Autologous Peripheral Blood Stem Cell Transplantation Research Articles

Non-cryopreserved autologous peripheral blood stem cell transplantation for multiple myeloma and lymphoma in countries with limited resources: practice considerations from the Worldwide Network for Blood and Marrow Transplantation.

Autologous peripheral blood stem cell (PBSC) transplantation is a standard treatment of multiple myeloma (MM), Hodgkin lymphoma and various subtypes of non-Hodgkin lymphoma. Cryopreservation of hematopoietic stem cells is standard practice that allows time for delivery of conditioning regimen prior to cell infusion. The aim of this Worldwide Network for Blood & Marrow Transplantation (WBMT) work was to assess existing evidence on non-cryopreserved autologous transplants through a systematic review/meta-analysis, to study feasibility and safety of this approach. We searched PubMed, Web of Science and SCOPUS for studies that utilized non-cryopreserved autologous PBSC transplantation. Identified literature was reviewed for information on mobilization, apheresis, preservation and viability, conditioning regimen, engraftment, response, and survival. Results highlight collective experience from 19 transplant centers (1686 patients), that performed autologous transplants using non-cryopreserved PBSCs. The mean of infused CD34+ was 5.6 × 106/kg. Stem cell viability at transplantation was >90% in MM and >75% in lymphomas, after a storage time of 24-144 h at +4 °C. Mean time-to-neutrophil engraftment was 12 days and 15.3 days for platelets. Pooled proportion estimates of day 100 transplant-related mortality and graft failure were 1% and 0%, respectively. Non-cryopreservation of apheresed autologous PBSCs appears feasible and safe.

Optimizing Autologous Stem Cell Transplantation in Multiple Myeloma: The Impact of Intensive Chemomobilization

Most transplant-eligible multiple myeloma (MM) patients undergo autologous peripheral blood stem cell collection (PBSC) using G-CSF with on-demand plerixafor (G ± P). Chemomobilization (CM) can be used as a salvage regimen after G ± P failure or for debulking residual tumor burden ahead of autologous peripheral blood stem cell transplantation (ASCT). Prior studies utilizing cyclophosphamide-based CM have not shown long-term benefits. At our center, intensive CM (ICM) using a PACE- or HyperCVAD-based regimen has been used to mitigate "excessive" residual disease based on plasma cell (PC) burden or MM-related biomarkers. Given the lack of efficacy of non-ICM, we sought to determine the impact of ICM on event-free survival (EFS), defined as death, progressive disease, or unplanned treatment escalation. We performed a retrospective study of newly diagnosed MM patients who collected autologous PBSCs with the intent to proceed immediately to ASCT at our center between 7/2020 and 2/2023. Patients were excluded if they underwent a tandem autologous or sequential autologous-allogeneic transplant, had primary PC leukemia, received non-ICM treatment (i.e., cyclophosphamide and/or etoposide), or had previously failed G ± P mobilization. To appropriately evaluate the impact of ICM among those who potentially could have received it, we utilized a propensity score matching (PSM) approach whereby ICM patients were compared to a cohort of non-CM patients matched on pre-ASCT factors most strongly associated with the receipt of ICM. Of 451 patients identified, 61 (13.5%) received ICM (PACE-based, n = 45; hyper-CVAD-based, n = 16). Post-ICM/pre-ASCT, 11 patients (18%) required admission for neutropenic fever and/or infection. Among 51 evaluable patients, the overall response rate was 31%; however, 46 of 55 evaluable patients (84%) saw a reduction in M-spike and/or involved free light chains. Among those evaluated with longitudinal peripheral blood flow cytometry (n = 8), 5 patients (63%) cleared circulating blood PCs post-ICM. Compared to patients mobilized with non-CM, ICM patients collected a slightly greater median number of CD34+ cells (10.8 versus 10.2 × 10⁶/kg, P = .018). The median follow-up was 30.6 months post-ASCT. In a PSM multivariable analysis, ICM was associated with significantly improved EFS (hazard ratio [HR] 0.30, 95% CI 0.14 to 0.67, P = .003), but not improved OS (HR 0.38, 95% CI 0.10 to 1.44, P = .2). ICM was associated with longer post-ASCT inpatient duration (+4.1 days, 95% CI, 2.4 to 5.8, P < .001), more febrile days (+0.96 days, 95% CI 0.50 to 1.4, P < .001), impaired platelet engraftment (HR 0.23, 95% CI 0.06 to 0.87, P = .031), more bacteremia (OR 3.41, 95% CI 1.20 to 9.31, P = .018), and increased antibiotic usage (cefepime: +2.3 doses, 95% CI 0.39 to 4.1, P = .018; vancomycin: +1.0 doses, 95% CI 0.23 to 1.8, P = .012). ICM was independently associated with improved EFS in a matched analysis involving MM patients with excessive disease burden at pre-ASCT workup. This benefit came at the cost of longer inpatient duration, more febrile days, greater incidence of bacteremia, and increased antibiotic usage in the immediate post-ASCT setting. Our findings suggest that ICM could be considered for a subset of MM patients, but its use must be weighed carefully against additional toxicity.

Pre-Apheresis Prediction of CD34 + Cell Yield from Collecting Efficiency Is Not Reliable in Peripheral Blood Stem Cell Collection

Introduction Procurement of enough CD34 + cells (CD34 +) by apheresis is essential for the successful engraftment of peripheral blood stem cell transplantation (PBSCT). To determine the processed blood volume of apheresis to obtain a certain number of CD34 +, collecting efficiency 2 (CE2) is generally used, which is calculated from the total amount of CD34 + in the product (PBSC-CD34 +) divided by pre-apheresis CD34 + in the peripheral blood (PB-CD34 +) and by processed blood volume, and CE2 is determined beforehand from the accumulated data in each apheresis site. However, we sometimes experience cases in which collected amount of CD34 + are far from our expected values. It is probably because of the introduction of various CD34 + mobilization methods, new automated blood cell separators and protocols. Hence, we investigated thoroughly the kinetics of CD34 + in PBSC collection. Patients and Methods PBSC collections in 55 subjects, including 46 patients undergoing autologous PBSCT and 9 healthy allogeneic PBSCT donors, were analyzed prospectively. All patients were administered G-CSF 10 μg/day sc for 4 days and plerixafor 0.24 mg/kg sc at 22:30 on day 4, and PBSC collection was started from 9 am on day 5. Donors were given G-CSF 10 μg/day for 4 to 5 days until 2x10 6/kg (pt's body weight) CD34 + were collected. Apheresis was performed using Spectra Optia ® in CMNC mode. The apheresis time was adjusted depending on the CD34 + yield. CD34 + was analyzed by flow cytometry according to the ISHAGE protocol. Peripheral blood samples were obtained before, and every 1-1.5 hour after the start until the end of apheresis. Samples were also taken from the apheresis collection bag at the same timings as PB. Collecting efficiencies were calculated as follows: CE1(%) = [collected CD34 +]x100/([prePB-CD34 +]+[postPB-CD34 +])/2 x [processed blood volume]). CE0(%) = [collected CD34 +]x100/sum of ([prePB-CD34 +]+[postPB-CD34 +])/2 x [processed blood volume]) in each section (*CE0 was defined in this particular study). This study was conducted as a part of the prospective study, which was approved by the Ethics Committee of Keio University School of Medicine. Results More than 2x10 6/kg CD34 + were collected in the first day in 48 subjects (87%). The median processed blood volume and time was 5575 (range 3873-10903) mL and 185 (range 120-292) min, respectively. CE2 was calculated as a median 53% (range 20-88) from this cohort, but it varied markedly; CE2&amp;gt;70% in 6 cases, and &amp;lt;30% in 4. On the other hand, CE1 was median 65.5% (range 26.2-106.4%), and it also varied markedly; CE1&amp;gt;80% in 6 cases, and &amp;lt;40% in 7. CE1 and CE2 correlated strongly with each other (r=0.93), but CE1 was higher than CE2 in all cases but one; median 124(range 95-149) % (Fig.1). The main reason why CE1 was always higher than CE2 was probably because PB-CD34 + concentration was always declining during apheresis, which might be more influenced in plerixafor mobilization where CD34 + concentration changed in an hour-depending manner. In some apheresis cases with extremely low CE, it was revealed that cell aggregates containing myriads of platelets might have blocked the outlet of the collection kit, which was difficult to be recognized during apheresis. CE1 in each apheresis section also changed markedly during each apheresis and CE2 was not helpful for predicting optimal apheresis time (Fig. 2). In the first 10-20 minutes until the interphase formation, a real collection was not yet started so that CE1 in the first 1 hour became low. In the following sections, collection was supposed to become relatively steady, where CE would be influenced largely by interphase stability. In the last part of collection, CE tended to be relatively high for unknown reasons. CEs varied markedly during the whole collection periods. Conclusions Because multiple factors are associated with CE variability, CD34 + yields were sometimes far from the expected values calculated from prePB-CD34 + and CE2. Therefore, enumeration of CD34 + in the product during apheresis is recommended for secure and effective collections.

Fluoroquinolone-Resistant Enterobacteriaceae Prevalence for Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation (aHSCT) in the Treatment of Multiple Myeloma (MM)

Background: Fluoroquinolones (FQL) are commonly used in antimicrobial prophylaxis in immunocompromised cancer patients (pts) during prolonged neutropenia. A possibly high and increasing proportion of pts harboring FQL-resistant Enterobacteriaceae (FRE) challenges the assumption that prophylaxis with FQLs is still of benefit in preventing sepsis. Previous studies reported that colonization of FRE in allogeneic transplant patients may be an infection risk factor (cf. Satlin et al. Clin Infect Dis 202;73:1257-65). This prospective study aims to determine the prevalence of FRE in defined pt populations in two metropolitan areas treated with dose-intense melphalan with autologous peripheral blood stem cell (PBSC) transplantation, and to determine the possible clinical effects of FRE in the host microbiome on transplant outcomes. Methods: Pts eligible for this prospective, ongoing study have a diagnosis of MM and are undergoing autologous PBSC transplantation after conditioning with dose-intense melphalan 200 mg/m 2 at Hackensack University Medical Center (HUMC) and MedStar Georgetown University Hospital (MGUH). Peri-rectal swabs are scheduled before chemotherapy mobilization of PBSC given with FQL prophylaxis, before transplant admission with initiation of antimicrobial prophylaxis, at time of hospital discharge, and 3 months after aHSCT. Prophylaxis is discontinued with fever or hospital discharge. Blood cultures are obtained at time of fever (&amp;gt;38 °C) with adjustments in antibiotics per standard of care. A central catheter is placed for venous access in all patients throughout their transplant course. Pts are discharged after achieving neutrophil (ANC) engraftment and control of conditioning regimen toxicities. Bacterial cultures from perirectal swabs (fresh or frozen for shipping) were purified on CHROMagar™ Orientation Plates and grown in the presence of ≥5 ug/ml ciprofloxacin to select for quinolone-resistant organisms. Results: To date, 39 pts are evaluable (Table 1). PBSC were mobilized using filgrastim/plerixafor (G-Moz) or cyclophosphamide/etoposide/dexamethasone (CDE) followed by filgrastim with levofloxacin prophylaxis. The quantity of CD34+ cells infused is in Table 1. All pts achieved ANC engraftment at a median of 10.8 days (range 9-14) and were hospitalized for a median of 13 days (range 11-24). 37/39 pts collected swabs before transplant admission (and swabs were obtained at discharge for the other 2 pts). 13/37 (35%) admission swabs demonstrated FRE colonization (Table 2). 6/33 swabs at time of discharge were positive for FRE including for 4 pts negative for FRE on transplant admission with a total of 17/39 pts (44%) showing FRE colonization at some point during the transplant admission. Samples collected at 3 months after transplantation for 24 pts reaching that timepoint showed FRE colonization for 4 pts including 2 pts not previously testing positive at time of transplantation. 27/107 samples tested positive for FRE and 21/39 pts (54%) had at least one FRE positive culture. Seven pts (20%) developed neutropenic fever but no pt experienced a blood-stream infection (BSI). One pt developed Clostridium difficile colitis during the period of neutropenia. One pt tested positive for MRSA colonization at admission but did not develop fever or BSI. One pt was readmitted after initial hospital discharge for evaluation of fever without a source of infection determined. Ten pts (5 FRE colonized during transplant course) were given prednisone for persistent diarrhea attributed to engraftment syndrome (cf: Spitzer TR. Bone Marrow Transplant 2001;27:893-8) commencing at a median of 10 (range, 8-13) days after aHSCT and not associated with CDE mobilization or detection of FRE. Nineteen other patients, 8 of whom tested positive for FRE, did not receive corticosteroids for management of regimen-related toxicities (an additional 7 pts received preplanned corticosteroids starting at day +8). No center effect is yet evident. Conclusions: FRE are detected in a high proportion of pts undergoing aHSCT in the treatment of MM. However, FQL prophylaxis is not associated with FRE BSI in this ongoing study. FRE colonization is not predictive of delayed engraftment or prolonged hospitalization, and does not appear predictive of non-infectious diarrhea.

Reverse Autologous Peripheral Blood Stem Cell Transplantation after Allogeneic Transplantation to Restore Immune Function and Pancytopenia

Despite advances in multiple myeloma treatment the disease remains challenging to treat with repeated relapses in most. For high-risk younger patients, allogeneic transplants are occasionally performed. While curative in some, complications can include the development of opportunistic infections and secondary malignancies. Furthermore, patients relapsing after an allogeneic transplant may have poor bone marrow reserve limiting the ability to use subsequent therapies. We describe two patients who underwent a “reverse” autologous peripheral blood stem cell rescue using stem cells banked prior to allogeneic transplantation. The outcomes were successful and led to full engraftment and correction of their immunodeficiencies and pancytopenia respectively. Case 1: A 37-year-old woman was diagnosed with multiple myeloma during routine testing for an in-vitro fertilization assessment. She had ISS stage 2 disease and was treated with CyBorD, followed by an autologous stem cell transplantation. Lenalidomide plus dexamethasone was used as maintenance. She relapsed after just one year then progressed through single agent carfilzomib and then bendamustine. After responding to 2 cycles of DCEP she had a 10/10 matched unrelated donor CD34-selected allogeneic transplant. The patient was EBV positive, but the donor was not. Four months post-transplant she developed tonsillar PTLD with a rising EBV DNA titer and was treated with rituximab. Her CD4 count was 46. Her multiple myeloma relapsed thereafter necessitating treatment with daratumumab. She then developed rituximab-resistant monomorphic PTLD which then responded to brentuximab-vedotin and donor lymphocyte infusions. The multiple myeloma relapsed again and was treated with daratumumab + pomalidomide + dexamethasone. After a rising EBV DNA titer, brentuximab-vedotin was restarted but the lymphoma progressed again with a 5 x 3 cm anterior mediastinal mass biopsy proven to be monomorphic PTLD. R-CHOP was given for 4 cycles but resulted in only a partial response. Due to subsequent rapidly symptomatic and progressive disease a decision was made to use high-dose melphalan (200 mg/m2) followed by a reinfusion of her previously collected autologous stem cells to restore her T-cell immunity and hopefully control her lymphoma. She engrafted uneventfully at Day + 12 with chimerism studies showing autologous hematopoiesis and a CD4 count of 856. Her post-transplant course was complicated by renal thrombotic microangiopathy treated successfully with eculizumab. After further myeloma relapses, she is currently alive and well and in remission while on teclistamab over 4 yrs after her 2 nd autologous PBSC transplant. Her lymphoma has resolved. Case 2: A 37-year-old-male with beta-thalassemia was noted to have an elevated total protein on routine blood testing for a life insurance policy. Work up revealed multiple myeloma with a t(4:14) abnormality and complex cytogenetics. After initial observation he was started on KRD for progressive anemia. A VGPR was obtained and consolidated with an autologous PBSC transplant. He was maintained on Ixazomib+lenalidomide+dexamethasone but relapsed 2 years later with a sacral mass. After progressions though daratumumab+pomalidomide+dexamethasone then carfilzomib and then XRT to a large chest mass followed by DCEP as salvage, he underwent a 9/10 mismatched allogeneic transplant. He developed Grade 2 skin GVH but had disease progression again after just 6 months. Salvage treatment with elotuzumab+pomalidomide+dexamethasone then DCEP and subsequently ciltacabtagene autoleucel were unsuccessful with progression after just 6 weeks from the latter. He was treated again with DCEP but became transfusion dependent after the 2 nd cycle and had progressive disease again. Due to symptomatic myeloma and pancytopenia he underwent a reverse autologous PBSC transplant using banked stem cells. He engrafted uneventfully on Day +11 and despite recurrent multiple myeloma, he is currently in remission while on talquetamab. His beta-thalassemia returned. These cases demonstrate the ability to reverse an allogeneic transplant successfully using previously stored autologous peripheral blood stem cells. The recovery allowed for resumption of effective anti-cancer treatment that became lifesaving. Whether this approach could correct patients with unrelenting GVH issues should be contemplated as well.

Efficacy and Safety of Etoposide Combined with Cyclophosphamide for Autologous Peripheral Blood Stem Cell Mobilization in Patients with Multiple Myeloma

To evaluate the efficacy and safety of etoposide combined with cyclophosphamide (EC) regimen for mobilization of autologous peripheral blood stem cells (APBSCs) in patients with multiple myeloma (MM). The clinical data of 48 MM patients who received APBSC transplantation (APBSCT) in Department of Hematology of the First Affiliated Hospital of Nanchang University from January 2015 to October 2021 were retrospectively analyzed. The mobilization success rate and mobilization optimal rate of EC regimen were counted, and its effect on transplant efficacy, adverse reactions, hematopoietic reconstitution after transplantation, and survival time of MM patients were analyzed. APBSCs were collected on day 14 (10-19) after EC administration. The median of collected CD34+ cells was 6.82 (1.27-22.57)×106/kg, and the median number of apheresis session was 2 (1-4). The mobilization success rate (collecting CD34+ cells≥2×106 cells/kg after completion of apheresis) was 98% (47/48), and mobilization optimal rate (collecting CD34+ cells≥5×106 cells/kg after completion of apheresis) was 71% (34/48). The depth of remission were improved after APBSCT, and the complete remission (CR) rate increased from 45.8% before transplantation to 87.5% after transplantation (P <0.01). There was no transplant-related death, no blood transfusion during mobilization, and no mucositis occurred in the patients. The most common complication was neutropenia, with an incidence of 75.0% (36/48). After transplantation, all the patients successfully achieved hematopoietic reconstitution. The median time to neutrophil engraftment was 10 (9-26) days, and median time to platelet engraftment was 10 (8-33) days. By the end of follow-up, both the median progression-free survival (PFS) and overall survival (OS) time were not reached. The 5-year estimated PFS rate and OS rate was 53.8% and 82.4%, respectively. The EC regimen for mobilization of APBSC has a high acquisition success rate and controllable adverse reactions, which can be an effective and safe mobilization regimen in MM patients.

Autologous peripheral blood stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia is safe but poses challenges for long-term maintenance of molecular remission: Results of the Auto-Ph17 study.

Autologous hematopoietic stem cell transplantation (SCT) is not a standard treatment option for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL); however, its position has been reassessed since the introduction of tyrosine kinase inhibitors (TKIs). We prospectively analyzed the efficacy and safety of autologous peripheral blood SCT (auto-PBSCT) for Ph+ALL patients aged between 55 and 70 years who had achieved complete molecular remission. Melphalan, cyclophosphamide, etoposide, and dexamethasone were used for conditioning. A total of 12 courses of maintenance therapy, including dasatinib, were performed. The required number of CD34+ cells was harvested in all five patients. No patient died within 100 days after auto-PBSCT, and no unexpected serious adverse events were observed. Although 1-year event-free survival was 100%, hematological relapse was observed in three patients at a median of 801 days (range, 389-1088 days) after auto-PBSCT. Molecular progressive disease was observed in the other two patients, although they maintained their first hematological remission at the last visit. Auto-PBSCT can be safely performed for Ph+ALL with TKIs. A limitation of auto-PBSCT was suggested, despite the increase in the intensity of a single treatment. The development of long-term therapeutic strategies by including new molecular targeted drugs is warranted to maintain long-term molecular remission.

A retrospective analysis of 124 patients with multiple myeloma who received up-front autologous hematopoietic cell transplantation following triplet induction therapy

The IFM/DFCI group reported that VRD induction followed by up-front autologous peripheral blood stem cell transplantation (ASCT) and maintenance therapy led to median PFS of 50 months, which established up-front ASCT as the standard of care even in the era of novel agents. We conducted a retrospective analysis on outcomes of patients who received triplet induction therapy followed by up-front ASCT at our institution. A total of 124 patients received ASCT between November 2016 and December 2021 at Japanese Red Cross Medical Center. Patient characteristics, treatment response before and after ASCT, and PFS and OS were retrospectively analyzed. VRD-based induction therapy was used for 94%. Among 118 evaluable patients, 116 (98%) received either consolidation and/or maintenance therapy. Best responses were ≥CR 77% and ≥VGPR 94%, respectively. Sixty-eight out of 104 patients achieved MRD-negativity by multiparameter FCM (<10-5). Five-year estimated PFS and OS were 54.7% and 80.2%, respectively. Age ≥65, high-risk cytogenetic abnormalities, and <VGPR before ASCT were identified as worse prognostic factors for PFS. Patients who achieved MRD negativity had significantly PFS (p=0.0048, 4-yr PFS 86.4% vs. 49.8%). The negative impact on PFS in the high-risk group can be overcome by achieving MRD-negativity. Prospective research is warranted to evaluate the effectiveness of consolidation therapy.

Effect of Body Mass Index on the Prognosis of Mantle Cell Lymphoma

To explore the correlation between different body mass index (BMI) and prognosis of mantle cell lymphoma (MCL). The clinical characteristics and biological indices of 108 patients with MCL treated in Fujian Medical University Union Hospital were retrospectively analyzed, and the effects of different BMI on overall survival (OS) and progression-free survival (PFS) were analyzed. The correlation between BMI and B symptoms, LDH and Ki-67 was further observed. Furthermore，the differences of BMI between Autologous peripheral blood stem cell transplantation(Auto-PBSCT) and conventional chemotherapy groups were explored. Among 108 patients, the median age at diagnosis was 59（25-79） years old, and the male to female ratio was 4.4∶1. 88.89% of patients with Ann Arbor staging III-IV, 63.89% with bone marrow involvement, and 49.07% with splenic infiltration. Patients with BMI ≥ 24 kg/m2 were divided into two groups: the high BMI group and the low BMI group. The 5-year PFS and OS of patients in the low BMI group were 31.9% and 47.0%, respectively, while those in the high BMI group were 64.6% and 68.7%, respectively. The incidence of death in the high BMI group was lower than that of the low BMI group (P＜0.01). In multivariate analysis, BMI was an independent predictor of PFS (HR=0.282; 95% CI: 0.122-0.651; P=0.003) and an independent predictor of OS (HR=0.299; 95% CI: 0.129-0.693; P=0.005). Also, patients with B symptoms had a lower BMI than those without B symptoms (P=0.01), but BMI had no effect on patients' LDH and Ki-67. The prognosis of 16 patients treated with Auto-PBSCT was significantly better than that of the conventional chemotherapy group. There was no significant difference in BMI between Auto-PBSCT group and conventional chemotherapy group. BMI is an independent prognostic factor for PFS and OS in MCL, and may be influenced by the effect of B symptoms on BMI.

Time-Series Reconstruction of CBC Profile of Pediatric Cancer Patients for Two Years after Hematopoietic Stem Cell Transplantation Using Language Programming

In this single center and retrospective study, we analyzed every single patient totaling 249 patients who was admitted and undergone hematopoietic stem cell transplantation (HSCT) at our institution from year 2013 to 2019. Twenty three patients were excluded mainly due to returning home country after HSCT without further follow up at our institution. We re-analyzed the remaining 226 patients (169 alive patients and 57 expired patients) and re-constructed time-series laboratory data of white blood cell (WBC) count (Figure 1), hemoglobin, platelet, absolute neutrophil count (ANC), monocytes number, blood urea nitrogen, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, lactate dehydrogenase (LDH), cyclosporine level, and/or tacrolimus level for up to two years since their last HSCT. These large sets of data were visualized by custom-written codes using language programming. We performed subgroup analysis of these patients' laboratory data according to the tumor type, which was grouped into acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), other types of leukemia not aforementioned, lymphoma, solid tumor, aplastic anemia and other diseases including neurologic disease or immunodeficiency. We also compared these patients' laboratory data according to immunosuppressant used (cyclosporine versus tacrolimus), and hematopoietic stem cell transplantation procedures employed (allogeneic peripheral blood stem cell transplantation (PBSCT), autologous PBSCT or bone-marrow transplantation). In all patients analyzed who remain alive after HSCT (male 100 patients (59%), female 69 patients (41%), the median WBC engraftment time was 13 days with interquartile range (IQR) of 11-15 days). Both WBC and ANC steadily increased after engraftment up to 400 days since HSCT and reached plateau level at 7,000cells/uL for WBC and 3,000cells/uL for ANC. Hemoglobin and platelet showed faster recovery time since HSCT as hemoglobin level of 12 g/dL and platelet count of 200x10^9/L both reached at 300 days since HSCT. Patients underwent HSCT due to the occurrence of solid tumor generally showed shorter WBC engraftment time of 11 days with IQR of 10-12 days while those with hematologic malignancy showed relatively longer WBC engraftment time of 14 days with IQR of 12-16 days. In subgroup analysis of hematologic malignancy categorized into ALL, AML, other leukemia not aforementioned and lymphoma, no significant differences in engraftment time or general trend over two-year time-course of WBC, ANC, hemoglobin and platelet. In sharp contrast, 57 patients who have expired since HSCT showed WBC recovery after engraftment - the median WBC engraftment time was 13 days with IQR of 11-16 days - up to 3,000cells/uL but the WBC count did not increase thereafter in the following two years. The hemoglobin and platelet plateau for these expired patients were markedly lower than those alive as hemoglobin level was maintained around 9 g/dL (Figure 2) and platelet count ranged from 50 to 90x10^9/L since HSCT. HSCT is not the end but the beginning of return to normal daily activities for many patients and vigilant long-term care of these patients is crucial not only for the patients but also for their families. As analogous to Fenton growth chart being used for premature babies and their parents to visually aid their growth progression at outpatient clinic, we aimed at constructing time-series laboratory data of HSCT patients since transplantation to serve as reference curves for HSCT patients at our institution with hope that these reference curves as a visual aid may better assist and assure those patients and their families with successful recovery and for those without successful course, early intervention and further treatment may be better understood and accepted by the patients and their families. Figure 1. Time course of white blood cell count for each patient after HSCT. Each line is color-coded differently and represents a single patient. Red curve is the median of all patients with error bars denoting interquartile range. Shaded area also represents interquartile range. Figure 2. Time course of hemoglobin trend for two years after HSCT. Median average of 169 alive patients' data (red) was compared with that of 57 expired patients (blue). Error bars represent interquartile ranges. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

How to Treat Isolated Leptomeningeal Relapse of Multiple Myeloma 11 Years after Autologous Stem Cell Transplantation (ASCT)

Post transplant relapse of Multiple Myeloma (MM) in the central nervous system (CNS) is rare and it is almost always associated with systematic relapse and in most instances, shortly after initial treatment. We did not encounter reports of relapse isolated to the CNS ten years post-transplant. In October 2009, a 49-year-old male presented with an IgG lambda MM, ISS II. He was treated with Bortezomib/Dexamethasone, autologous PBSCT, followed by two years maintenance with Lenalidomide, attaining stringent CR, confirmed by PET/CT. He discontinued follow up and returned after 11y/8m progression free survival, in June 2021 with paraplegia due to cauda equina syndrome. NMR consistent with leptomeningeal infiltration, single focal intramedullary lesion at L1 level without bone affectation. No MM defining criteria (CRAB). Normal levels of serum Immunoglobulins (IGs), serum and urine immunofixation, and serum free light chains. Flow cytometry negative in bone marrow. Spinal tap was unsuccessful and through an Ommaya reservoir, that was placed after NMR showed evidence of cranial leptomeningeal involvement, CSF showed infiltration by countless malignant plasma cells. Patient received immediate conformational radiotherapy and biweekly IT methotrexate and hydrocortisone. A month later his course was complicated by left leg proximal deep vein thrombosis and pulmonary embolism which was treated with Apixaban. Given the rarity of this type of relapse, we questioned the appropriateness of the treatment and searched the literature with respect to the accessibility of the CNS by the different novel drugs used to treat MM in order to determine the most effective strategy. In addition to corticosteroids, there is clinical evidence that thalidomide crosses the blood-brain barrier (BBB), in murine models pomalidomide also has good penetration into the CNS. Both have a penetration of 30 to 40% into the CSF. Among proteasome inhibitors, only marizomib has been observed to cross the BBB in a murine model, while bortezomib does not. With respect to anti CD38 monoclonal antibodies, mass spectrometry at 12, 15, and 19 days after daratumumab infusion showed antibody levels in CSF 71 times less than in serum on the three sample days. It is not known if weekly doses of daratumumab could attain therapeutic levels in CSF. We found only 14 cases of isolated CNS relapse in patients with MM treated with ASCT with a median interval between transplant and relapse of 3 months (0.5-96m), with only one reported relapse 7.5 years after autologous transplant and the median overall survival was only 3 months. Two cases died in less than a month and only one case survived for a year after the CNS relapse.To date, our patient has received 12 cycles of Pomalidomide/dexamethasone with progressive improvement, now he is able to carry on his life unassisted and there is no evidence of MM relapse anywhere. The rarity of this case scenario highlights the lack of knowledge regarding the best approach to CNS MM relapse. There is no evidence of the effectiveness of methotrexate and Ara C, in MM, and no novel drug can be instilled into the CSF. We conclude that the systemic use of pomalidomide and dexamethasone should be the best approach of MM isolated CNS relapse. Further investigations will clarify if other novel drugs are active in this context.

Clinical trial and translational research for cancer immunology in Asian countries: Understanding the new frontier.

e14510 Background: Among the major advances in cancer treatment is the progress in cancer immunotherapy; however, despite the strides, there is few information specific to the Asian population. It is unclear to what extent clinical trial and translational research in cancer immunology are conducted in Asian institutions. Methods: This questionnaire-based survey was conducted among researchers and healthcare professionals who are involved in cancer immunology research and therapeutics in Asia-Pacific countries. The study identified the involvement of respondents in various phases of clinical trials, and immunotherapy research. In addition, the current capabilities of the institutions to conduct translational research were surveyed. Results: We received a total of 122 responses from 20 Asia-Pacific countries. More than half (58%) of the responders are currently conducting clinical trials on cancer immunology with 25% having performed more than 10 Phase 3 trials in the last 3 years. In clinical trials and clinical practice, immune checkpoint inhibitors were performed in most countries (81.8% and 88.6%, respectively). Clinical trials and clinical practice of CAR-T and TCR-T were performed only in some countries (CAR-T; 22.7% and 15.9%, TCR-T; 2.3% and 0%, respectively). In the absence of novel therapeutics in their institution, 18% of the responders refer their patient to facilities that have ongoing clinical trials. Among the institutions that perform Hematopoietic stem cell transplant (55.1%), the most common type offered include autologous (81.3%) and allogenic (70.8%) peripheral blood stem-cell transplantation. About 51.7% of the respondents have institutions that can conduct early drug phase development studies with only 11.2% capable of utilizing their own immunotherapeutic agents. Less than half of the respondents (40.7%) belong to institutions that have conducted translational researches using patient-derived samples for the last three years. Furthermore, more than half of the respondent institutions have no personnel that is experienced to handle and/or run patient-derived fresh peripheral blood or fresh tumors. Collaboration among neighboring countries can allow send out of specimens to other institutions that have such capability, however, 56.9% of countries have regulations or restrictions in transporting lymphocytes or tumor tissues. Conclusions: Oncologists and researchers in Asia recognize the importance of cancer immunology researches for patients. There were institutional and inter-country differences particularly in the conduct of early phase clinical drug development and translational research.

Survival and prognostic analysis of T-cell lymphoblastic lymphoma patients treated with dose-adjusted BFM-90 regimen.

We aimed to investigate the long-term prognosis and prognostic factors of T-cell lymphoblastic lymphoma (T-LBL) patients who received dose-adjusted Berlin–Frankfurt–Münster (BFM)-90 regimen as first-line therapy in our center. A total of 145 T-LBL patients who underwent first-line dose-adjusted BFM-90 was retrospectively reviewed. Conditional survival analysis was used to evaluate the long-term prognosis of patients. Receiver operating characteristic (ROC) curve was applied to determine the optimal cut-off value for neutrophil-to-lymphocyte ratio (NLR). Estimated 3-year overall survival (OS) and progression-free survival (PFS) rates for overall were 66.8% and 58.4%, respectively. Conditional survival analysis showed that for patients having survived 3 and 5 years or more after the completion of the treatment, the estimated subsequent 3-year OS thereafter increased to 85.7% and 94.3, respectively. Patients receiving consolidation APBSCT (Autologous peripheral blood stem cell transplantation) after BFM-90 regimen had superior 3-year OS than those with non-APBSCT (79.1% vs. 33.4%, p<0.001). We also discovered that baseline NLR ≥4.95 was negatively associated with OS (HR=2.75, 95% CI 1.55-4.89, p=0.015) and PFS (HR=2.07, 95% CI 1.25-4.96, p=0.021) via multivariable analysis. Conclusions: The survival probability of T-LBL patients treated with first-line dose-adjusted BFM-90 has improved significantly as patients have survived for every additional year. The addition of consolidation APBSCT following dose-adjusted BFM-90 therapy bring further survival benefits for those patients. Baseline NLR ≥4.95 was an independent risk factor for T-LBL patients in our study.

Dose-enhanced immunochemotherapy followed by first-line autologous peripheral blood stem cell transplantation for young patients with high-risk aggressive B-cell lymphoma: an efficacy and prognostic factor analysis

目的探讨增强剂量免疫化疗联合自体外周血造血干细胞移植（ASCT）治疗初治、年轻、高危侵袭性B细胞淋巴瘤患者的疗效及预后因素。方法回顾性分析2011年1月至2018年12月在中国医学科学院血液病医院应用增强剂量免疫化疗联合ASCT治疗的63例初治、年轻、高危侵袭性B细胞淋巴瘤患者的临床和生存资料。结果63例患者的中位年龄为40（14～63）岁。诱导治疗方案包括R-DA-EP(D)OCH（52例）和R-HyperCVAD/R-MA（11例）。16例（25.4％）患者中期疗效评估为部分缓解，其中10例移植后获得完全缓解。中位随访50（8～112）个月，3年无进展生存（PFS）率和总生存（OS）率分别为（83.9±4.7）％和（90.4±3.7）％。单因素分析显示年龄调整的国际预后指数评分≥2分是影响OS的预后不良因素（P＝0.039），骨髓受累（BMI）是影响OS（P<0.001）和PFS（P＝0.001）的预后不良因素。多因素分析显示BMI是OS（P＝0.016）和PFS（P＝0.001）的唯一独立预后不良因素。结论一线应用增强剂量免疫化疗联合ASCT治疗年轻、高危侵袭性B细胞淋巴瘤可获得良好的长期疗效，BMI为不良预后因素。

HIV-negative plasmablastic lymphoma sustaining long-term response after autologous peripheral blood stem cell transplantation

The patient is a 34-year-old HIV antibody-negative female with normal immunocompetence. The patient was referred to the hospital of the current study due to diarrhea and abdominal pain, which developed in May 2014. On conducting computed tomography (CT), remarkable wall thickening was noted in the terminal ilium over the ascending colon, suggesting a malignant tumor. However, making a definite diagnosis by lower gastrointestinal endoscopic biopsy and left hemicolectomy was not possible. The dense proliferation of plasma cell-like cells and plasmablasts was noted; CD20, CD19, CD79a, CD3, CD4, and Epstein-Barr virus-encoded miRNAs (EBER) were negative and CD138 was positive on immunostaining. Based on the aforementioned data, the patient was diagnosed with plasmablastic lymphoma (PBL). High-dose chemotherapy combined with autologous peripheral blood stem cell transplantation (PBSCT) was performed in the first remission period after the completion of four cycles of hyper CVAD/MTX-AraC alternating therapy. Remission was confirmed by FDG-PET/CT 3 months after autologous PBSCT. No signs of recurrence have been observed in 6 years after the transplantation. Although no standard treatment for PBL has been established, autologous peripheral blood stem cell transplantation combined with high-dose chemotherapy during the first remission period may be a beneficial treatment option.

Real-world Experience of Improvement in the Survival of Lymphoma and Myeloma Patients with Autologous Stem Cell Transplantation over a 25-year Period

Background/Aims: The first autologous peripheral blood stem cell transplantation (ASCT) in Korea was performed for a small-cell lung cancer patient at Asan Medical Center (AMC) in 1993. Recently, lymphoma and myeloma have been the main indications; there has been progress in the treatments for these lymphoid malignancies. We explored the real-world experience of ASCT for lymphoma and myeloma at AMC over a 25-year period.Methods: We used the AMC ASCT registry, which has collected ASCT data prospectively since January 1993. Data for Hodgkin lymphoma, non-Hodgkin lymphoma, and multiple myeloma patients were analyzed. Patients transplanted up to December 2018 were included to assess adequate survival data. The ASCT time period was divided arbitrarily into 1994-1999, 2000-2009, and 2010-2018. In cases of multiple myeloma, we analyzed the 1st ASCT data only.Results: Survival of these lymphoid malignancy patients after ASCT has progressively improved. The increase in survival may be related to advances in various medical skills supporting ASCT. However, overall survival has improved much more than progression-free survival. This suggests that better salvage therapies after ASCT failure have mainly affected the improvement in overall survival. The hematopoietic cell transplantation-specific comorbidity index could not be used as a survival indicator in this analysis.Conclusions: This real-world experience study showed that the survival of lymphoid malignancy patients treated with ASCT has improved over the past 25 years.

A Randomized Study Comparing the Effects of G-CSF and G-CSF/GM-CSF for the Mobilization of Peripheral Blood Stem Cells by Mitoxantrone and High-Dose Cytarabine Chemotherapy

We investigated the efficiency of mitoxantrone (MIT) and high-dose cytarabine (Ara-C) chemotherapy followed by G-CSF and G-CSF/GM-CSF treatments for the mobilization of peripheral blood stem cells (PBSCs) in patients with leukemia and lymphoma. MIT was intravenously injected at 10 mg/(m2·d) for 2 to 3 days, followed by Ara-C injected intravenously at 2 g/m2 every 12 hours for 1 to 2 days. When white blood cell count recovered from the lowest value, 5 to 7.5 μg/ (kg·d) G-CSF was administered in 23 patients for 5 to 7 successive days. Another 27 patients received 3-5 μg/ (kg·d) G-CSF and 3-5μg/ (kg·d) GM-CSF. Autologous peripheral blood mononuclear cells were collected. Levels of CFU-GM and CD34+ cells were determined after unfreezing. The CD34+ cells and CFU-GM yields of 27 patients in G-CSF plus GM-CSF combination group [(8.79±3.11)×106/kg, (3.52±1.34)×105/kg, respectively] were significantly higher than those of patients receiving G-CSF alone (n=23) [(6.14±2.06)×106/kg, (2.03±1.06)×105/kg, respectively (P &lt; 0.05)]. No obvious changes of T lymphocyte subsets in patients were observed when using G-CSF/GM-CSF, but levels of CD34+ cells increased gradually (P&gt;0.05). The end-point separation blood volume was all above trebling TBV. No severe complications were observed during the mobilization and collection. Autologous PBSCT obtained quick hematopoietic reconstitution. In conclusion, MA chemotherapy combined with G-CSF alone and G-CSF/GM-CSF can safely and effectively mobilize autologous PBSCs, while G-CSF plus GM-CSF is superior to G-CSF alone. Large volume leukapheresis is an important method to enhance the production rate of stem cells and decrease harvesting time.

Prophylactic Peripheral Blood Stem Cell Collection in Patients with Extensive Bone-Marrow Infiltration of Neuroendocrine Tumours Prior to Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE.

Peptide receptor radionuclide therapy (PRRT) of metastatic neuroendocrine tumors (NET) can be successfully repeated but may eventually be dose-limited. Since 177Lu-DOTATATE dose limitation may come from hematological rather than renal function, hematological peripheral blood stem cell backup might be desirable. Here, we report our initial experience of peripheral blood stem-cell collection (PBSC) in patients with treatment-related cytopenia and therefore high risk of bone-marrow failure. Five patients with diffuse bone-marrow infiltration of NET and relevant myelosuppression (≥grade 2) received PBSC before one PRRT cycle with 177Lu-DOTATATE (7.6 ± 0.8 GBq/cycle). Standard stem-cell mobilization with Granulocyte-colony stimulating factor (G-CSF) was applied, and successful PBSC was defined as a collection of >2 × 106/kg CD34+ cells. In case of initial failure, Plerixafor was administered in addition to G-CSF prior to apheresis. PBSC was successfully performed in all patients with no adverse events. Median cumulative activity was 44.8 GBq (range, 21.3–62.4). Three patients had been previously treated with PRRT, two of which needed the addition of Plerixafor for stem-cell mobilization. Only one of five patients required autologous peripheral blood stem-cell transplantation during the median follow up time of 28 months. PBSC collection seems to be feasible in NET with bone-marrow involvement and might be worth considering as a backup strategy prior to PRRT, in order to overcome dose-limiting bone-marrow toxicity.

MM-254: Autologous Hematopoietic Stem Cell Transplantation in Elderly Patients with Multiple Myeloma as a Standard Therapeutic Procedure. Is it Feasible? Single Center Experience

Context Autologous peripheral blood stem cell transplant (PBSCT) ideally should be performed in every myeloma patient, but in the elderly, the procedure might be risky because of comorbidities, and the possibility of the organism to fully compensate possible complications. Objective Our main goal was to show that the age limit for autologous PBSCT in myeloma patients can be safely shifted upwards. Design We used conditioning with melphalan, followed by autologous PBSCT for elderly patients with myeloma, using the age limit of 65 years. Setting All patients were transplanted in the bone marrow transplant unit in the University Clinic for Hematology Skopje. They underwent standard post-transplant preventive and prophylactic measures during the period of pancytopenia. Patients or Other Participants We have done a retrospective analysis of patients with MM where autologous SCT was done. The main inclusion criteria was the diagnosis, age over 65, acceptable comorbidity profile. Interventions Mobilizing and harvesting of stem cells, melphalan conditioning, and application of the graft via central venous catheter were standard for all patients. Main Outcomes Measures We evaluated the rates of transplant related mortality (TRM), post-transplant follow-up, complete remission (CR). Results Our analysis of data for 20 years shows that we performed autologous PBSCT on 25 patients with myeloma at the age of 65 or older. 17 males (68%) and 8 female (32%). Average age was 67 years (65-73). All patients received melphalan conditioning. In 23 of the patients, we used non-cryopreserved hematopoietic stem cells. In two patients we performed tandem autologous PBSCT with no major complications. 75% had HTA, 20% some level of cardiomyopathy, 48% diabetes, and 12% with inserted prosthetic aortic valves. Our oldest patient was 73 years old and was still alive 2 years posttransplant. Our transplant related mortality was 0%. Conclusions Autologous PBSCT in elderly myeloma patients can be safe and effective, with careful selection of patients, balancing the risk profile of the patient, and the benefit of the procedure. Affective supportive care, monitoring, and reducing the risk of complications is an imperative to a good result. Autologous peripheral blood stem cell transplant (PBSCT) ideally should be performed in every myeloma patient, but in the elderly, the procedure might be risky because of comorbidities, and the possibility of the organism to fully compensate possible complications. Our main goal was to show that the age limit for autologous PBSCT in myeloma patients can be safely shifted upwards. We used conditioning with melphalan, followed by autologous PBSCT for elderly patients with myeloma, using the age limit of 65 years. All patients were transplanted in the bone marrow transplant unit in the University Clinic for Hematology Skopje. They underwent standard post-transplant preventive and prophylactic measures during the period of pancytopenia. We have done a retrospective analysis of patients with MM where autologous SCT was done. The main inclusion criteria was the diagnosis, age over 65, acceptable comorbidity profile. Mobilizing and harvesting of stem cells, melphalan conditioning, and application of the graft via central venous catheter were standard for all patients. We evaluated the rates of transplant related mortality (TRM), post-transplant follow-up, complete remission (CR). Our analysis of data for 20 years shows that we performed autologous PBSCT on 25 patients with myeloma at the age of 65 or older. 17 males (68%) and 8 female (32%). Average age was 67 years (65-73). All patients received melphalan conditioning. In 23 of the patients, we used non-cryopreserved hematopoietic stem cells. In two patients we performed tandem autologous PBSCT with no major complications. 75% had HTA, 20% some level of cardiomyopathy, 48% diabetes, and 12% with inserted prosthetic aortic valves. Our oldest patient was 73 years old and was still alive 2 years posttransplant. Our transplant related mortality was 0%. Autologous PBSCT in elderly myeloma patients can be safe and effective, with careful selection of patients, balancing the risk profile of the patient, and the benefit of the procedure. Affective supportive care, monitoring, and reducing the risk of complications is an imperative to a good result.

Correlation between peripheral blood automated hematopoietic progenitor cell counts and flow cytometric CD34+ cell counts differs according to diagnosis in patients undergoing autologous peripheral blood stem cell transplantation.

An automated hematopoietic progenitor cell count measurement in Sysmex XN analyzer (XN-HPC) has been developed to assist flow cytometry CD34+ cell count measurement, which requires technical expertise and a long turnaround time. Here, we evaluated the correlation between XN-HPC count and flow cytometric CD34+ cell count in pre-harvest peripheral blood (PB) samples from patients undergoing autologous peripheral blood stem cell (PBSC) transplantation according to diagnosis and investigated the possible cause of the decreased correlation in plasma cell neoplasm patients. We retrospectively included 399 patient data that had matched PB XN-HPC count and CD34+ cell count of PB and apheresis product from Samsung Medical Center (SMC) and the Hematopoietic Stem Cell (HSC) registry. We assessed the diagnostic accuracy and the potential cutoff values of XN-HPC count for predicting adequate PBSC collection. The PB XN-HPC count was 1.6 and 1.3-fold higher than the CD34+ cell count in SMC (25.0 vs 15.9/μl) and the HSC registry (20.0 vs 15.2/μl), respectively. Overall the correlation between the PB XN-HPC and CD34+ cell count was moderate (SMC, r=0.71; HSC registry, r=0.66). A significant proportional and systemic bias with overestimation of XN-HPC count were noted in the plasma cell neoplasm patients in both SMC and the HSC registry. However, no significant difference in correlation was observed according to myeloma-related laboratory parameters in plasma cell neoplasm patients. Our results suggest that XN-HPC count should be interpreted cautiously in cancer patients undergoing autologous PBSC transplantation, especially in those with plasma cell neoplasm.