After Autologous Hematopoietic Stem Cell Transplantation Research Articles

Plerixafor-based mobilization and mononuclear cell counts in graft increased the risk of engraftment syndrome after autologous hematopoietic stem cell transplantation.

Engraftment syndrome (ES) is one of the most common complications in the early phase after autologous hematopoietic stem cell transplantation (ASCT), and we aimed to evaluate the incidence and risk factors for ES patients receiving ASCT in the era of plerixafor-based mobilization. A total of 294 were enrolled, and 16.0% (n = 47) experienced ES after ASCT. The main clinical manifestations were fever (100%), diarrhea (78.7%), skin rash (23.4%), and hypoxemia/pulmonary edema (12.8%). Plerixafor-based mobilization was associated with higher counts of CD3+ cells, CD4+ cells, and CD8+ cells in grafts. In univariate analysis of the total cohort, age ≥60 years, receiving ASCT at complete remission (CR), higher number of mononuclear cell (MNC), CD3+ cell counts, CD4+ cells as well as CD8+ cells transfused and plerixafor-based mobilization were associated with ES after ASCT. Multivariate analysis showed that age ≥60 years (P = .0014), receiving ASCT at CR (P = .002), and higher number of MNC transfused (P = .026) were associated with ES in total cohort. In plasma cell disease subgroup, age ≥60 years (P = .013), plerixafor-based mobilization (P = .036), and receiving ASCT at CR (P = .002) were associated with ES. Patients with more risk factors had a higher risk of ES. The 1-year probabilities of relapse, non-relapse mortality, and survival were comparable between patients with and without ES. Thus, plerixafor-based mobilization may influence the composition of T lymphocytes in grafts and increase the risk of ES, particularly in patients with plasma cell disease.

(328) The Relationship Between Multiple Myeloma and Hypogonadism: A Systematic Review

Abstract Introduction Hypogonadism has been reported with substantial frequency in patients with various types of malignancies. Multiple myeloma (MM) is a cancer that affects plasma cells, a type of white blood cell responsible for producing antibodies. It is the second most common blood cancer, accounting for approximately 10% of hematologic malignancies. However, the prevalence, pathophysiology, and significance of hypogonadism as a sequela of MM or its standardized treatment regimens has not been extensively studied. Objective To characterize the existing literature on hypogonadism in patients with MM, including the prevalence, underlying mechanisms, and link to overall disease prognosis. Furthermore, we will examine the effects of testosterone therapy on MM and its hypogonadal symptomatology. Methods Relevant studies published up to November 2022 were retrieved through a search of PubMed using the keywords ‘hypogonadism’, ‘multiple myeloma’, and ‘testosterone’. Studies that reported on the presentation, management, or outcomes of patients with MM and how they were affected by a hypogonadal state were included. The search yielded 72 studies, of which 11 met the inclusion criteria. Results The most comprehensive assessment of the frequency of hypogonadism in a MM cohort found that 74% of 561 MM patients were classified as hypogonadal compared to 33% of patients in a control population. Further evaluation found that male patients with MM were found to have significantly lower levels of testosterone than control (p<0.0001). Another assessment of hormone level differences between MM patients and controls found that male patients had higher: FSH, LH, estrogen, and E/T ratios than healthy controls. Testosterone supplementation was found to lower interleukin-6 (IL-6) levels, which could potentially contribute to the adverse effects of MM. This effect could arise from the finding that IL-6 concentration was independently associated with severe symptomatology in MM patients on multivariate analysis in a study by Wang et al. (p=0.004). Hypogonadism can occur as an adverse effect of MM treatment with immunotherapy/chemotherapy initiation. A small study by Greenfield et al. found that 65% of patients intensively treated for MM were subsequently hypogonadal. This was further supported by a study by Anderson et al. examining sexual function after autologous hematopoietic stem cell transplant (AHSCT), which saw a significant increase in erectile dysfunction at 1-month follow-up from 68.4% to 100% of all patients. Conclusions There appears to be a relationship between MM and hypogonadism, potentially due to the inflammatory state caused by the disease itself. This may have some association with the inflammatory cytokine IL-6. However, there is a paucity of data fully exploring this relationship, the underlying mechanisms, and the effects of testosterone therapy on MM. The true relationship is likely multifactorial, given the mixture of studies that found hypogonadism in MM at baseline as well as after systemic treatment. Future prospective and randomized studies are necessary to elucidate the true link between MM and/or its treatment and hypogonadism. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Hims & Hers Inc, Coloplast, Clarus Therapeutics, Antares Pharma, Acerus.

Risk Factors and the Effect of Antiviral Prophylaxis for Herpes Zoster in Multiple Myeloma Patients

To study the incidence and risk factors of herpes zoster in patients with multiple myeloma and to evaluate the preventive effect of antiviral therapy. The clinical features of multiple myeloma patients with herpes zoster were retrospectively analyzed, the risk factors of herpes zoster and the effect of antiviral prophylaxis were analyzed. Among 180 patients with multiple myeloma, 23 cases developed herpes zoster (12.8%). The incidence of herpes zoster was 19.1% in patients with renal dysfunction and 23.5% after autologous hematopoietic stem cell transplantation (ASCT). The incidence of herpes zoster was higher in patients receiving bortezomib-containing regimens (21/137, 15.3%) than that in those without bortezomib (2/43, 4.7%), but there was no statistical difference (P =0.067). Antiviral prophylaxis was associated with fewer zoster infections, 8/111(7.2%) developed herpes zoster in patients who received antiviral prophylaxis, and 15/69 (21.7%) in those receiving no prophylaxis(P =0.005). 65.2% of patients with herpes zoster did not receive antiviral prophylaxis. Multivariate analysis showed that bortezomib treatment, AHSCT and renal dysfunction were independent risk factors for multiple myeloma with herpes zoster, while antiviral prophylaxis was independently associated with reducing the risk of herpes zoster. Herpes zoster had no effect on OS in patients with multiple myeloma. The risk of herpes zoster in multiple myeloma patients was increased. Antiviral prophylaxis can reduce the risk of herpes zoster in patients on bortezomib-based therapy.

Daratumumab Maintenance after Autologous Hematopoietic Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma

Background: Maintenance therapy after autologous hematopoietic stem cell transplantation (ASCT) is a standard of care in newly diagnosed multiple myeloma (NDMM). Lenalidomide maintenance after transplantation is the most frequently recommended regimen. Daratumumab has been increasingly used as a maintenance drug in NDMM. However, there is no enough clinical information about daratumumab as maintenance strategy after ASCT. This study is aim to evaluate the efficacy and safety of daratumumab as maintenance after ASCT for NDMM. Patients and Methods: Clinical data, hematological and renal response, and safety of 15 post-transplant patients with NDMM who had received daratumumab maintenance between 1 May 2022 and 30 June 2023 were retrospectively analyzed. Daratumumab-naive patients received weekly dosing (16mg/kg) for the first 8 weeks. Results: Fifteen patients (11 males and 4 females) with median age of 58 years (41～72 years) , were included. Thirteen patients were daratumumab native, 6 patients had renal impairment, and 2 patients with high-risk cytogenetics. The median infusion times of daratumumab were 12 (6～17) times. Efficacy was evaluable in all 15 patients，and daratumumab maintenance therapy increase the rate of stringent complete response (from 6 [40%] to 9 [60%] ) by 20%，improved the renal response rate and median eGFR in patients with renal injury. During maintenance therapy with daratumumab, the most common hematological grade 3 adverse events(AE) were lymphopenia (4 [26.67%] of 15 patients), non-hematologic adverse events were infusion-related reactions (7 [46.67%] of 15 patients) and grade 3 pneumonia (5 [33.33%] of 15 patients). These 5 pneumonia patients were daratumumab naive ( 5 [38.46%] of 13 patients) , with median 8 (6～10)infusions. Among them, 3 patients chest CT showed interstitial infiltrates, and combination of methylprednisolone was effective. With a median follow-up of 12 months, one patient had died (not related to daratumumab treatment), 1-year OS rate was 93.33%. Conclusions: Daratumumab was safe and effective as a maintenance agent for post-ASCT patients with NDMM, and adverse events were controllable. The most common AE is grade 3 pneumonia, maybe a less dose-intense maintenance regimen for the first 8 weeks can reduce the incidence of pneumonia.

Longitudinal Assessment of Minimal Residual Disease (MRD) in the ATLAS Randomized Phase 3 Trial of Post-Transplant Treatment with Carfilzomib, Lenalidomide, and Dexamethasone (KRd) Versus Lenalidomide (R) Alone in Patients with Newly Diagnosed Multiple Myeloma (NDMM)

Introduction The interim results of the ATLAS trial (Dytfeld, Lancet Oncology 2023) suggest a progression-free survival (PFS) benefit for NDMM patients after autologous hematopoietic stem cell transplantation (ASCT) treated with MRD-directed and risk-adapted maintenance using KRd compared to single-agent R. In order to gain a better understanding of the differences in response dynamics and depth achieved by the two regimens, we conducted a detailed analysis of MRD results assessed at multiple timepoints. Methods ATLAS is an ongoing phase 3 trial that randomized 180 patients with NDMM after ASCT to receive maintenance therapy with KRd or R. In the KRd arm, patients with standard-risk cytogenetics who achieved MRD-negativity after cycle 6 de-escalated therapy to receive R alone, starting from cycle 9. MRD assessments were performed using multicolor flow cytometry (MFC) with a limit of detection (LoD) of 10 -5 and next-generation sequencing (NGS) with LoD 10 -6 at screening, cycle 6 (C6), C12, C18, C24, and C36. Patients with MRD>10 -5 were considered MRD positive. When both MFC and NGS results were available, at least one positive result qualified a patient as MRD-positive. In line with the MRD reporting harmonization guidelines (Costa, Leukemia 2021), patients who have not reached a landmark timepoint for analysis were excluded from the denominator. MRD rates between the treatment arms were compared using the chi-square test. PFS and MRD-free survival (death, progression or MRD resurgence counted as an event) were analyzed using the Kaplan-Meier method to calculate survival rates, and the log-rank test was performed to compare the groups. Results We previously reported MRD rates at the end of 6 cycles (Dytfeld, Lancet Oncology2023). In this analysis, MRD results were evaluable for the following number of subjects at the respective timepoints: 180 at screening, 180 at C6, 180 at C12, 179 at C18, 175 at C24, and 160 at C36. All the reported data, including MRD results, response rates, and time to event, were obtained at the cut-off date 31-DEC-2021, as in the Lancet Oncology manuscript. In the landmark analysis, MRD-negativity after C6 was associated with improved PFS for the entire study patient population [HR=0.49 (95% CI: 0.27-0.90), p=0.01]. Although the proportion of MRD-negative patients at screening was higher in the R arm (46/87, 53%) compared to the KRd arm (36/93, 39%, p=0.06), MRD-negative rates were higher in the KRd arm in the subsequent landmark evaluations. The MRD-negativity rates for KRd and R were: 61/93 (66%) vs 41/87 (47%, p=0.01) at C6; 49/93 (53%) vs 41/87 (47%, p=0.46) at C12; 48/93 (52%) vs 35/86 (41%, p=0.14) at C18; 43/90 (48%) vs 26/85 (31%, p=0.02) at C24; 34/82 (41%) vs 16/78 (21%, p= 0.004) at C36. These findings were consistent with a higher number of patients in the KRd arm who converted from MRD-positivity at screening to MRD-negativity at any timepoint (Figure 1). Of the 50 patients with detectable MRD at screening in the KRd arm, 33 (66%) achieved MRD-negativity as their best response. Among them, 24 achieved MRD-negativity at the end of C6, with 2 patients converting as late as C24. The numbers were significantly lower for the R arm, with 14 out of 32 (44%) MRD-positive patients at screening achieving MRD-negativity (p=0.047). Sustained MRD-negativity for at least 12 months was reached in 51 out of 93 patients (55%) in the KRd arm and in 36 out of 87 (41%) in the R arm (p=0.06). Those who achieved sustained MRD-negativity have had significantly longer PFS (HR=0.35 (0.20-0.59), p<0.0001). Among patients with sustained MRD-negativity, patients in the KRd arm had superior PFS [HR=0.30 (0.12-0.79), p=0.01], and MRD-free survival [HR=0.42 (0.20-0.89), p=0.02, Figure 2]. In the KRd arm, sustained MRD-negativity was confirmed in 32 out of 41 (78%) patients who had de-escalated therapy from KRd to R. In this group there were 8 events (25%) of progressive disease or MRD resurgence, which compared favorably to 17/36 (47%, p=0.057) events observed in the R arm. Conclusions The improved PFS in patients with NDMM receiving post-ASCT KRd maintenance may be attributed to higher rates of MRD conversion and longer duration of MRD-negativity. Importantly, this benefit, compared to R alone, appears to be sustained even in the subset of patients who received only 8 cycles of MRD-directed, risk-adapted KRd and subsequently de-escalated to R alone.

A pilot study of cord blood-derived natural killer cells as maintenance therapy after autologous hematopoietic stem cell transplantation.

Natural killer (NK) cell based immunotherapy is an emerging strategy in hematologic malignancies because allogeneic NK cells can provide potent antitumor immunity without inducing graft-versus-host disease. Thus, we expanded cord blood-derived NK (CB-NK) cells ex vivo from random (MHC mismatched and KIR mismatched) donors, and investigate the feasibility and efficacy of repeated infusions CB-NK cells as maintenance therapy after autologous hematopoietic stem cell transplantation (ASCT). Thirty-one patients with acute myeloid leukemia and high-risk lymphoma received ASCT and the adoptive CB-NK cell multiple infusions for maintenance therapy. Patients received a median dose of 5.98 × 107/kg (range, 1.87-17.69 × 107/kg) CB-NK cells and 23 patients completed four infusions, 8 patients received three infusions. Only mild infusion reactions occurred in 15.5% of 116 infusions. Compared to a contemporaneous cohort of 90 patients who did not receive NK cell therapy, the adoptive transfer of CB-NK cells as maintenance treatment showed a tendency of difference in decreasing the relapse rate between CB-NK group and control group (9.7% vs 24.4%). The patients who receiving NK cell infusions had a better PFS and OS than controls (4 year PFS, 84.4 ± 8.3% vs 73.5 ± 5.4%; and 4 year OS, 100% vs 78.1 ± 5.4%) . These findings demonstrate safety and validity of maintenance therapy using CB-NK cells multiple infusions after ASCT, and it is worthy of further clinical trial verification.

Cardiotoxicity after autologous hematopoietic stem cell transplantation (AHSCT): longitudinal and observational study

Objectives: To assess incidence and extent of early cardiotoxicity after autologous hematopoietic stem cell transplantation (AHSCT).
 Methods: Study carried out in two bone marrow transplant centers, in public and private hospital, located in interior of Minas Gerais, Brazil. All patients who underwent AHSCT at centers between March 2018 and May 2019 and October 2019 were included. Altered results were classified according to Brazilian Cardio-Oncology Guidelines.
 Results: Of the 36 patients evaluated, seven (21.2%) had cardiotoxicity on echocardiography, with mean left ventricular ejection fraction decreasing from 71.53 to 64.75% before and after conditioning (p = 0.00013). Clinical cardiovascular alterations were associated with advanced staging and time of more than one year between diagnosis and AHSCT (p=0.01 in both cases). Specific clinical signs of congestion were correlated with radiotherapy to the mediastinum and a dose >400 mg of doxorubicin before AHSCT (p=0.02 and p=0.01, respectively).
 Conclusions: Thus, higher incidence of cardiac injury was observed after AHSCT, which was related to type of pre-transplant therapy. This fact reflects our limitations and leads us to seek improvements in cardiovascular assessment of patients undergoing AHSCT, in order to reduce morbidity and mortality associated with myocardial injuries in these patients.

A Prospective, Randomized Trial Examining the Use of G-CSF Versus No G-CSF in Patients Post-Autologous Transplantation

Contemporary, prospective data regarding the impact of granulocyte-colony stimulating factor (G-CSF) on outcomes after autologous hematopoietic stem cell transplantation (Auto-HSCT) in an era when stem cell grafts are more qualitatively robust are limited. Recent retrospective analyses have not supported a beneficial effect of post-transplantation G-CSF use on major outcomes after Auto-HSCT leading to strategies to delay or eliminate the use of G-CSF altogether in this context. To test the hypothesis that the infusion of consistently higher doses of stem cells (defined as ≥4 × 106/kg) in Auto-HSCT will obviate the need for post-transplantation G-CSF. If so, the impact of withholding G-CSF will be noninferior to the use of G-CSF in terms of length of stay (LOS). The specific objectives were to conduct a prospective, randomized clinical trial primarily examining the impact of post-transplantation G-CSF on LOS, and secondarily on engraftment, infectious complications, antibiotic usage, and incidence of engraftment syndrome after Auto-HSCT in patients receiving versus not receiving G-CSF after Auto-HSCT. Patients with multiple myeloma or non-Hodgkin lymphoma (NHL) who underwent Pegfilgrastim plus Plerixafor-primed stem cell collection followed by Auto-HSCT were randomized to the G-CSF group (receive G-CSF starting at day 3 after Auto-HSCT) or the no G-CSF group (G-CSF withheld after Auto-HSCT). Seventy patients per arm were planned to demonstrate the primary endpoint of noninferiority in LOS between the G-CSF and the no G-CSF groups. Patient outcomes in the two groups were followed up and compared after Auto-HSCT, and an interim analysis for futility was planned when accrual reached 50%.The primary finding of this study was that despite only a 2-day longer median absolute neutrophil count (ANC) recovery in the no G-CSF arm (median 11 versus 13 days; P = .001), LOS was 4 days longer in patients not treated with G-CSF (median 11 days versus 15 days; P = .001). G-CSF use was associated with more robust incremental daily increases in ANC once recovered (P = .001), fewer days of febrile neutropenia (P = .001), and fewer days on antibiotics (P = .001), potentially contributing to this disproportionate finding. Inferiority in LOS in the no G-CSF group was demonstrated on the interim analysis, and the study was closed at the half-way point. There were no significant group differences in platelet recovery, documented infections, hospital readmissions, or overall survival at 1 year. Engraftment syndrome occurred in 54.3% of patients and was not related to G-CSF use. These results suggest that the increased LOS associated with the omission of G-CSF is largely due to concerns regarding the potential for infection in patients without a stable, recovered ANC in a hospital setting. Engraftment syndrome represented a significant source of febrile neutropenia further contributing to patient safety concerns and requires strategies to decrease its incidence. Infectious complications and death were not affected by the omission of G-CSF supporting a carefully monitored outpatient approach to Auto-HSCT in which white blood cell growth factor is eliminated or given as needed for documented infection.© 2023 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

The prognostic value of dynamic minimal residual disease after autologous hematopoietic stem cell transplantation in patients with multiple myeloma in novel-agent era

Objective: To investigate the clinical prognostic value of dynamic minimal residual disease (MRD) after autologous hematopoietic stem cell transplantation (AHSCT) in patients with multiple myeloma (MM). Methods: Patients with MM who underwent AHSCT in Beijing Chao-Yang Hospital from February 2016 to December 2019 were enrolled in this study. All the patients in the study had complete baseline data at the diagnosis. AHSCT was performed after induction chemotherapy. Response evaluation was performed after induction therapy. All the patients were assessed at approximately 100 days after AHSCT. Bone marrow MRD by NGF was performed every three months and dynamically monitored for at least 12 months. All the patients were divided into different groups according to cytogenetics and MRD status. Survivals in different groups were analyzed by IBM SPSS 22.0 statistical software. Results: A total of 150 patients with MM were enrolled in this study at last, including 66 patients in the cytogenetic standard risk group and 84 patients in the cytogenetic high-risk group. The median age was 54 years (range 30-68 years) and 87 male patients (58.0%) was in the study. The median follow-up was 36 months (range 16-72 months). Patients in the standard-risk group had better clinical prognosis than those in the high-risk group [median PFS in the standard-risk group was not achieved, and median PFS in the high-risk group was 45 months (P<0.001); median OS of both groups was not reached, and the estimated 3-year OS rate of the standard-risk group and the high-risk group was 95.2% and 78.9%, respectively (P=0.001)]. According to MRD status of patients, patients in each group were divided into three subgroups: persistent positive (Ppos), transient negative (Tneg) and persistent negative (Pneg). The median OS and median PFS of all subgroups in the standard-risk group was not reached (P=0.324 and P=0.086). In high-risk group, the median OS of MRD Pneg subgroup was not reached, and the estimated 3-year OS rate was 100%; The median OS of MRD Ppos subgroup was 52 months, and MRD Tneg subgroup only 31 months (P=0.002); the median PFS of MRD Pneg group was not reached, and the estimated 3-year PFS rate was 85.4%; median PFS of MRD Ppos subgroup was 40 months, and MRD Tneg subgroup only 17 months (P=0.001). Conclusions: MRD Pneg might overcome the adverse prognosis of MM patients with high-risk cytogenetics. However, MRD Tneg might be a poor prognostic factor for the patients with cytogenetic high-risk MM.

The Prognostic Value of Early Relapse after Autologous Hematopoietic Stem Cell Transplantation in Newly Diagnosed Multiple Myeloma

To assess the impact of early relapse (ER) after autologous hematopoietic stem cell transplan-tation (AHSCT) on overall survival (OS) for multiple myeloma (MM) patients. Clinical data of 37 patients with MM undergoing AHSCT in department of hematology of Shanxi Bethune Hospital from January 2012 to December 2017 were retrospectively analyzed. The effect of ER on OS of patients was analyzed. The effects of international staging system (ISS) staging, cytogenetics, pre-transplant efficacy, minimal residual disease, and age on OS of the patients were also analyzed respectively. Among the 37 patients, 13 cases (35.1%) had ER, and 24 cases (64.9%) had non-ER. 3 patients with ER had extramedullary disease, but none with non-ER showed extramedullary disease. More than or equal to very good partial rate (VGPR) in patients with ER and without ER were 3 cases (23.1%) and 15 cases (62.5%), respectively, and the curative effect of the former was significantly lower than that of the latter (P<0.05). The median follow-up time was 31 (12-96) months, and median OS time was 93 months in all the patients. The median survival time of patients with ER was 17 months, and the median progression free survival was 7 months, both were significantly shorter than 93 months and 38 months of patients with non-ER (P<0.05). Univariate analysis showed that the OS was affected by ER, cytogenetic abnormalities (FISH), and ≥VGPR before transplantation. Multivariate analysis showed that ER was an independent prognostic factor. The prognosis of patients with ER after AHSCT in newly diagnosed MM is poor. ER is an independent prognostic factor of survival.

Selective cognitive dysfunction and physical disability improvement after autologous hematopoietic stem cell transplantation in highly active multiple sclerosis

The aim was to assess the cognitive dysfunction and physical disability after autologous hematopoietic stem cell transplantation (AHSCT), to explore the potential factors influencing disability regression after AHSCT and to estimate the safety of low-dose immunosuppressive therapy in highly active Multiple Sclerosis (MS) patients. In single-center prospective study patients who failed to conventional therapies for highly active relapsing MS underwent the AHSCT. The disability was followed up with Expanded Disability Status Scale and cognition with Brief International Cognitive Assessment for Multiple Sclerosis. Twenty four patients [18 (72.0%) female] underwent AHSCT. Two patients of 13 had one relapse during the first year and three patients—during the second year after AHSCT. Disability regression was found in 84.6% of patients. The scores of information processing speed and verbal learning were significantly higher at month 12 after AHSCT. The clinical variable that explained the disability regression at months 6 and 12 after AHSCT was the disability progression over 6 months before AHSCT. No transplant related-deaths were observed. Selective cognitive improvement was found after AHSCT in MS patients. The disability may be temporarily reversible after AHSCT in a significant proportion of highly active RMS patients if AHSCT is well-timed performed.

Early changes in IL-21, IL-22, CCL2, and CCL4 serum cytokines after outpatient autologous transplantation for multiple sclerosis: A proof of concept study.

Changes in serum cytokines after autologous hematopoietic stem cell transplantation (AHSCT) in multiple sclerosis (MS) patients were documented. Thirty-six consecutive MS patients who had their Expanded Disability Status Scale (EDSS) scored before AHSCT were prospectively enrolled. Cyclophosphamide (Cy) was infused at 200mg/kg in two administrations given 10days apart: the first dose for mobilization, the second as the conditioning regimen. Patients were mobilized with 10µg/kg/day subcutaneous G-CSF. Serum was collected 14days before and 14 after AHSCT. IL-6, IL-9, IL-10, IL 17-A, IL-21, IL-22, IL-23, TNF-A, CCL2, CCL3, and CCL4 were measured by magnetic bead-based immunoassay. t Test and Wilcoxon test were used to compare cytokine levels before and after AHSCT. There were 28 women and 8 men with a median age of 46 (15-62) years, median duration of MS was 9.5 (1-32) years, and EDSS score was 5.7 (1.5-8.0). Patients had a decrement of pro-inflammatory IL-21 and IL-22 (p=.003 and p=.028) and an increment of anti-inflammatory CCL2 and CCL4 (p<.001 and p=.039) after AHSCT. Decrease of IL-21 and IL-22 coupled with an increment of CCL2 and CCL4 could reflect the immunomodulatory effect of auto-HSCT and be an early indicator of its efficacy.

Depth of Response and Outcomes by Initial Therapy Prior to Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma

Second generation proteasome inhibition can increase the depth of response in multiple myeloma (MM) patients (pts), which may be important for progression free (PFS) and overall survival (OS) after autologous hematopoietic stem cell transplantation (AHCT). We evaluated response and post-AHCT outcomes in pts treated with lenalidomide and dexamethasone with bortezomib (VRD) or carfilzomib (KRD).

Clinical implication of minimal residual disease monitoring by 10-color flow cytometry in multiple myeloma

目的采用十色流式细胞术监测多发性骨髓瘤（MM）患者治疗后骨髓微小残留病（MRD），探讨其对MM患者预后的预测价值。方法回顾性分析2015年7月至2017年7月苏州大学附属第一医院收治的150例MM患者的临床资料，十色流式细胞术检测MRD水平。结果①诱导治疗结束后采用十色流式细胞术监测MRD的87例MM患者中，MRD阴性者34例（39.1%）。自体造血干细胞移植后1年内行十色流式细胞术监测MRD的69例患者中，MRD阴性者34例（49.3%），诱导治疗结束和移植后MRD阴性患者的无进展生存（PFS）期优于MRD阳性患者（未达到对21个月，P=0.022；未达到对18个月，P<0.001）。②根据移植前后MRD的动态改变将MM患者分为MRD持续阴性、阳性转阴性、持续阳性、阴性转阳性四组，四组的2年PFS率分别为83%、82%、44%、0（P=0.002）。③多因素分析显示诱导治疗结束后的MRD水平是影响PFS的独立预后因素[P=0.002，HR=4.808（95%CI 1.818~12.718）]。结论治疗后MRD转阴提示更好的临床预后，MRD水平对于MM患者的预后价值优于血清学疗效评估，可以联合R-ISS分期及细胞遗传学异常评估患者预后。

Bortezomib and Vorinostat Therapy as Maintenance Therapy after Autologous Transplant for Multiple Myeloma

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.

PB2330 EFFICACY OF MAINTENANCE THERAPY AFTER AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN HIGH‐RISK AGGRESSIVE LYMPHOMA: A SINGLE‐CENTER NON‐RANDOMIZED STUDY

Background:Autologous hematopoietic stem cell transplantation is the main treatment for lymphoma. While relapse after autologous hematopoietic stem cell transplantation (ASCT) is still challenging for high‐risk aggressive lymphoma.Aims:This study was to investigate the efficacy and safety of maintenance therapy post‐ASCT.Methods:From June 2009 to December 2018, patients with high‐risk aggressive lymphoma in our hospital were treated with maintenance therapy post‐ASCT according to the patient's needs and wishes, and then assigned to maintenance group or observation group. The end point of follow‐up was disease progression or death. The 4‐year overall survival (OS) and disease‐free survival (DFS) were compared between these two groups.Results:A total of 92 patients were enrolled, apart from 2 cases of early death, the remaining 90 patients underwent ASCTsuccessfully and achieved CR post‐ASCT. 59 patients were assigned to the observation group, and 31 patients to the maintenance group, including 22 with rituximab regimen,7 with DPP/DCEP‐G alternation regimen, and 2 with Chidamideregimen. There were no significant differences in gender, age,diagnosis,IPI score,pre‐transplant disease status, and hematopoietic reconstitution between the two groups. The main causes of death were disease recurrence. No serious adverse reactions occurred during the maintenance treatment period. After a median follow‐up of 616 days (12‐2854 days), and the DFS of the 1st, 2nd,3rd and 4thyears were67.1% VS 95.2%, 51.1% VS 90.5%, 48.1% VS 90.5%, 43.8% VS 90.5% (P = 0.002), respectively. The OS of the 1st, 2nd, 3rd and 4thyears were 90.0% VS 100%, 84.4% VS 95.2%, 77.3% VS 95.2%, 73.3% VS 95.2% (P = 0.126), respectively.For the overall survival rate, single factor analysis showed age &lt;30 years old, LDH increased before ASCTwere prognostic factors affecting OS; COX multi‐factor regression analysis showed age &lt;30 years old, LDH increased before ASCTwere independent prognostic factors for OS. The risk of death in patients &lt;30 years of age was 4.376 times higher than that in patients aged 30 years or older (P = 0.026, HR = 4.376, 95% CI = 1.188‐16.116). The risk of death in patients with LDH increased before ASCT was 5.165 times higher than in patients with normal LDH before ASCT (P = 0.015, HR = 5.165, 95% CI = 1.375‐19.395).For the disease‐free survival rate, single factor analysis showed that the initial admission to LDH increased, LDH increased before ASCT, IPI score≥2 points, maintenance treatment after ASCT were prognostic factors for DFS; COX multi‐factorregression Analysis showed that LDH increased before ASCTand maintenance treatment after ASCT were independent prognostic factors for DFS. The risk of recurrence of patients with LDH increased before ASCT was 2.648 times higher than that of normal LDH patients before ASCT (P = 0.034, HR = 2.648, 95% CI = 1.078‐6.507), and the risk of recurrence in maintenance‐treated patients after ASCT was 0.130 times than that in patients without maintenance therapy after ASCT (P = 0.006, HR = 0.130, 95% CI = 0.031‐0.557).Conclusion: Maintenance therapy post‐ASCT could reduce the risk of relapse and promote disease‐free survival, which deserves further investigation.Summary/Conclusion:Maintenance therapy post‐ASCT could reduce the risk of relapse and promote disease‐free survival, which deserves further investigation.image

S826 IMPROVED EFFICACY AND SAFETY OF A DUAL‐TARGET CAR‐T CELL THERAPY TARGETING BCMA AND CD38 FOR RELAPSED/REFRACTORY MULTIPLE MYELOMA FROM A PHASE I STUDY

Background:Encouraging results are seen from several early phase clinical trials on the cellular immunotherapy for relapsed/refractory (RR) multiple myeloma (MM), including anti‐B cell maturation antigen (BCMA) CAR‐T cell therapy and anti‐CD38 daratumumab (DARA) monotherapy. We conducted an anti‐BCMA and anti‐CD38 dual‐target CAR‐T cell in order to avoid negative relapse of single‐target loss. Here we report a promising results on 12 patients about the efficacy and safety in the ongoing phase I study.Aims:1.To evaluate the safety of the anti‐BCMA and anti‐CD38 dual‐target CAR‐T cell in RRMM, including cytokine release syndrome (CRS), neurotoxicity and other adverse events. 2.To assess the efficacy of the anti‐BCMA and anti‐CD38 dual‐target CAR‐T cell in RRMM, including the overall response rate(ORR),duration of remission and Progression‐free survival(PFS). 3.To estimate the proliferation and persistence of the dual‐target CAR‐T cell in the blood of RRMM patients.Methods:A phase I clinical trial (ChiCTR1800018143) has been launched to evaluate the efficacy and safety of the dual‐target CAR‐T cell product for RRMM. The enrolled RRMM patients had received at least 2 prior treatment regimens, including a proteasome inhibitor and an immunomodulatory agent, or are double‐relapsed or relapse after autologous hematopoietic stem cell transplantation(ASCT). Patients were subjected to a lymphodepleting regimen with Cy(250 mg/m2,d‐5 to d‐3) and Flu(25 mg/m2,d‐5 to d‐3) daily prior to the CAR‐T infusion (d0).The median number of infused cells was 2.17(0.5∼4.0) × 106 CAR+ cells/kg. The median follow‐up times is 21.5(6∼33)weeks and 66.7%(8/12) are more than 5 months. The efficacy was assessed by the International Uniform Response Criteria for Multiple Myeloma(2016), and the toxicity was graded by CTCAE 5.0.Results:As of January 31, 2019, 12 patients consisting of 66.67%(8/12) with genetic abnormalities,16.7%(2/12) with ASCT and 16.7%(2/12) with extrandal disease, have been infused with thedual‐target CAR‐T cell product. The overall response rate(ORR) is 83.3%(10/12), including 5 sCR, 2 VGPR and 3 PR. the shortest duration of sCR is 8 weeks and the longest one is over 26 weeks and 60%(3/5) have still maintained sCR more than 2 month. More encouragingly, 60%(6/10) have still kept sustained remission and allextramedullary lesions have been eliminated.The 8‐week Progression‐free survival(PFS) is 0.90 and 12‐week PFS is 0.77. Up to now, the CAR‐T cells still exists in the patients’ peripheral blood by flow cytometry and q‐PCR. The peak time of CAR‐T cells proliferation of sCR patients is about the 2nd week after infusion, which is earlier than other patients. 83.3%(10/12) were observed with cytokine release syndrome (CRS) and severe CRS(≥ Grade 3) accounted for 33.33%(4/12). No neurotoxicity was observed. Almost all the patients were observed with hematological toxicities. 16.7%(2/12) of patients was observed with hepatotoxicity and one patient with nephrotoxicity, which were relieved after symptomatic treatment.Summary/Conclusion:Our study demonstrates an improved efficacy with dual‐target CAR‐T therapy targeting BCMA and CD38 for RRMM with a high ORR, especially a higher rate and a longer duration of sCR. CRS and hematological toxicities are observed but manageable. Other toxicity is rare. These initial data provide strong evidence to support the further development of the dual‐target CAR‐T therapy for RRMM.ChiCTR1800018143 image

PB2175 LONG TERM FOLLOW‐UP OF MAINTENANCE THERAPY WITH INTEREFRON ALPHA AFTER AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANT IN MULTIPLE MYELOMA PATIENTS–SINGLE CENTER EXPERIENCE

Background:Maintenance therapy after autologous hematopoietic stem cell transplantation (AHSCT) in multiple myeloma (MM) patients was a matter of debate until recently, when lenalidomide in this setting proved to increase overall survival (OS). Before lenalidomide interferon alpha (IFN) was standard maintenance therapy.Aims:The aim of this analysis was to determine the impact of maintenance therapy after AHSCT on progression free survival (PFS) and OS in MM patients treated at our institution between 1993 and 2014.MethodsWe performed a retrospective analysis of outcomes of MM patients autografted at our institution between 1993 and 2014. We identified 274 pts. who had PFS at least 6 months posttransplant; median age was 57, range 28‐71, 48% were male. 124 of them received tandem and 150 single AHSCT. Median follow‐up was 62 mo. Posttransplant 200 patients received IFN, 44 thalidomide and 30 no maintenance according to physicians’ choice.Results:Patients receiving IFN had longer 5‐year PFS compared to patients receiving thalidomide or no maintenance (52% vs. 34% vs. 31%, respectively, p &lt; 0.001). OS was best in the IFN group, intermediate in the thalidomide and worst in the no maintenance group (67% vs. 59% vs. 32%, respectively, p &lt; 0.001). The difference was limited to patients receiving tandem transplants. In this group 5‐year PFS was 61% vs. 35% vs 0% (p &lt; 0.001) and OS 85% vs. 67% vs. 65% (p = 0.003) in the IFN, thalidomide and no maintenance group respectively. In patients that received a single transplant 5‐year PFS was 43% vs. 33% vs 36% (p = 0.157) and 5‐year OS 70% vs. 75% vs. 54% (p = 0.06) in the IFN, thalidomide and no maintenance group respectively.Summary/Conclusion:Our results indicate that maintenance therapy has beneficial effects on OS and PFS in MM patients treated with tandem, but not single AHSCT. IFN is superior in this setting to thalidomide and could be considered as a treatment option when lenalidomide is not available.

Efficacy of Revaccination after Autologous Hematopoietic Stem Cell Transplantation in Lymphoma Patients with or without Rituximab Exposure

Guidelines recommend reimmunization starting 12 months after autologous hematopoietic stem cell transplant (AHCT). We aimed to evaluate the impact of rituximab, which may impair humoral immunity, on responses to revaccination after AHCT in pts with B-cell Non-Hodgkin Lymphoma (B-NHL), T-cell NHL (T-NHL), and Hodgkin Lymphoma (HL), with the latter two groups not routinely receiving rituximab. Lymphoma pts who underwent AHCT between 2012 - 2016 were identified from the institutional database and included if they had completed the primary series and had pre- and post-vaccination titers to evaluate for response. Pts were classified as responders, non-responders, immune by pre-vaccination titer, and not evaluable due to missing data. Descriptive statistics were used to summarize results, and the Fishers exact test was used for comparisons. Of the 161 pts meeting inclusion criteria, 104 (65%) received rituximab pre-AHCT with 20% of these receiving additional rituximab post-HCT. Of the 57 pts who did not receive pre-AHCT rituximab, 2% received post-AHCT rituximab. The median age of the whole group was 53 years (range 19-73), with patients not receiving rituximab being younger (median age 43 years (range 19-71) vs 58 years (21-73), p Most patients received the completed series for each vaccine (84% Haemophilus influenzae, 99% pneumococcus, 96% polio, 66% tetanus, 76% diphtheria, 91% pertussis, 78% Hepatitis A, and 84% Hepatitis B), but vaccine responses varied by vaccine type (Figure 1). No patients retained immunity to pneumococcus or diphtheria on the pre-vaccine titers. Univariate analyses were performed for pertussis, diphtheria, Hepatitis A, Hepatitis B and Pneumococcal vaccines evaluating the association with age, gender, disease type, and rituximab exposure. More females than males responded to B. pertussis (90% vs 78%, p=0.045). Hepatitis A and Hepatitis B response was associated with a younger age (50.7 years vs 59.6 years, p=0.037 and 54.2 years vs 62.4 years, p=0.007, respectively), and disease type was associated with pneumococcal response (62% HL vs 39% NHL, p=0.022). Patients who did not receive rituximab were more likely to respond to pneumococcus and Hepatitis B (63% vs 35%, p=0.001, and 82% vs 56%, p=0.026, respectively, Figure 2). Antibody response to reimmunization with inactivated vaccines in lymphoma patients after AHCT is similar to previously reported populations, but prior rituximab exposure appears to impact response.

The use of granulocyte colony stimulating factor after autologous hematopoietic stem cell transplantation.

Granulocyte colony stimulating factor (G-CSF) is commonly used after AHSCT to accelerate stem cell engraftment to minimize the morbidity and mortality associated with prolonged neutropenia. However, there is no consensus on the optimal timing of G-CSF after HSCT. A total of 117 patients with lymphoid malignancies who underwent AHSCT were included. All patients received G-CSF (filgrastim 5 μg/kg s.c.) daily after AHSCT (43 patients on day 6-8 and 74 patients on day 3 or 4). All patients received standard conditioning regimen for the underlying disease, and standard supportive treatment, including treatment of febrile neutropenia. The incidence of severe neutropenia was 81 % vs 17 %, and very severe neutropenia 61 % vs 4 % in the delayed and early G-CSF groups, respectively (p < 0.0001). The rate of fungal infection was higher in the group of patients who received delayed G-CSF (p < 0.005). An early administration of G-CSF after AHSCT (on day 3 or 4) accelerates neutophil engraftment; decreases the incidence of severe neutropenia and the risk of infectious complications (especially fungal infections) (Tab. 1, Fig. 3, Ref. 22).