a strong prognostic factor in multiple myeloma (MM) particularly for upfront autologous hematopoietic cell transplant (AHCT) recipients. We hypothesized that new drug classes and combinations employed prior to AHCT as well as after post-AHCT relapse may have changed the natural history of MM in this population. We analyzed the Center for International Blood and Marrow Transplant Research database to track overall survival (OS) of MM patients receiving single AHCT within 12 months after diagnosis (N=3,256) and relapsing early post-AHCT (1 line of induction and lack of maintenance. Post-AHCT early relapse remains a poor prognostic factor, even though outcomes have improved over time.

Management of venous thromboembolism (VTE) remains challenging in patients with hematologic malignancy who undergo hematopoietic cell transplantation (HCT) due to prolonged thrombocytopenia. This study aims to (1) determine the incidence of VTE recurrence and bleeding during autologous HCT, (2) assess the impact of continuing vs temporarily withholding anticoagulation during thrombocytopenia, and (3) explore the impact of platelet threshold among other variables on the risk of bleeding. We performed this observational study in adults with lymphoma and myeloma who underwent autologous HCT between 2006 and 2015. We selected patients with index VTE prior to HCT and assigned them to different cohorts based on antithrombotic management at the onset of thrombocytopenia. Primary outcomes included VTE recurrence and major bleeding by 30 days after HCT. Secondary outcomes included platelet and red blood cell transfusions, time to engraftment, and overall survival. Of the 1631 patients who underwent autologous HCT, 204 patients (12.5%) had preceding index VTE events, and among them, 132 patients continued and 72 patients temporarily withheld anticoagulation during thrombocytopenia. There were no significant differences in VTE recurrence (1.5% vs 1.4%) or major bleeding (3.8% vs 4.2%) between 2 groups by 30 days. The number of platelet transfusions was significantly higher in the first group. Baseline elevated bilirubin, creatinine, and prothrombin time were independently associated with increased risk in major bleeding, whereas neither platelet threshold nor average platelet count was predictive. Our findings suggest that for many patients undergoing autologous HCT, temporarily withholding anticoagulation during thrombocytopenia may offer the best risk-benefit tradeoff among available options.

Introduction: Inflammatory breast cancer (IBC) is a rare aggressive form of breast cancer. It is well known that the long-term survival and progression-free survival of IBC are worse than that of non-IBC. We report the long term outcomes of patients with IBC and non-IBC who had undergone high-dose chemotherapy (HDC) with autologous hematopoietic cell transplantation (AHCT). Methods: All 3387 patients with IBC or non-IBC who underwent HDC with AHCT between1990-2002 and registered with CIBMTR were included in this analysis. Transplant-related mortality (TRM), disease relapse/progression, progression-free survival (PFS) and overall survival (OS) were compared between the two cohorts. Multivariate Cox regression model was used to determine the independent impact of stage on outcomes. Results: 527 patients with IBC and 2,860 patients with non-IBC were included; the median age at transplantation (47 vs 46 years old) and median follow-up period in the 2 groups (167 vs 168 months) were similar. The most common conditioning regimen was cyclophosphamide and carboplatin based in both groups (54% in IBC and 50% in non-IBC). AHCT was well tolerated in both groups. TRM was similar in both groups (one year TRM was 2% for IBC and 3% for non-IBC, p=0.16). The most common cause of death was disease progression or relapse (81% in IBC and 75% in non-IBC). The median survival for both IBC and non-IBC was the same at 40 months. The PFS at 10 years was 27% (95% CI: 23-31%) for IBC and 24% (95% CI: 22-26%) for non-IBC (p=0.21), and the OS at 10 years was 31% (95% CI: 27-35%) for IBC and 28% (95% CI: 26-30%) for non-IBC (p=0.16). In univariate analysis, patients with stage III IBC and no active diseases at transplantation had lower PFS and OS than that in non-IBC. In multivariate analysis, controlling for age, disease status at AHCT, hormonal receptor status, time from diagnosis to AHCT, and performance status at AHCT, patients with stage III IBC had higher mortality (HR 1.16, 95% CI: 1-1.34, p= 0.0459), worse PFS (HR: 1.17, 95% CI: 1.01-1.36, p= 0.0339) and higher risk of disease relapse/progression (HR: 1.24, 95% CI: 1.06-1.45, p= 0.0082) as compared to stage III non-IBC. Amongst all patients a higher stage disease was associated with worse PFS, OS and disease relapse/progression. Conclusions: Long-term outcomes of stage III IBC patients who underwent AHCT were poorer than that in non-IBC patients confirming that the poor prognosis of IBC even in the setting of HDC with AHCT.

Background: In multiple myeloma (MM), relapse is a frequent complication after autologous hematopoietic stem cell transplant (ASCT). To reduce the risk of relapse, additional therapy has been added post-ASCT. In a nontransplant relapse setting, the combination of intravenous bortezomib and oral vorinostat (BV) was studied and showed efficacy. Therefore, it was reasonable to study this combination therapy post-ASCT. Patients and Methods: We report on BV given post-ASCT. All 30 patients underwent conditioning for ASCT with high-dose melphalan. After recovery from the acute transplant-related toxicity, BV therapy was started and given for a total of 12 (28-day) cycles. Results: The most common toxicities were hematological, gastrointestinal (diarrhea and nausea), fatigue, and peripheral neuropathy. The median follow-up for BV patients is 7.8 (range: 6.12–9.03) years. After BV therapy, 18 patients (60%) are alive, and 9 (30%) are alive without disease progression. Conclusions: BV can be given post-ASCT with an acceptable toxicity profile and produces reasonable disease-free and overall survival rates. A randomized study comparing the BV regimen to single-agent lenalidomide or bortezomib is needed.

The curative potential of autologous hematopoietic cell transplantation (autoHCT) for male germ cell tumors (GCTs) is well established. The optimal timing and number (single transplant [ST] versus tandem transplants [TT] versus triple transplants) of autoHCT are controversial, with wide practice variations. We examined survival trends among 2395 recipients of autoHCT for male GCTs between 1990 and 2015 reported to the Center for International Blood and Marrow Transplant Research. Trends and outcomes were analyzed by year of transplantation for intervals 1990 to 1994 (N = 288), 1995 to 1999 (N = 351), 2000 to 2004 (N = 376), 2005 to 2009 (N = 509), and 2010 to 2015 (N = 871). Multivariate analysis was restricted to the subset from 2000 to 2015 with research-level data (n = 267). The median duration of follow-up was 51 months. The median age at autoHCT was 31 years; 633 patients (26%) had primary extragonadal GCT, and 1167 (49%) underwent TT. The 3-year progression-free (PFS) and overall survival (OS) improved from 24% (95% confidence interval [CI], 18% to 31%) and 35% (95% CI, 29% to 40%), respectively, in 1990 to 1994 to 47% (95% CI, 43% to 50%) and 54% (95% CI, 50% to 57%), respectively, in 2010 to 2015 (P < .0001). TT recipients were more likely than ST recipients to undergo autoHCT as first salvage treatment. The proportion of TTs increased from 38% of all autoHCTs in 2000 to 2004 to 77% in 2010 to 2015. Nonseminoma histology, residual disease at autoHCT, >1 line of pretransplantation chemotherapy, and ST versus TT were associated with inferior PFS and OS. Post-transplantation survival has improved significantly over time for relapsed/refractory male GCT and is associated with the increased use of TTs (compared with STs) and performance of autoHCT earlier in the disease course.

The Revised International Staging System (R-ISS) and the International Myeloma Working Group 2014 (IMWG 2014) are newer staging systems used to prognosticate multiple myeloma (MM) outcomes. We hypothesized that these would provide better prognostic differentiation for newly diagnosed multiple myeloma (MM) compared with ISS. We analyzed the Center for International Blood and Marrow Transplant Research database from 2008 to 2014 to compare the 3 systems (N = 628) among newly diagnosed MM patients undergoing upfront autologous hematopoietic cell transplantation (AHCT). The median follow-up of survivors was 48 (range, 3 to 99) months. The R-ISS provided the greatest differentiation between survival curves for each stage (for overall survival [OS], the differentiation was 1.74 using the R-ISS, 1.58 using ISS, and 1.60 using the IMWG 2014) . Univariate analyses at 3 years for OS showed R-ISS I at 88% (95% confidence interval [CI], 83% to 93%), II at 75% (95% CI, 70% to 80%), and III at 56% (95% CI, 3% to 69%; P < .001). An integrated Brier score function demonstrated the R-ISS had the best prediction for PFS, though all systems had similar prediction for OS. Among available systems, the R-ISS is the most optimal among available prognostic tools for newly diagnosed MM undergoing AHCT. We recommend that serum lactate dehydrogenase and cytogenetic data be performed on every MM patient at diagnosis to allow accurate prognostication.

High-dose melphalan and autologous stem cell transplantation (HDM/SCT) is an effective treatment modality for immunoglobulin light-chain (AL) amyloidosis; however, its application remains restricted to patients with good performance status and limited organ involvement. In recent years, the paradigm for AL amyloidosis has changed with the introduction of novel agents such as immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). We hypothesized that use of novel agent induction regimens has improved outcomes for patients with AL amyloidosis undergoing HDM/SCT at our center.All patients with AL amyloidosis, age ≥18 years who underwent HDM/SCT between 2001 and 2014 at the Fred Hutchinson Cancer Research Center and University of Washington Medical Center were included in this study. Any regimen administered within 6 months prior to HDM/SCT including an IMiD or a PI was considered a novel induction regimen. Use of induction regimen was evaluated in a Cox proportional hazard model for association with progression-free survival (PFS) and overall survival (OS).Forty-five patients with AL amyloidosis underwent HDM/SCT. The median age was 57.2 years (range 39-74.4), 15 (33.3%) were women. The median number of organs involved was 2 (range 1-5), with 20 patients having only 1 (44.4%), 10 patients having 2 (22.2%), and 15 patients (33.3%) having ≥ 3 organs involved. Novel agent induction regimens were used prior to HDM/SCT in 21 patients (46.7%); these comprised PI in 13/21 (57.1%), IMiD alone in 6/21 (28.6%), PI and cyclophosphamide (CyBorD) in 3/21 (14.3%), and IMiD and PI in 3/21 (14.3%). Use of a novel agent induction regimen was associated with improved, but not OS. The 3-year PFS for patients who received a novel agent induction was 79%, while for those who did not was 53% (hazard ratio [HR] = 0.317, p = 0.048). The 3-year OS for patients who received novel agent induction regimens was 95%, while for those who did not was 71% (HR = 0.454, p = 0.247).Our data suggest that use of a novel agent induction regimen including an IMiD or PI prior to HDM/SCT for patients with AL amyloidosis could improve outcomes, with improvement in PFS. Although these results are limited by sample size and lack of randomization, these results support possible further investigation of novel agent induction regimens in the context of a prospective clinical trial.

Conventional cytogenetics and interphase fluorescence in situ hybridization (FISH) identify high-risk multiple myeloma (HRM) populations characterized by poor outcomes. We analyzed these differences among HRM versus non-HRM populations after upfront autologous hematopoietic cell transplantation (autoHCT). Between 2008 and 2012, 715 patients with multiple myeloma identified by FISH and/or cytogenetic data with upfront autoHCT were identified in the Center for International Blood and Marrow Transplant Research database. HRM was defined as del17p, t(4;14), t(14;16), hypodiploidy (45 chromosomes excluding -Y) or chromosome 1 p and 1q abnormalities; all others were non-HRM. Among 125 HRM patients (17.5%), induction with bortezomib and immunomodulatory agents (imids) was higher compared with non-HRM (56% versus 43%, P .001) with similar pretransplant complete response (CR) rates (14% versus 16%, P .1). At day 100 post-transplant, at least a very good partial response was 59% in HRM and 61% in non-HRM (P = .6). More HRM patients received post-transplant therapy with bortezomib and imids (26% versus 12%, P = .004). Three-year post-transplant progression-free (PFS) and overall survival (OS) rates in HRM versus non-HRM were 37% versus 49% (P .001) and 72% versus 85% (P .001), respectively. At 3 years, PFS for HRM patients with and without post-transplant therapy was 46% (95% confidence interval [CI], 33 to 59) versus 14% (95% CI, 4 to 29) and in non-HRM patients with and without post-transplant therapy 55% (95% CI, 49 to 62) versus 39% (95% CI, 32 to 47); rates of OS for HRM patients with and without post-transplant therapy were 81% (95% CI, 70 to 90) versus 48% (95% CI, 30 to 65) compared with 88% (95% CI, 84 to 92) and 79% (95% CI, 73 to 85) in non-HRM patients with and without post-transplant therapy, respectively. Among patients receiving post-transplant therapy, there was no difference in OS between HRM and non-HRM (P = .08). In addition to HRM, higher stage, less than a CR pretransplant, lack of post-transplant therapy, and African American race were associated with worse OS. In conclusion, we show HRM patients achieve similar day 100 post-transplant responses compared with non-HRM patients, but these responses are not sustained. Post-transplant therapy appeared to improve the poor outcomes of HRM.

Autologous hematopoietic cell transplantation (HCT) is a treatment option for many patients diagnosed with lymphoma. The effects of patient-specific factors on outcomes after autologous HCT are not well characterized. Here, we studied a sequential cohort of 754 patients with lymphoma treated with autologous HCT between 2000 and 2010. In multivariate analysis, patient-specific factors that were statistically significantly associated with non-relapse mortality (NRM) included hematopoietic cell transplantation comorbidity index (HCT-CI) scores of ≥ 3 (hazard ratio [HR] 1.94, P = 0.05), a history of alcohol use disorder (AUD) (HR 2.17, P = 0.004), and older age stratified by decade (HR 1.29, P = 0.02). HCT-CI ≥ 3, a history of AUD, and age > 50 were combined into a composite risk model: non-relapse and overall mortality rates at 5 years increased from 6% to 30% and 32% to 58%, respectively, in patients with zero versus all 3 risk factors. The HCT-CI is a valid tool in predicting mortality risks after autologous HCT for lymphoma. AUD and older age exert independent prognostic impact on outcomes. Whether AUD indicates additional organ dysfunction or socio-behavioral abnormality warrants further investigation. The composite model may improve risk-stratification prior to autologous HCT.

These NCCN Guidelines Insights highlight the important updates/changes specific to the 2016 version of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. These changes include updated recommendations to the overall management of multiple myeloma from diagnosis and staging to new treatment options.

This study was conducted to compare long-term outcomes in patients with refractory/relapsed grades 1 and 2 follicular lymphoma (FL) after allogeneic (allo) versus autologous (auto) hematopoietic cell transplantation (HCT) in the rituximab era. Adult patients with relapsed/refractory grades 1 and 2 FL undergoing first reduced-intensity allo-HCT or first autograft during 2000 to 2012 were evaluated. A total of 518 rituximab-treated patients were included. Allo-HCT patients were younger and more heavily pretreated, and more patients had advanced stage and chemoresistant disease. The 5-year adjusted probabilities, comparing auto-HCT versus allo-HCT groups for nonrelapse mortality (NRM) were 5% versus 26% (P < .0001); relapse/progression: 54% versus 20% (P < .0001); progression-free survival (PFS): 41% versus 58% (P < .001), and overall survival (OS): 74% versus 66% (P = .05). Auto-HCT was associated with a higher risk of relapse/progression beyond 5 months after HCT (relative risk [RR], 4.4; P < .0001) and worse PFS (RR, 2.9; P < .0001) beyond 11 months after HCT. In the first 24 months after HCT, auto-HCT was associated with improved OS (RR, .41; P < .0001), but beyond 24 months, it was associated with inferior OS (RR, 2.2; P = .006). A landmark analysis of patients alive and progression-free at 2 years after HCT confirmed these observations, showing no difference in further NRM between both groups, but there was significantly higher risk of relapse/progression (RR, 7.3; P < .0001) and inferior PFS (RR, 3.2; P < .0001) and OS (RR, 2.1; P = .04) after auto-HCT. The 10-year cumulative incidences of second hematological malignancies after allo-HCT and auto-HCT were 0% and 7%, respectively. Auto-HCT and reduced-intensity–conditioned allo-HCT as first transplantation approach can provide durable disease control in grades 1 and 2 FL patients. Continued disease relapse risk after auto-HCT translates into improved PFS and OS after allo-HCT in long-term survivors.

Relapsed or refractory primary CNS non-Hodgkin’s lymphoma (rrPCNSL) is a rare and challenging malignancy for which better evidence is needed to guide management. We present a retrospective cohort of 70 consecutive patients with rrPCNSL treated at the University of Washington between 2000-2020. HIV positive and secondary CNS lymphoma patients were excluded. During a median follow-up of 19.8 months, median overall survival (OS) was 18.30 months and median progression-free survival (PFS) was 12.67 months. At all stages of disease (diagnosis, first relapse, multiple relapses), PFS was an excellent predictor of OS. There was a small effect of age < 70 on PFS after initial diagnosis (PFS1), but no effect on PFS after first (PFS2) or subsequent (PFS3+) relapses. There was no effect of age < 60 on PFS1, PFS2, or PFS3+. Patients reinduced with high-dose methotrexate-based (HD-MTX) regimens had an overall response rate (ORR) of 86.7% and median PFS 17.2 months. For patients who responded to reinduction therapy, those consolidated with autologous stem cell transplant (ASCT) had median PFS of 30.3 months (n=11) compared with 12.1 months for other consolidation strategies (n=9), and 9.0 months for no consolidation (n=20). Although patients receiving ASCT were younger, KPS, sex, and the median number of recurrences were similar between consolidation groups. We conclude that PFS is a useful endpoint for rrPCNSL which predicts OS and is not associated with age. Using PFS as an endpoint, we did not detect a benefit to any consolidation strategy other than ASCT.

Mantle cell lymphoma (MCL) is an aggressive and incurable lymphoma. Standard of care for younger patients with MCL is induction chemotherapy followed by autologous stem cell transplantation (auto-HCT). Rituximab maintenance after auto-HCT has been shown to improve progression-free survival (PFS) and overall survival (OS) in MCL. Bortezomib maintenance therapy has also been shown to be tolerable and feasible in this setting. However, the combination of bortezomib and rituximab as maintenance therapy post-auto-HCT has not been studied. We conducted a multicenter, phase II trial of bortezomib given in combination with rituximab as maintenance in MCL patients after consolidative auto-HCT. Enrolled patients (n = 23) received bortezomib 1.3 mg/m2 subcutaneously weekly for 4 weeks every 3 months (up to 24 months) and rituximab 375 mg/m2 intravenously weekly for 4 weeks every 6 months (up to 24 months) for a total duration of 2 years. The primary study endpoint was disease-free survival (DFS). With a median follow-up of 35.9 months, the 2-year DFS probability was 90.2% (95% CI 66–97), and 2-year OS was 94.7% (95% CI 68–99). The most frequent grade 3/4 toxic events were neutropenia (in 74% of patients) and lymphopenia (in 35%). The incidence of peripheral neuropathy was 48% for grade 1, 9% for grade 2, and 0% for grade 3/4. We also examined the role of quantitative cyclin D1 (CCND1) mRNA in monitoring minimal residual disease. Combined bortezomib and rituximab as maintenance therapy in MCL patients following auto-HCT is an active and well-tolerated regimen. ClinicalTrials.gov NCT01267812 , registered Dec 29, 2010.

We previously reported initial results in 102 multiple myeloma (MM) patients treated with sequential high-dose melphalan and autologous hematopoietic cell transplantation followed by 200 cGy total body irradiation with or without fludarabine 90 mg/m2 and allogeneic hematopoietic cell transplantation. Here we present long-term clinical outcomes among the 102 initial patients and among 142 additional patients, with a median follow up of 8.3 (range 1.0-18.1) years. Donors included human leukocyte antigen identical siblings (n=179) and HLA-matched unrelated donors (n=65). A total of 209 patients (86%) received tandem autologous-allogeneic upfront, while thirty-five patients (14%) had failed a previous autologous hematopoietic cell transplantation before the planned autologous-allogeneic transplantation. Thirty-one patients received maintenance treatment at a median of 86 days (range, 61-150) after allogeneic transplantation. Five-year rates of overall survival (OS) and progression-free survival (PFS) were 54% and 31%, respectively. Ten-year OS and PFS were 41% and 19%, respectively. Overall non-relapse mortality was 2% at 100 days and 14% at five years. Patients with induction-refractory disease and those with high-risk biological features experienced shorter OS and PFS. A total of 152 patients experienced disease relapse and 117 of those received salvage treatment. Eighty-three of the 117 patients achieved a clinical response, and for those, the median duration of survival after relapse was 7.8 years. Moreover, a subset of patients who became negative for minimal residual disease (MRD) by flow cytometry experienced a significantly lower relapse rate as compared with MRD-positive patients (P=0.03). Our study showed that the graft-versus-myeloma effect after non-myeloablative allografting allowed long-term disease control in standard and high-risk patient subsets. Ultra-high-risk patients did not appear to benefit from tandem autologous/allogeneic hematopoietic cell transplantation because of early disease relapse. Incorporation of newer anti-MM agents into the initial induction treatments before tandem hematopoietic cell transplantation and during maintenance might improve outcomes of ultra-high-risk patients. Clinical trials included in this study are registered at: clinicaltrials.gov identifiers: 00075478, 00005799, 01251575, 00078858, 00105001, 00027820, 00089011, 00003196, 00006251, 00793572, 00054353, 00014235, 00003954.