Autologous Stem Cell Transplantation Setting Research Articles

Determinants of Interpatient Variability in Treosulfan Pharmacokinetics in AML Patients Undergoing Autologous Stem Cell Transplantation.

Limited data on treosulfan pharmacokinetics in adults, particularly regarding autologous stem cell transplantation (ASCT) in acute myeloid leukemia (AML), is available to date. Furthermore, correlations between treosulfan exposure, toxicity, and clinical outcome remain understudied. In this single-center retrospective study, we analyzed data from 55 AML patients who underwent HDCT with treosulfan (14 g/m2) and melphalan (140 mg/m2 or 200 mg/m2) (TreoMel) between August 2019 and November 2023 at the University Hospital of Bern. We assessed treosulfan pharmacokinetics and correlations with several physiological parameters with potential impact on its interpatient variability. We further analyzed how treosulfan exposure correlates with toxicity and clinical outcomes. Women above 55 years showed higher area under the curve (AUC) levels (median: 946 mg*h/L, range: 776-1370 mg*h/L), as compared to women under 55 (median: 758 mg*h/L, range: 459-1214 mg*h/L, p = 0.0487). Additionally, women above 55 showed higher peak levels (median: 387 mg/L, range: 308-468 mg/L), as compared to men of the same age range (median: 326 mg/L, range: 264-395 mg/L, p = 0.0159). Treosulfan levels varied significantly with body temperature, liver enzymes, hemoglobin/hematocrit., and treosulfan exposure correlated with diarrhea severity in women over 55 (p = 0.0076). Our study revealed age- and gender-related variability in treosulfan pharmacokinetics, with higher plasma levels observed in female patients above 55. Moreover, our data suggest that treosulfan plasma levels may vary with several physiological parameters and that higher treosulfan exposure may impact toxicity. Our study underlines the need for further research on treosulfan pharmacokinetics, especially in older patients undergoing HDCT in the ASCT setting.

Gut Microbiota Diversity and Composition Is Associated with High-Risk Myeloma

Background: High-dose melphalan conditioning followed by autologous stem cell transplantation (ASCT) is standard therapy for newly diagnosed multiple myeloma (MM) patients with standard-risk (SR) or high-HR disease. Despite significant improvements in the depth of response by induction therapy prior to ASCT and consolidation and maintenance therapy post-ASCT, most MM patients with HR cytogenetics relapse quickly post-ASCT with a median PFS ranging between 1 and 2 years. It remains unclear as to why patients identified as relapse earlier than those with SR disease (SR). We ask whether the variability in outcome is due to differences in the diversity and composition of the gut microbiome given its role as a predictor and modulator of tumorigenesis, anti-tumor immunity and response to therapy. Two preclinical studies have shown progression of MM is accelerated by a T H17-associated gut commensal (Calcinotto et al. Nat Commun, 2018) and nitrogen-cycling bacteria (Zhu et al. Microbiome, 2020). In MM patients, lower peri-engraftment diversity predicted inferior outcomes after ASCT (Khan et al. Blood, 2021) and sustained minimal residual disease-negativity was associated with butyrate-producing bacteria and plant-based diets (Shah et al. Clin Cancer Res, 2022). In this study, we analyzed the association between gut microbiota and HR cytogenetic features in MM patients in the ASCT setting. We also determined the cause-and-effect relationship between gut microbiota and disease progression in the 5TGM1 mouse model. Methods and Results: We prospectively collected stool samples from 55 MM patients at time of melphalan conditioning (pre-ASCT), engraftment (72hrs of absolute neutrophil count ≥ 500/mcL), and 60-120 days post-ASCT. The median age of patients (35 males, 20 females) was 63.1 (range 45.6-77.2) years. After a median follow-up of 54 months (range 1-81), the median PFS of patients was 37 months (range 1- 76). We profiled the gut microbiome of SR (n=29) and HR (n=26) MM patients using 16S rRNA sequencing of the V4-V5 region. Amplicon sequence variants (ASV) were annotated against the NCBI 16S database using BLAST. We chose to identify gut microbiota features associated with HR cytogenetics in samples during peri-engraftment when microbial dysbiosis and impaired immune function is most pronounced. The alpha diversity was higher in HR patients using Inverse Diversity index (p<0.020). However, we did not observe significant differences in beta-diversity between groups. Random forest prediction classifier method and Shapley Additive exPlanations (SHAP), a post-hoc explainability algorithm identified Schaalia, Streptococcus, Bifidobacterium with the highest variable of importance (Fig. 1A) These findings were further validated by linear discriminant analysis of effect size (LEfSe). To establish causality, we generated two isogenic C57BL/KaLwRij strains that harbor differences in the complexity and richness of naturally occurring gut microbiota, using complex microbiota targeted rederivation. We observed significant baseline differences in richness (p<0.001), β-diversity (Bray Curtis, p=0.0001), hierarchical clustering and relative abundance among GM1 (low richness), GM4 (intermediate richness) and our original (Orig) GM strain (high richness) bred in our vivarium. The median overall survival for MM-bearing GM1, GM4 Orig GM mice were 31, 35 and 39 days post-5TGM1 transplantation (Fig. 1B). Conclusions: These studies suggest that distinct gut microbiota signatures are associated with HR and SR disease. Furthermore, our preclinical findings suggest a causal relationship between gut microbiota and severity of disease further highlighting the influence of the gut microbiome on progression of disease. Taken together, these findings provide the rationale for microbiota-centered interventions to improve immune-mediated control of MM and overturn resistance to therapy.

The Impact of Epstein-Barr Virus Infection on Second Cancer Development in Newly Diagnosed Myeloma Patients Treated with Lenalidomide in the UK NCRI Myeloma XI Trial

Background Several factors have been linked to second primary malignancy (SPM) development in myeloma patients, including advanced age, immunocompromise and therapy, such as melphalan and lenalidomide (len). The impact of infection, including EBV is yet to be elucidated. Here we address this in the context of the UK NCRI Myeloma XI Trial for newly diagnosed transplant eligible (TE) and transplant non-eligible (TNE) patients. Methods Myeloma XI was a phase III, randomised, multi-centre, parallel group design, open-label trial comparing cyclophosphamide, thalidomide, len, carfilzomib and bortezomib induction combinations and len maintenance treatment in TE and TNE patients. TE patients received high dose melphalan supported by autologous stem cell transplantation (ASCT). Patients in both pathways were randomised to maintenance with len or observation. In total, 4358 patients entered. Planned SPM analysis was conducted in May 2019, with 318 patients developing an SPM prior to that point. Median follow-up from trial entry was 60 months (IQ range 47-76). A nested cohort analysis was performed to determine EBV infection and immunity status in 170 SPM patients for which serum samples were available. Forty-two trial patients who did not develop an SPM were used as a control group. EBV assessment time-points included pre-induction, post induction, 4 months post ASCT (TE only) and 1 year post induction. Peripheral blood serum samples were tested for EBV EBNA IgG Antibody/index (LIAISON®), EBV VCA IgM Antibody/Index (LIAISON®) and EBV positivity was determined using the artus® EBV RG PCR Kit from Qiagen. Active or recent EBV infection was evidenced by a positive EBV IgM antibody and/or EBV PCR. Results Of the 170 patients, 208 SPM were noted with 147 patients developing 1 SPM and 23 patients developing ≥2. One hundred and five patients developed an SPM following maintenance randomisation, with 76 receiving len and 29 being observed. The remaining 65 patients developed an SPM prior to maintenance. Eighty-four SPMs were diagnosed in 68 TE patients and 124 SPMs in 102 TNE patients. Of the 170 SPM patients, 8 had evidence of recent or active infection at the time of testing, evidenced by either IgM EBV antibodies (n=5), positive EBV PCR (n=2) or both (n=1). The median EBV DNA copies/ml was 353 (range 337-428). The median IgM antibody titre was 71.5U/ml (26 - >160). No patients in the control group had evidence of recent EBV infection (p=0.36). Of the 8 patients with evidence of EBV infection, 6 developed >1 SPM, Table 1. Five had been treated in the TE pathway, with all developing post maintenance randomisation, and 4 of the 5 receiving len maintenance. None of the 3 TNE patients received len maintenance, with 2 developing an SPM prior to maintenance randomisation. The median time from EBV testing to SPM diagnosis was 17·9 months (0.5-51.7). Two of the EBV positive patients developed a haematological SPM: myelodysplastic syndrome and Hodgkin lymphoma. Four patients developed a solid malignancy: lung, breast, ovary, and colon. The remaining cases were non-melanoma skin cancers, Table 1. Immune status (EBV IgG) was also determined. In TE patients, the median EBV IgG titre was 65.3U/ml at diagnosis (<3 - 600, n=48), falling to 28.1U/ml following induction (<3 - 326, n=41) and recovering to 44.2U/ml one year post ASCT (<3 - 600, n=22). In TNE patients, the median IgG titre at diagnosis was 39.1U/ml (<3 to 517, n=72), falling to 31.2U/ml 4 months post induction (<3 - 287, n=42) and recovering to 51.3U/ml after 1 year (<3 - 554, n=41). In the SPM patients the IgG EBV titres were noted to be <20U/ml in 5 of the 8 patients. Three of the eight patients had no detectable EBV IgG level (<3U/ml) Conclusions These data suggest that EBV infection is unlikely to be a risk factor for SPM development in myeloma patients. This is supported by the finding that EBV IgG titres were consistent with immunity in most patients (>20U/ml) and even in the patients with possible EBV infection, EBV DNA was only identified in 3 patients, and at a low level. In addition, the SPM developed are not classically associated with EBV infection or reactivation. It is noted that EBV infection status was not always determined at the time of SPM development. Despite this, the data does show that EBV immunity recovers following therapy, even in the post ASCT setting. EBV monitoring is therefore not supported by this work, although in patients who develop ≥2 SPM, further clarification is required.

PARP1 and POLD2 as prognostic biomarkers for multiple myeloma in autologous stem cell transplant.

Multiple Myeloma (MM) is an incurable plasma cell malignancy often treated by autologous stem cell transplant (ASCT). Clinical response to ASCT has been associated with DNA repair efficiency. Here we interrogated the role of the base excision DNA repair (BER) pathway in MM response to ASCT. Across 450 clinical samples and six disease stages, expression levels of genes in the BER pathway were found to be highly upregulated during the development of MM. In a separate cohort of 559 patients with MM treated with ASCT, expression of BER pathway members MPG and PARP3 was positively associated with overall survival (OS) while expression of PARP1, POLD1, and POLD2 was negatively associated with OS. In a validation cohort of 356 patients with MM treated with ASCT, PARP1 and POLD2 findings were replicated. In patients with MM who never received ASCT (n=319), PARP1 and POLD2 were not associated with OS, suggesting that the prognostic effect of these genes may be treatment-dependent. In preclinical models of MM, synergy was observed in anti-tumor activity when poly (ADPribose) polymerase (PARP) inhibitors (olaparib, talazoparib) were used in combination with melphalan. The negative prognosis associated with PARP1 and POLD2 expression along with the apparent melphalan-sensitizing effect of PARP inhibition may suggest this pathway as a potential biomarker in patients with MM in the setting of ASCT. Further understanding of the role of the BER pathway in MM is vital to improve therapeutic strategies related to ASCT.

Eight-color multiparameter flow cytometry (EuroFlow-NGF) is as sensitive as next-generation sequencing in detecting minimal/measurable residual disease in autografts of patients with multiple myeloma.

The prognostic value of minimal/measurable residual disease (MRD) detection in autografts of patients with multiple myeloma (MM) in an autologous stem-cell transplantation setting has been reported. Next-generation flow (NGF) cytometry has lower sensitivity (2×10-6) to detect MRD than next-generation sequencing (NGS) (<10-6). We compared the clinical value of high-sensitivity NGF (cutoff: <10-6) and NGS (cutoff: 10-6) for the detection of MRD in the cryopreserved autografts of 49 patients with newly diagnosed MM. The sensitivity test using frozen/thawed autografts revealed a strong correlation among MRD levels of 5×10-7 and 1×10-4 (r=0.9997, p<0.0001) when an adequate number of cells were analyzed. Autograft MRD levels determined using NGF and NGS were highly correlated (r=0.811, p<0.0001). MRD-negative patients identified with NGF (cutoff: <10-6) showed significantly longer progression-free survival (PFS) than MRD-positive patients (p=0.026). The PFS of MRD-negative patients determined by NGS (cutoff: 10-6) was similar to that determined by NGF. These results show that the high-sensitivity NGF method can assess MRD in frozen/thawed autografts, and its prognostic value is comparable to that of NGS.

The Evolving Role of Radiation Therapy in DLBCL: From Early-Stage to Refractory Disease.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Historically, radiation therapy (RT) served as the primary treatment modality for patients with localized disease. While still an option for select patients who are not candidates for systemic therapy, RT is currently used most frequently as a consolidation treatment after chemoimmunotherapy. Consolidation RT is most commonly recommended after an abbreviated course of systemic therapy in patients who have bulky disease or multiple risk factors, or in the setting of a partial response. Consolidation RT is also appropriate in some patients with advanced DLBCL, including those presenting with bulky disease (≥7.5 cm). While many patients achieve sustained remissions after first-line therapy, up to 50% of patients with DLBCL will eventually relapse. The most common salvage options include second-line chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) and chimeric antigen receptor (CAR) T-cell therapy. RT can be used in both settings to optimize clinical outcomes. This includes consolidation RT in patients with localized presentations or bulky disease in the setting of ASCT and bridging RT in select patients undergoing CAR T-cell therapy. RT is also a valuable modality in any patient with symptomatic disease requiring palliation.

Multiple-day administration of fosaprepitant combined with tropisetron and olanzapine improves the prevention of nausea and vomiting in patients receiving chemotherapy prior to autologous hematopoietic stem cell transplant: a retrospective study

Chemotherapy-induced nausea and vomiting (CINV) is common in patients with lymphoma and multiple myeloma (MM) receiving high-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT). Despite a standard triple antiemetic regimen of a neurokinin-1 (NK1) receptor antagonist (RA), a 5-hydroxytryptamine-3 (5-HT3) RA, and dexamethasone is recommended, how to control the protracted CINV in ASCT setting remains an intractable problem. Here, we retrospectively analyze CINV data of 100 patients who received either SEAM (semustine, etoposide, cytarabine, melphalan) or MEL140-200 (high-dose melphalan) before ASCT, evaluate the efficacy and safety of multiple-day administration of fosaprepitant combined with tropisetron and olanzapine (FTO), and compare the results to those of patients who received a standard regimen of aprepitant, tropisetron, and dexamethasone (ATD). The overall rate of complete response (CR), defined as no emesis and no rescue therapy, is 70% in the FTO group compared to 36% in the ATD group. Although CR rates are comparable in the acute phase between the two groups, significantly more patients treated by FTO achieve CR in the delayed phase than those treated by ATD (74% vs. 38%, p < 0.001). Moreover, FTO treatment significantly reduced the percentage of patients who are unable to eat, as well as the requirement for rescue medications. Both regimens are well tolerated and most adverse events (AEs) were generally mild and transient. In conclusion, the antiemetic strategy containing multiple-day administration of fosaprepitant is safe and effective for preventing CINV in lymphoma and MM patients, particularly in the delayed phase.

Prospective Comparison Study of Prognostic Value of MRD Detected By 8-Color MFC (EuroFlow-NGF) and NGS in Patients with Multiple Myeloma in ASCT Setting

Background: Novel agents capable of inducing deeper responses dramatically improve the prognosis of patients with multiple myeloma (MM). Innovative technologies such as multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) are utilized to assess minimal residual disease (MRD) for further stratification of patients who achieve a complete response (CR). EuroFlow-next-generation flow (EuroFlow-NGF) is one of the gold standard MFC methods. Recently, both NGF and NGS have been used in many clinical trials to assess MRD levels associated with progression-free survival (PFS) and overall survival (OS). The present study prospectively assessed MRD levels by both NGF and NGS to elucidate the prognostic impact of both methods and clarify their characteristics in MM patients in an autologous stem cell transplantation (ASCT) setting.Methods: We prospectively assessed the response in Japanese patients with newly diagnosed MM who underwent ASCT and lenalidomide-based maintenance therapy at multiple Japanese medical centers between September 2016 and July 2021. The diagnosis of MM and patients' responses to therapy were assessed using the IMWG criteria. Only patients with CR or stringent CR on days 100-365 post-ASCT were included, and bone marrow (BM) samples were obtained to assess MRD. Four milliliters of BM was divided equally. Cells derived from 2 mL BM were analyzed by the NGF method (Flores-Montero et al., Leukemia 2017) at Kanazawa University, and DNA extracted from the remaining 2 mL BM cells was processed by Adaptive Biotechnologies' standardized NGS-MRD assay (Seattle, WA) (Ching et al., BMC Cancer 2020) to assess MRD levels. MRD levels in BM were also monitored at 1-year (± 20 days) and 2-year (± 20 days) post-ASCT. The prognostic value of MRD levels in BM was assessed, and their correlation between NGF and NGS was compared at a cut-off value of 1×10 -5. Sustained MRD negativity was defined as the maintenance of MRD negativity in the BM for more than 6 months. BM cells were analyzed for high-risk cytogenetics (del(17p), t(4;14), and t(14;16)) by FISH.Results: A total of 60 patients (male = 29, female = 31) underwent bortezomib-based induction therapy, ASCT conditioned with high-dose melphalan, and lenalidomide-based maintenance. The median age was 62 years at the ASCT (range 36-71; ISS 1 [n = 13], 2 [n = 24], and 3 [n = 23]). Thirty-three percent of patients showed high-risk chromosomal abnormalities (del17p (n=11), t(4;14) (n=10), t(14;16) (n=2)), 3 patients had double hit diseases, and five patients had extramedullary diseases. With a median follow-up of 3 years, the 3-year progression-free survival (PFS) and 3-year overall survival (OS) rates were 69.2% and 94.2%, respectively. In total, 148 samples were analyzed using NGF and 138 were analyzed using NGS. The rates of MRD negativity at least once using NGF and NGS were 80% and 61%, respectively. The patients who achieved at least one MRD negativity exhibited significantly better 3-year PFS (82.9% by NGF; 84.8% by NGS) than those who did not (P < 0.0001, 0% by NGF; P = 0.005, 49.1% by NGS). Patients who sustained MRD negativity for more than 6 months also showed significantly better 3-year PFS (96.7% by NGF; 92.3% by NGS) compared with those without sustained MRD negativity (Figure; P < 0.0001, 37.1% by NGF; P < 0.01, 50.9% by NGS). The MRD levels between the NGF and NGS methods were significantly correlated with each other (r = 0.9295, P < 0.0001). Among the 17 patients who developed PD after ASCT, seven cases showed discrepancies in the MRD results and two cases in which one case was MRD-positive and the other was MRD-negative by both methods progressed with extramedullary diseases. Five of the seven cases were MRD-positive by NGS and MRD-negative by NGF.Conclusions: In this prospective comparison study of MRD assessment in BM cells using EuroFlow-NGF and NGS approaches, MRD levels highly correlated with each other, and MRD negativity and sustained MRD negativity were significantly associated with prolonged PFS. Multiple MRD assessments by NGF or NGS are essential for predicting durable remission and prolonged clinical outcomes. [Display omitted] DisclosuresTakamatsu: Bristol-Myers Squibb: Honoraria, Research Funding; Adaptive Biotechnologies, Eisai: Honoraria; SRL: Consultancy; Janssen: Consultancy, Honoraria, Research Funding. Yoshihara: Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Matsumoto: Sanofi: Honoraria; Janssen: Honoraria; Ono: Honoraria; Bristol-Myers Squibb: Honoraria. Yamashita: Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; celgene: Honoraria; Takeda: Honoraria. Fuchida: Takeda Pharmaceutical Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb Co., Ltd.: Honoraria; Celgene Co., Ltd.: Honoraria. Hiragori: BML: Current Employment. Suzuki: Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; ONO: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Abie: Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Nakao: Symbio: Consultancy; Kyowa Kirin: Honoraria; Novartis Pharma: Honoraria; Alexion Pharma: Research Funding. Durie: Amgen: Other: fees from non-CME/CE services ; Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy.

Comparison of MRD Detection in Autografts in Multiple Myeloma between Novel High-Sensitivity Euroflow-NGF and NGS

Background: Autologous stem cell transplantation (ASCT) remains the gold-standard treatment for multiple myeloma (MM). To date, we have reported the prognostic value of minimal residual disease (MRD) detection in autografts in an ASCT setting using EuroFlow next-generation flow (NGF) and next-generation sequencing (NGS) (Takamatsu et al., ASH 2018, 2020). The main problem with NGF is its lower sensitivity (2 × 10 -6) compared with that of NGS (<1 × 10 -6).Methods: We reanalyzed 11 autografts in which the MRD were negative on NGF but positive (n = 7) or negative (n = 4) on NGS (Takamatsu et al., ASH 2018, abstract #258) using 5-20 mL of autografts with NGF to increase the sensitivity of MRD detection. Additionally, we enrolled 9 patients with newly diagnosed MM, from whom 5-20 mL of apheresed autografts were cryopreserved. We included 20 patients with newly diagnosed MM. The median age at ASCT was 60 (range, 45-67) years, and the patients included 12 men and 8 women at International Staging System I (n = 3), II (n = 13), and III (n = 4), 6 of whom harbored high-risk chromosomal abnormalities, including t(4;14) (n = 3), t(14;16) (n = 1), del17p (n = 1), and t(4;14) and del 17p (n = 1). All patients received bortezomib-based chemotherapy for induction followed by melphalan at a dose of 200 mg/m 2 for conditioning before ASCT. Three patients received consolidation therapy with carfilzomib-lenalidomide-dexamethasone (n = 2) or bortezomib-lenalidomide-dexamethasone (n = 1), and 18 patients received lenalidomide (n = 16), thalidomide (n = 1), or thalidomide and lenalidomide (n = 1) maintenance. Frozen autografts (n = 20) were thawed for MRD assessment using NGF and NGS. The NGF method was based on a previous report (Flores-Montero et al., Leukemia 2017). NGS-based MRD assessment was performed using Adaptive's standardized NGS-MRD assay (Seattle, WA) (Ching et al., BMC Cancer 2020). The NGF method was modified to increase the sensitivity of MRD detection by capturing up to 6 × 10 7 cells.Results: Frozen autografts were used in this study; therefore, we performed a sensitivity test using a dilution of frozen/thawed primary MM cells in an autograft with NGF. The sensitivity test revealed a strong correlation between 5 × 10 -7 and 1 × 10 -4 MRD levels (Figure 1A; r = 0.999, P <0.0001). Next, MRD in autografts (n = 20) was evaluated using NGF and NGS. The sensitivity of NGS was 1.7 × 10 -7-8.7 × 10 -5 (median, 7 × 10 -7) using 2-4 mL of autografts; the sensitivity of NGF was 1.6 × 10 -7-3.7 × 10 -6 (median, 3 × 10 -7) using up to 20 mL of autografts based on the detection of ≥10 abnormal cells. MRD levels in autografts using NGF and NGS were correlated (Figure 1B; r = 0.979, P <0.0001). There was no discrepancy in the MRD negativity between both methods except for two cases (MRD-negative on NGF/positive on NGS [n = 2]). All high-risk chromosomal abnormality cases (n = 6) revealed MRD levels <10 -5 butonly three patients achieved MRD levels <10 -6. The best responses included 16 cases of a stringent complete response and 4 of a very good partial response. Three patients with positive MRD in the autograft exhibited progression. With a median follow-up period of 41 months after ASCT, the 3-year progression-free survival (PFS) was 90%, and the 3-year overall survival was 95%. There was no significant difference in the PFS based on the MRD levels between NGF and NGS. MRD negative cases tended to show better PFS than MRD positive ones (Figure 1C; P = 0.077 by NGF; P = 0.111 by NGS).Conclusion: The modified EuroFlow-NGF method may be used to assess MRD in frozen/thawed autografts, and its sensitivity may increase up to 5 × 10 -7, which is comparable to that of NGS. [Display omitted] DisclosuresYamashita: Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; celgene: Honoraria; Takeda: Honoraria. Nakao: Novartis Pharma: Honoraria; Symbio: Consultancy; Kyowa Kirin: Honoraria; Alexion Pharma: Research Funding. Takamatsu: Adaptive Biotechnologies, Eisai: Honoraria; SRL: Consultancy; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.

P-043: Comparison of MRD detection of autografts in multiple myeloma between novel high-sensitivity EuroFlow-NGF and NGS

<h3>Background</h3> Autologous stem cell transplantation (ASCT) is still a gold standard treatment in multiple myeloma (MM). So far, we have reported the prognostic value of minimal residual disease (MRD) detection in autografts at ASCT setting using EuroFlow next-generation flow (NGF) and next-generation sequencing (NGS) (Takamatsu et al, ASH 2018). The main problem of EuroFlow-NGF is its lower sensitivity (2×10^-6) compared with that of NGS (<1×10^-6). <h3>Methods</h3> The study enrolled 9 newly-diagnosed MM patients whose frozen autografts' cells were preserved. The median age at ASCT was 52 (range 47-61) years and included 4 males and 5 females at ISS I (n=2), II (n=6) and III (n=1). Of there, 4 patients harbored high-risk chromosomal abnormalities including t(4;14) (n=1), t(14;16) (n=1), del17p (n=1), and t(4;14) and del 17p (n=1). All patients received bortezomib-based chemotherapy for induction together with melphalan at 200 mg/m² for conditioning before ASCT. Two patients received consolidation therapy with carfilzomib-lenalidomide-dexamethasone (KRD) and all patients received lenalidomide maintenance until progressive disease. Frozen autografts (n=9) and primary myeloma cells (n=1) were thawed for MRD assessment by EuroFlow-NGF and NGS. The EuroFlow-NGF method was based on the previous report (Flores-Montero et al., Leukemia 2017). NGS-based MRD assessment was performed using Adaptive's standardized NGS-MRD Assay (Seattle, WA) (Ching et al., BMC Cancer 2020). The EuroFlow-NGF method was modified to increase the sensitivity of MRD by capturing cells up to 5×10⁷. <h3>Results</h3> Because frozen autografts were used in this study, we performed the sensitivity test using the dilution of frozen/thawed primary MM cells in an autograft by EuroFlow-NGF. The sensitivity test revealed a strong correlation between 1×10^-7 and 1×10^-4 of MRD level (r=0.9996, p<0.0001). Next, MRD in autografts (n=9) was evaluated using EuroFlow-NGF and NGS. The sensitivity of NGS was 6×10^-7–8.7×10^-5 (median, 8×10^-7) using 2–4 mL of autografts; the sensitivity of EuroFlow-NGF was 4×10^- ⁷–8×10^-7 (median, 5×10^-7) using up to 20 mL of autografts. MRD levels in autografts using EuroFlow-NGF and NGS correlated with one another (r = 0.9964, P < 0.0001). There was no discrepancy of MRD levels between both methods: negative (n=2), 10^-6-10^-5 (n=4), 10^-5-10^-4 (n=2), 10-4 < (n=1). All high-risk chromosomal abnormality cases (n=4) achieved MRD level <10^-5. The response on day 100-300 post-ASCT included 6 sCR, 2 CR and 1 VGPR before consolidation/maintenance therapy and all patients achieved sCR at two years post-ASCT and maintained it at three years post-ASCT during lenalidomide maintenance. No progression was observed. <h3>Conclusions</h3> This modified EuroFlow-NGF method can assess MRD of frozen/thawed autografts and its sensitivity can be increased up to 4×10^-7 that is comparable to NGS.

Effectiveness and Cost-Effectiveness of Prophylactic Voriconazole and Fluconazole Regarding Prevention of Post-hematopoietic Stem Cell Transplantation Invasive Fungal Infection and Its Related Death: A Single Center Experience.

Analyzing effectiveness and cost-effectiveness of voriconazole versus fluconazole prophylaxis in hematopoietic stem cell transplantation (HSCT). The research included 70 patients; 34 undergoing allogeneic HSCT and 36 undergoing autologous stem cell transplantation (ASCT), alternated to receive either voriconazole or fluconazole prophylaxis for 180days on a 1:1 basis. Patients were monitored for occurrence of invasive fungal infections (IFI), IFI-related death (IRD) and total death events. Cost-effectiveness of both agents in both groups was also assessed. Antifungal prophylactic drug had no impact on incidence of IFI and IRD in both allogeneic HSCT and ASCT (P = .452 and P = 1.000; P = .457 and P = .146 respectively). An insignificant difference occurred among patients receiving voriconazole or fluconazole regarding overall survival (OS) and fungal infection-free survival (FFS) in both groups (P = .705 and P = .879; P = .713 and P = .681 respectively). Regarding cost-effectiveness, voriconazole dominated fluconazole regarding prevention of IFI and IRD but was less costly/less effective regarding prevention of total death events and gaining life years in the allogeneic HSCT setting. In the ASCT setting, voriconazole was not cost-effective regarding avoidance of IFI and IRD and was dominated by fluconazole regarding avoidance of total death events and gaining life years. Voriconazole does not differ from fluconazole regarding its efficacy in prevention of IFI and IRD and does not improve OS and FFS in both allogeneic HSCT and ASCT settings. Voriconazole is cost-effective regarding protection from IFI and IRD in allogeneic HSCT but not cost-effective in ASCT.

Autologous Stem Cell Transplant for Waldenström Macroglobulinemia in the Era of Novel Therapies: Still an Underutilized Tool?

Background Waldenstrom macroglobulinemia (WM) is a rare and incurable lymphoproliferative disease. The advent of novel therapies such as proteasome inhibitors and monoclonal antibodies has expanded the therapeutic armamentarium for treatment of WM. Due to the rare nature of the disease, most reported studies on the use of autologous stem cell transplant (ASCT) in WM are small and retrospective in nature. Since the advent of novel agents, few studies have reported whether these agents influence the disease course in the ASCT setting. Herein we present outcomes of patients with WM who underwent ASCT at three Mayo Clinic sites. Methods Records of all patients with WM who underwent ASCT between 8/2005 and 11/2017 were reviewed. Time-to-event analyses were performed from ASCT using the Kaplan-Meier method. Response criteria from the 6th International WM Workshop were used. Results Patient characteristics are described in Table 1. Two patients had large cell transformation; one prior to ASCT and one post-ASCT. The overall response rate to transplant was 100% (3 complete responses [CR], 8 very good partial responses [VGPR] and 6 partial responses [PR]). After a median follow-up of 58 months, the median progression free survival (PFS) after ASCT was 66 months and the median overall survival (OS) was not reached (NR). The relapse rate was 65% (11 out of 17 patients relapsed). The treatment related mortality was 0% and relapse mortality was 12%. The 2 deaths in the cohort were the patients who had large cell transformation and they died at 18 and 25 m post-ASCT, respectively. The treatment immediately prior to transplant, irrespective of the use of rituximab (R), did not impact the PFS (median PFS 47 m with prior R v 66 m without prior R, p=0.82, Fig. 1A). Similarly, prior exposure to a bortezomib (V)-based regimen did not impact the PFS (median NR v. 47 m, p=0.19 respectively, Fig. 1B). Achieving ≥VGPR after ASCT did not result in superior PFS compared to patients who achieved a PR (47 m vs. NR, p=0.59, respectively, Fig. 1C). Patients who had ASCT after >2 lines of therapy had an inferior PFS compared to patients who had ASCT ≤2 lines of therapy (41 m vs. 112 m, p=0.03, respectively, Fig 1D). Patients with large cell transformation at any point, had inferior PFS after transplant compared to those who did not (10m vs. 66m, p Conclusions ASCT for patients with WM is a safe and efficacious treatment modality with an ORR of 100% and affords eligible patients a median treatment-free interval of 4 years. The use of V or R prior to ASCT does not impact the depth of response or PFS after ASCT. To obtain the maximum PFS benefit, ASCT should be performed earlier in the disease course, prior to receiving more than 2 lines of therapy.

Immune Monitoring of CD34+ Placental Cell Derived Natural Killer Cell Therapy (PNK-007) in Phase I Study of Multiple Myeloma

Background: Natural Killer (NK) cells are innate immune lymphocytes with cytotoxic function and are critical for immune surveillance. Unlike T cells which rely on antigen-specific responses, NK cells recognize transformed cells through a variety of NK cell-specific receptor-ligand interactions. Clinical studies have highlighted the therapeutic potential of NK cell-based therapies and Celularity has developed a GMP procedure for generating PNK-007: an off-the-shelf and allogeneic NK cell product culture-expanded and differentiated from human placental CD34+ stem cells. PNK-007 was evaluated as a single-dose allogeneic cell therapy in a phase I dose-escalation study for multiple myeloma (MM) patients receiving autologous stem cell transplant (ASCT) (NCT02955550). 12 of 15 patients received subcutaneous IL-2 every 48 hours for 10 days following PNK-007 cell infusion while 3 patients in a separate cohort did not receive IL-2. Here, we report translational studies evaluating post-treatment immune reconstitution, minimal residual disease (MRD) detection at 10-5 threshold, and serum profiling of cytokines and chemokines. Methods: Patient bone marrow aspirate was collected for EuroFlow MRD assessment and immune phenotyping by flow cytometry at baseline, 90-100 days, 6 months and 1 year post-ASCT. Peripheral blood was collected at baseline, then weekly for six weeks following PNK-007 infusion, at 6 months and at 1 year post-ASCT. PNK-007 persistence, leukocyte populations, and HLA antibody panels were determined by flow cytometry. Serum was analyzed by Luminex for panel cytokines, chemokines and soluble cytokine receptors. All patients and PNK-007 drug product were typed for HLA and killer-cell immunoglobulin-like (KIR) genotype. Results: PNK-007 infusion did not interfere with immune reconstitution kinetics post-ASCT. Cohorts receiving PNK infusion 14 days post-ASCT had already recovered white blood cell counts to normal levels. One cohort receiving 3x107 PNK cells/kg 7 days post-ASCT showed an immune deficient environment (0.05x103 ± 0.004x103 leukocytes/ml, n=3), but recovered their white blood cell counts by day 21 (6.8x103 ± 1.8x103 leukocytes/ml, n=3). Using a validated Euro-flow MRD assay, 4/15 patients were MRD(-) at pre-ASCT baseline, and by day 90, 10/15 pts were MRD(-). PNK-007 persistence was not detected in patients by flow cytometry with the earliest timepoint tested being 7 days post-infusion. Panel HLA serum antibodies were not detected at any timepoint indicating the absence of alloantibodies. Withholding IL-2 administration in one cohort allowed us to evaluate its potential effects on NK cell recovery and immune reconstitution. We found that subcutaneous IL-2 q.o.d. for 10 days following PNK-007 infusion did not affect recovery kinetics and concentration of endogenous NK cells. However, these patients showed a 5-10 fold increase in serum soluble IL-2RA from baseline and elevated regulatory T cell (Treg) count in the blood versus baseline (167 ± 107 Treg/mL vs. 61 ± 33 Treg/mL, p=0.0075). Patients not receiving IL-2 saw no change in serum soluble IL-2RA or blood Treg level from baseline. CD4 and CD8 T cells from all patients retained their ability to become activated in response to ex vivo stimulation and favored release of IL-2 and IFNg. T cell effector function was maintained in all patients post-ASCT but was lost in a subset of patients at 1 year. Serum analysis showed low levels of free IL-15 at the time of PNK dosing despite the transient lymphodepleted state associated with ASCT. Cytokines associated with myeloid inflammation and T cell immunity in the month post dosing were within normal homeostatic level. Serum TGFβ was significantly lower at the day of PNK infusion compared to normal homeostatic levels. Conclusion: Translational data from a Phase I study of PNK-007 in post-ASCT MM established that dosing up to 3x107 cells/kg at 14 or 7 days post-transplant did not impair engraftment or immune reconstitution. EuroFlow MRD assessment of the bone marrow showed conversion of 6/11 patients from MRD(+) to MRD(-) by day 90 post transplant. The administration of IL-2 in this clinical study did not appear to benefit NK cell reconstitution but instead favored soluble IL2RA antagonism and increased systemic levels of Treg. These results demonstrate the feasibility of allogeneic NK cell therapy in the MM + ASCT setting and will help inform the design of further clinical studies. Disclosures Van Der Touw: Celularity, Inc.: Employment, Patents &amp; Royalties. Kang:Celularity, Inc.: Employment, Patents &amp; Royalties. Stout:Celularity, Inc.: Employment. Voskinarian-Berse:Celularity, Inc.: Employment. Rousseva:Celularity, Inc.: Employment. Hariri:Celularity Inc: Employment. Zhang:Celularity Inc: Employment.

Clinical outcomes of hepatitis B or C virus infections in patients with malignant lymphoma receiving autologous stem cell transplantation: on behalf of the Adult Lymphoma Working Group of the Japan Society for Haematopoietic Cell Transplantation (JSHCT)

Clinical outcomes of hepatitis B or C virus infections in patients with malignant lymphoma receiving autologous stem cell transplantation: on behalf of the Adult Lymphoma Working Group of the Japan Society for Haematopoietic Cell Transplantation (JSHCT)

Infectious Complications in the Outpatient and Inpatient Autologous Stem Cell Transplantation Setting for Patients with Multiple Myeloma. Princess Margaret Cancer Center Experience

Background: Autologous stem cell transplant (ASCT) for multiple myeloma (MM) can be feasible and safe in the outpatient setting and has become standard of care at many centers. Limited literature, however, exists on the types of infectious complications, including specific pathogenic isolates and resistance patterns in the outpatient (OP) setting and whether these differ from the inpatient (IP) setting. This creates uncertainty and variation among local treatment guidelines on antibiotic prophylaxis and treatment of infections in the outpatient population.Methods:In this retrospective study, at total of 240 patients who underwent ASCT at our institution from 2015 to 2016 were reviewed. Study objectives included: 1) to describe the types of infections and pathogenic isolates in MM patients during the acute transplant period and 2) compare isolate results between patients undergoing OP vs IP ASCT. We also aimed to assess 30-day post-ASCT all-cause mortality, readmission rates, and incidence of multidrug resistant bacterial infections in each cohort. As per standard transplant protocol at our institution, all patients received ciprofloxacin and fluconazole prophylaxis and standardized initial therapy for febrile neutropenia with piperacillin-tazocin. Daily GCSF support was routinely used starting day +7 for IPs, and on demand only for OPs.Results:Patient, disease and transplant characteristics:Baseline demographics of both OP and IP cohorts are shown in Table 1 (total n=240; 109 OP, 131 IP). As expected, IPs had poorer performance status (KPS<90), more comorbidities (HCT-CI ≥3), more advanced stage MM, had worse pre-transplant renal function, and were more likely to receive Melphalan dose reductions. Median time to engraftment was similar between groups - 12 days for IP and 13 days for OP (range 9-25), with duration of neutropenia <0.5x10^9/L exceeding 7 days in 46% of the cohort. Median length of stay in hospital was 17 days (12-55) for the inpatients. In the OP cohort, 63.9% of patients required readmission to hospital, with median 3-day hospital stay. In total, only 4 (1.7%) patients required ICU admission.Infections in total cohort (OP and IP):Overall, 121 of 240 patients (50.4%) developed febrile neutropenia, with most common causes including: blood stream infection (BSI) (n=35, 29%), pneumonia (n=18, 14.8%) and respiratory virus infections (n=16, 13.2%). Opportunistic infections were uncommon (n=6, 2.5%) with 1 case of invasive aspergillosis and 5 cases of CMV infection.Of the 43 cases of BSI, 33 (76%) were identified as central line associated blood stream infections (CLABSI), 20 (46.5%) due to gram positive and 20 (46.5%) due to gram negative organisms. Multi-drug resistant gram negative organism isolates were observed in 22 patients (51%), including 5 cases of extended spectrum beta lactamase producing bacteria (ESBL; 11.6%), 9 cases of gram negative bacteria carrying inducible AmpC gene (SPICE; 20.1%), and 10 (23%) cases of quinolone resistant gram negative BSI.Comparison of IP vs OP infections:Although the OP cohort were less frail with fewer comorbidities than the IP cohort, they had more episodes of febrile neutropenia (64% vs 51%; p=0.042), worse mucositis (22.0% vs 10.8%, p= 0.021), and more BSI (24.7% vs 12.9% p=0.019). In the multivariable analysis, only OP status (OR 2.4, p=0.03) and baseline ANC<1.5 pre ASCT (OR 6.3, p=0.003) predicted for BSI occurrence.At 18 months, OS was 98.5% and PFS was 68% for all patients, with no difference between IP and OP (p=0.772). PFS was worse in patients with BSI (p=0.0031, HR 8.7), with gram positive infections in particular (p=0.0264, HR 4.9)Conclusions:In our autotransplant experience, blood stream and lung infections are common, with multi-drug resistance a concern. We were surprised to report that patients undergoing outpatient-based transplant had more BSI, presumably central line-related, and that this may impact disease outcomes (PFS). We hypothesize that outpatients may undergo additional line manipulation or inferior line hygiene, suggesting that enhanced patient/staff education on infection control measures should be a focus. In general, though, outpatient ASCT patients had excellent outcomes, with similar engraftment rates, short readmission rates, low ICU usage, as the entire cohort. DisclosuresTiedemann:Novartis: Consultancy; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Merck: Consultancy; Roche: Consultancy. Chen:Amgen: Honoraria.

CD19-CAR Therapy Using Naive/Memory or Central Memory T Cells Integrated into the Autologous Stem Cell Transplant Regimen for Patients with B-NHL

Autologous stem cell transplantation (ASCT) remains an important consolidative therapy for patients with recurrent non-Hodgkin lymphoma (NHL), but is limited by the high incidence of NHL relapse. We report a Phase I clinical trial of ASCT followed by CD19-specific CD28-costimulatory chimeric antigen receptor (CD19:28z-CAR) T cells, with the goal of reducing NHL relapse rates. Safety and feasibility were the primary objectives, with CAR T cell persistence and expansion in the myeloablative ASCT setting as secondary objectives.This study examines safety and feasibility for two manufacturing platforms that differed in the T cell subset composition used for CAR engineering. Initially, the T cell population for CAR transduction was central memory (Tcm)-enriched: participants' peripheral blood mononuclear cells (PBMC) were depleted for CD14+ monocytes, CD25+ Tregs, and CD45RA+ naïve and stem-memory T cells, after which they were selected for CD62L+ Tcm (Wang et al. Blood;127:2980). Based on comparative preclinical data, a second arm was added to the trial to evaluate a Tn/mem-derived manufacturing platform that enriched central memory, naïve, and stem memory T cells (no CD45RA+ depletion). Either Tcm- or Tn/mem-enriched T cells were activated with CD3/CD28 beads, transduced with lentiviral vector encoding the CD19:28z-CAR, and expanded ex vivo.This phase I trial used the toxicity equivalence range design (Blanchard and Longmate. Contemp Clin Trials; 32;114) with an equivalence range for DLTs of 0.20-0.35 and a target toxicity rate of 0.25. The first 3 participants on each arm were followed one at a time, with later accrual in cohorts of 3. Twenty-three participants underwent ASCT and received CD19:28z-CAR T cells 2 days post stem cell infusion at the assigned dose level (DL): 17 on the Tcm arm (DL 50 million [M] CAR+ T cells [n=3], 200 M [n=5], 600 M [n=9]); 6 on the Tn/mem arm (DL 200 M). Participants were followed for dose limiting toxicity (DLT) for 28 days. Table 1 shows results by arm and DL. Both arms demonstrated safety and feasibility. There was no delayed hematopoietic reconstitution on either arm. On the Tcm arm, the only DLT was at DL 600 M (1 of 9 at 600 M). The Tn/mem arm was opened at 200 M and 6 participants were treated with no DLTs. The dose was not escalated as the protocol management team had seen activity at the 200M level in 2 other trials using the Tn/mem product.Tcm Arm: Fourteen of 17 participants (82%) had a diagnosis of diffuse large B-cell lymphoma (DLBCL) and 3 had mantle cell lymphoma. The mean age of the participants on the Tcm arm was 57 (35-75). The median number of prior chemotherapy regimens was 2 (1-5). The median progression-free survival (PFS) was 34.6 months 95% CI [21.8, undefined]. Seven of 17 participants (41%) have progressed, 1 died in remission of unrelated intracranial hemorrhage (6%), 7 (41%) remain in CR and are still in follow-up, and 2 are lost to follow-up (12%). All 17 participants achieved a CR or a continuing CR after ASCT and T cells.Tn/mem arm: Five of 6 participants (83%) had a DLBCL diagnosis, and 1 was NHL not otherwise specified. The mean age of the participants was 50 (40-72). The median number of prior chemotherapy regimens was 2.5 (1-3). The median follow-up time for the Tn/mem arm was 12 months, with median PFS not yet reached. One of 6 (17%) has progressed, 4 (66%) remain in CR and are still in follow-up, and 1 is lost to follow-up (17%). Five of 6 (83%) participants achieved a best response of CR or continuing CR after therapy.Several differences were observed between the manufacturing platforms. Since the Tn/mem production platform has fewer depletion steps, it resulted in a higher product yield, which shortened the ex vivo expansion period by 4.1 days (95% CI [1.5%, 6.6%]) from 18.9 days (15-24) for Tcm to 14.8 days (12-18) for Tn/mem (P<0.005). Notably in the ASCT minimal disease burden setting, the Tn/mem-derived CD19:28z-CAR T cell products exhibited significantly higher in vivo CAR T cell expansion compared to Tcm products at the 200M DL (Figure 1). We conclude that although both Tcm- and Tn/mem-enriched CD19CAR T cell therapies are safe, the Tn/mem product is more promising due to its 1) shorter production time, 2) higher cell yield, and 3) better in vivo expansion, despite the low antigen drive in these patients post-salvage and ASCT therapy. Longer follow-up for the 2-year PFS secondary objective will indicate if improved Tn/mem expansion impacts tumor control. DisclosuresWang:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Budde:Mustang Therapeutics: Consultancy, Other: Licensing Agreement, Patents & Royalties, Research Funding. Brown:Mustang Therapeutics: Consultancy, Other: Licensing Agreement, Patents & Royalties, Research Funding. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

Fluoroquinolone Prophylaxis Is Highly Effective for the Prevention of Central Line-Associated Bloodstream Infections in Autologous Stem Cell Transplant Patients.

Patients undergoing stem cell transplant (SCT) for the treatment of hematologic malignancy are at increased risk for central line-associated bloodstream infections (CLABSIs). The use of prophylactic antibiotics to prevent CLABSIs in the setting of autologous SCT is of unclear benefit. We aimed to evaluate the impact of levofloxacin prophylaxis on reducing CLABSIs in this high-risk population. Patients undergoing autologous SCT at a tertiary care hospital received levofloxacin prophylaxis from January 13, 2016 to January 12, 2017. Levofloxacin was administered from autologous SCT (day 0) until day 13, absolute neutrophil count > 500/mm3, or neutropenic fever, whichever occurred first. Clinical outcomes were compared with a baseline group who underwent autologous SCT but did not receive antibacterial prophylaxis during the previous year. The primary endpoint was incidence of CLABSIs assessed using Cox proportional hazards regression. A total of 324 patients underwent autologous SCT during the entire study period, with 150 receiving levofloxacin prophylaxis during the intervention period. The rate of CLABSIs was reduced from 18.4% during the baseline period to 6.0% during the intervention period. On multivariable analysis levofloxacin prophylaxis significantly reduced CLABSI incidence (hazard ratio, .33; 95% confidence interval [CI], .16 to .69; P = .003). There was also a reduction in the risk of neutropenic fever (odds ratio [OR], .23; 95% CI, .14 to .39; P < .001) and a trend toward a reduction in intensive care unit transfer for sepsis (OR, .33; 95% CI, .09 to 1.24; P = .10) in patients receiving levofloxacin prophylaxis. Notably, there was no increase in Clostridium difficile infection in the levofloxacin group (OR, .66; 95% CI, .29 to 1.49; P = .32). Levofloxacin prophylaxis was effective in reducing CLABSIs and neutropenic fever in patients undergoing autologous SCT. Further studies are needed to identify specific patient groups who will benefit most from antibiotic prophylaxis.

Consolidative Radiotherapy After Autologous Stem Cell Transplantation for Relapsed or Refractory Diffuse Large B-cell Lymphoma.

We evaluated the role of consolidative radiotherapy (RT) for patients undergoing high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) for relapsed or refractory diffuse large B-cell lymphoma (DLBCL). We reviewed the medical records of 72 consecutive patients who had undergone ASCT for relapsed or refractory DLBCL at our institution from 2006 to 2014. Pretransplant conditioning consisted of HDC and total body irradiation. Of the 72 patients, 13 received post-transplant consolidative RT at the discretion of the consulted radiation oncologist. Consolidative RT was associated with significantly improved 2-year locoregional control (LRC) (92% vs. 68%; P= .04). However, no difference was seen in either the 2-year progression-free survival (PFS) (69% vs. 54%; P= .25) or overall survival (OS) (85% vs. 59%; P= .44). Analysis of the subgroup of 19 patients with persistent residual masses≥ 2 cm on post-transplant imaging demonstrated a significant improvement in LRC (100% vs. 36%; P< .01), PFS (88% vs. 27%; P= .01), and OS (100% vs. 45%; P=.02) with consolidative RT. The use of consolidative RT after HDC and ASCT for relapsed or refractory DLBCL appears to significantly improve LRC. For patients with masses≥ 2 cm after ASCT, improved 2-year PFS and OS were seen. Prospective trials are needed to further identify the patients who would derive the most benefit from consolidative RT in the ASCT setting.

Propylene glycol-free melphalan as conditioning regimen for autologous transplantation in myeloma.

High-dose melphalan has been the drug of choice for preparative regimens for autologous stem cell transplantation in multiple myeloma. Propylene-free melphalan (Evomela™) is a newer formulation of melphalan, which incorporates Captisol® to produce a stable product upon reconstitution. In addition to avoiding propylene glycol with its' potential side effects, this approach improves the overall stability of reconstituted melphalan and can ensure intended dose delivery. In this paper, we review the published literature regarding this formulation. We focus on its' chemistry, pharmacokinetics and clinically available data for its use in myeloma autologous stem cell transplantation setting.

Correlation Between Actual Stem Cells Collected By Apheresis and Predicted Stem Cells Based on Pre-Apheresis Peripheral Blood CD34+ Cell Counts

Introduction. Stem cell (SC) mobilization and collection from peripheral blood (PB) is a broadly used strategy in the setting of autologous stem cell transplantation (ASCT). An adequate correlation between CD34+ cell count in PB and CD34+ cell count in apheresis product is essential for the planning of the mobilization-apheresis process. Prediction of SC yield in the basis of peripheral blood stem cell (PBSC) number and blood volume processed (BVP) was proposed by Pierelli et al (Vox Sanguinis (2006)91:126-34).Objective. Evaluation of correlation between pre-apheresis PBSC count and CD34+ cell dose collected in the first apheresis procedure. Evaluation of correlation between predicted CD34+ yield by Pierelli's method and actual CD34+ yield collected in the first apheresis procedure.Patients and Methods. Eighty-four apheresis procedures performed to 79 patients in a single institution between 2008 and 2015 were retrospectively evaluated. Data analyzed included age, gender, body weight, diagnosis, date of first apheresis, pre-apheresis PB CD34+ counts, CD34+ cell dose collected in the first apheresis product and total BVP. Only patients in whom pre-apheresis PBSC count was available were included in this analysis. Median age was 52 years (16-66), 30 (38%) were females. Median body weight was 71 kg (47 - 120). Diagnosis was non-Hodgkin lymphoma (48%), multiple myeloma (24%), Hodgkin lymphoma (22%), acute myeloblastic leukemia (4%), amyloidosis (1%) and solid tumor (1%). Using the method described by Pierelli et al, predicted CD34+ yields were calculated (predicted CD34+ cells/kg= PB CD34+ cells/mL x 0.4 x BVP per kg (mL/kg). Correlation between variables was analyzed by Pearson's coefficient (r). An r value close to 1 indicates significant correlation between variables. An r value close to 0 indicates no statistical correlation. Predicted yields were classified in low (lower than 2 x 106 CD34+ cells / kg) (n=34), intermediate (2 to 5) (n=28) or high (higher than 5) (n=22), according with the conventional limits for SC dose in the setting of ASCT. Positive predictive value (PPV) of predicted yields was calculated as the proportion of actual yields falling into each category of predicted yields.Results. Median pre-apheresis PBSC count was 25 CD34+ cells / uL (5-310). Median BVP was 240 mL/kg (143-360). Median predicted CD34+ yield was 2.1x106 CD34+ cells/kg (0.5-29.41) and median actual CD34+ yield was 2.84 x106 CD34+ cells/kg (0.26-38.21). Pearson's correlation coefficient (r) between pre-apheresis PBSC and collected CD34+ cells was 0.842 (p=0.000). Pearson's correlation coefficient (r) between predicted and actual CD34+ was 0.836 (p=0.000). Median ratio actual CD34+ cells / predicted CD34+ cells was 1.10 (0.31-4.55). PPV of predicted yields higher than 5 x 106 CD34+ cells /kg was high (95%). Only 18% of cases with a predicted yield between 2 and 5 x 106 CD34+/kg had an actual CD34+ yield lower than 2 x 106 CD34+/kg.Conclusion. The results show a significant correlation between PBSC count and collected SC during the first apheresis procedure. A significant correlation between predicted and actual CD34+ yields reproduce what has been shown by others regarding the predictive power of this formula. The PPV of this method is higher for predicted CD34+ yields higher than 5 x 106 CD34+ cells/kg. DisclosuresNo relevant conflicts of interest to declare.