ABSTRACT
BACKGROUND: Isatuximab, an anti-CD38 antibody, has been widely used in treatments for patients with relapsed/refractory multiple myeloma (MM). Despite its high efficacy, not all patients achieve a lasting therapeutic response with isatuximab. OBJECTIVE: We tried to identify biomarkers to predict the effectiveness of isatuximab by focusing on the host's immune status before treatment. METHODS: We retrospectively analyzed the cases of 134 relapsed/refractory MM patients in the Kansai Myeloma Forum database who had received only a first isatuximab treatment. RESULTS: Among the 134 patients, an isatuximab, pomalidomide and dexamethasone (Isa-PD) regimen, isatuximab, carfilzomib and dexamethasone (Isa-KD) regimen and isatuximab and/or dexamethasone (Isa-D) regimen were used in 112, 15 and 7 patients, respectively. The median age at treatment, number of prior treatment regimens, and progression-free survival (PFS) were 71, 6, and 6.54 months, respectively. Multivariate analysis showed that the PFS under the Isa-PD regimen was longer in patients with higher lymphocyte/monocyte ratio (LMR ≥ 4), fewer prior treatment regimens (< 6), and no use of prior daratumumab treatment. The OS under the Isa-PD regimen was longer in patients with higher white blood cell counts (WBC counts ≥ 3000/µL) and higher LMR. The PFS under the Isa-D regimen was longer in patients with fewer prior treatment regimens in univariate analysis, but no parameters were correlated with PFS/OS under the Isa-KD regimen. CONCLUSION: We found that the patients with higher LMR (≥ 4) could obtain longer PFS and OS under the Isa-PD regimen. Other cohort studies of isatuximab treatment might be necessary to substantiate our results.
Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Lymphocytes , Monocytes , Multiple Myeloma , Thalidomide , Humans , Multiple Myeloma/drug therapy , Multiple Myeloma/mortality , Female , Male , Thalidomide/analogs & derivatives , Thalidomide/therapeutic use , Thalidomide/administration & dosage , Aged , Middle Aged , Retrospective Studies , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Monocytes/immunology , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Adult , Aged, 80 and over , PrognosisABSTRACT
Haploidentical hematopoietic cell transplantation (HCT) using glucocorticoids for acute graft-versus-host disease prophylaxis (GC-haplo) may become a curative treatment option for nonremission acute myeloid leukemia (AML). This retrospective study aimed to identify pre-HCT predictors of survival in a cohort of 97 nonremission AML treated with GC-haplo in Hyogo Medical University Hospital between 2010 and 2020. Relapse and primary induction failure included in 70 (72%) and 27 (28%) patients, respectively. Sixty-one patients (63%) had undergone previous HCT. Multivariate analysis revealed that ≤ 6 months' duration between first complete remission (CR1) and first relapse (Rel1) (CR1-Rel1 interval) (hazard ratio 2.11, 95% confidence interval [CI] 1.15-3.89, P = 0.016) and serum albumin before starting the conditioning treatment of ≤ 3.5 g/dL (hazard ratio 1.80, 95%CI 1.09-2.96, P = 0.022) as risk factors for overall survival. Among three groups categorized according to serum albumin and CR1-Rel1 interval, the best 3-year overall survival was observed in patients with albumin > 3.5 g/dL and CR1-Rel1 interval > 6 months or primary induction failure (50.2%, 95%CI 28.9%-68.3%, P < 0.001), revealing that survival could be predicted using albumin and past CR duration in patients with very high-risk AML not in remission before GC-haplo.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Humans , Transplantation, Haploidentical/adverse effects , Retrospective Studies , Remission Induction , Graft vs Host Disease/etiology , Graft vs Host Disease/prevention & control , Recurrence , Serum Albumin , Steroids/therapeutic use , Transplantation ConditioningABSTRACT
The impact of absolute neutrophil count (ANC) before allogenic hematopoietic stem cell transplantation (HSCT) on the outcomes for patients with aplastic anemia (AA) remains unclear. We retrospectively evaluated the relationship between ANC before transplantation and patient outcomes, involving 883 adult Japanese patients with AA who underwent allogeneic HSCT as their first transplantation between 2008 and 2020. Patients were divided into three groups based on ANC: 0/µL (n = 116); 1-199 (n = 210); and ≥ 200 (n = 557). In the low ANC groups (ANC < 200), patient age was higher, previous anti-thymocyte globulin (ATG) treatments were infrequent, duration from diagnosis to transplantation was shorter, hematopoietic cell transplantation-comorbidity index (HCT-CI) was higher, ATG-based conditioning was used infrequently, and peripheral blood stem cell from related donor and cord blood were used frequently. In multivariate analysis, patient age, previous ATG treatment, HCT-CI, stem cell source, and ANC before transplantation were significantly associated with 5-year overall survival (OS) ("ANC ≥ 200": 80.3% vs. "ANC 1-199": 71.7% vs. "ANC 0": 64.4%). The cumulative incidence of bacterial infection, invasive fungal disease, and early death before engraftment were significantly higher in the low ANC groups. Among patients with ANC of zero before transplantation, younger patient age, shorter duration from diagnosis to transplantation, HCT-CI of 0, and bone marrow from related donor as stem cell source were significantly associated with better OS. Consequently, ANC before allogeneic HSCT was found to be a significant prognostic factor in adult patients with AA. Physicians should pay attention to ANC before transplantation.
Subject(s)
Anemia, Aplastic , Hematopoietic Stem Cell Transplantation , Neutrophils , Humans , Anemia, Aplastic/therapy , Anemia, Aplastic/mortality , Anemia, Aplastic/blood , Adult , Male , Female , Middle Aged , Retrospective Studies , Adolescent , Young Adult , Aged , Leukocyte Count , Antilymphocyte Serum/therapeutic use , Survival Rate , Transplantation, Homologous , Transplantation Conditioning , AllograftsABSTRACT
Elotuzumab-based regimens are sometimes selected for multiple myeloma treatment after daratumumab-based regimens. However, there has been insufficient discussion on the efficacy of elotuzumab after daratumumab. We used Kansai Myeloma Forum registration data in a multicenter retrospective evaluation of the efficacy of elotuzumab after daratumumab. Overall survival (OS) rate and time to next treatment (TTNT) were significantly worse in the cohort given elotuzumab after daratumumab (Dara cohort, n = 47) than in the cohort with no history of daratumumab administration before elotuzumab (No-Dara cohort, n = 80, OS: P = 0.03; TTNT: P = 0.02; best response: P < 0.01). In the Dara cohort, OS and TTNT rates were worse with sequential elotuzumab use after daratumumab than with non-sequential (OS: P = 0.02; TTNT: P = 0.03). In patients given elotuzumab < 180 days after daratumumab, OS (P = 0.08) and best response (P = 0.21) tended to be worse, and TTNT was significantly worse (P = 0.01), than in those given elotuzumab after ≥ 180 days. These findings were confirmed by subgroup analyses and multivariate analyses. Monoclonal-antibody-free treatment might be preferable after daratumumab-based regimens. If possible, elotuzumab-based regimens should be considered only ≥ 180 days after daratumumab use.
ABSTRACT
BACKGROUND AND OBJECTIVES: ABO blood group mismatch between the donor and the recipient can affect the success of the transplant as well as problems with the red blood cells during allogeneic haematopoietic cell transplantation (HCT). However, the impact of the Rhesus (Rh) D mismatch on transplant outcomes in allogeneic HCT has been poorly elucidated. MATERIALS AND METHODS: We retrospectively evaluated the impact of the RhD mismatch on post-transplant outcomes in 64,923 patients who underwent allogeneic HCT between 2000 and 2021 using a Japanese registry database. RESULTS: Out of the whole group, 64,293, 322, 270 and 38 HCTs were done when the recipient or donor was RhD-mismatched with (+/+), (-/+), (+/-) or (-/-) combinations. The difference in RhD between recipient/donor (-/+), (+/-) and (-/-) did not affect haematopoietic recovery, acute and chronic graft-versus-host disease (GVHD), overall survival (OS), non-relapse mortality (NRM) or relapse when RhD (+/+) was used as the reference group in multivariate analysis. CONCLUSION: Our registry-based study demonstrated that RhD mismatch between recipient and donor did not significantly impact haematopoietic recovery, GVHD, OS, NRM or relapse after allogeneic HCT. These data suggest that RhD mismatches may not need to be avoided for recipient and donor combinations in allogeneic HCT.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Registries , Rh-Hr Blood-Group System , Humans , Female , Male , Graft vs Host Disease/mortality , Adult , Middle Aged , Japan , Retrospective Studies , Adolescent , Blood Group Incompatibility , Transplantation, Homologous , Child , Child, Preschool , Infant , East Asian PeopleABSTRACT
Hematopoietic cell transplantation (HCT) for hematologic malignancies with non-remission disease and/or prior post-transplant relapse have poor relapse-free survival. We previously demonstrated the efficacy of haploidentical reduced-intensity HCT regimen with glucocorticoid-based graft-versus-host disease (GVHD) prophylaxis. We recently showed a possible association between rabbit antithymocyte globulin (rATG) exposure and acute GVHD (aGVHD) risk, leading to hypothesize that optimization of rATG exposure may further improve this regimen. We retrospectively examined the exposure-response association of rATG and key clinical outcomes post haploidentical HCT. We subsequently developed an individualized rATG dosing that optimizes rATG exposure using a previously developed population pharmacokinetic model. Of the 103 patients analyzed, the median age was 47 years (range: 17-70) and majority had a non-remission disease prior to HCT (88%). rATG concentration on day 0 of HCT (Cday_0 ) was the strongest predictor of Grade 2-4 aGVHD through day +100. Patients with Cday_0 ≥ 20 µg/mL had an approximately 3-fold lower risk of Grade 2-4 aGVHD (hazard ratio [HR]: 0.32, 95% confidence interval [CI]: 0.16, 0.62) and Grade 3-4 aGVHD (HR: 0.33, 95% CI: 0.16, 0.68) as well as an approximately 2-fold lower risk of overall mortality (HR: 0.47, 95% CI: 0.28, 0.77) and relapse (HR: 0.50, 95% CI: 0.26, 0.94). In conclusion, this reduced-intensity haploidentical HCT regimen with exposure-optimized rATG may provide a promising option to patients undergoing high-risk HCT for hematologic malignancy. The developed rATG dosing warrant prospective validation.
Subject(s)
Antilymphocyte Serum , Hematologic Neoplasms , Hematopoietic Stem Cell Transplantation , Adult , Humans , Middle Aged , Antilymphocyte Serum/therapeutic use , Graft vs Host Disease/etiology , Graft vs Host Disease/prevention & control , Hematologic Neoplasms/drug therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Neoplasm Recurrence, Local/drug therapy , Recurrence , Retrospective Studies , Transplantation Conditioning , Adolescent , Young Adult , AgedABSTRACT
Recently, more than 200 live births following ovarian tissue cryopreservation (OTC) and transplantation in cancer survivors have been reported worldwide. However, cancer survivors with minimal residual disease (MRD) in cryopreserved ovarian tissue are at the risk of relapse through the graft. Here, we report a rare case of a 19-year-old female patient with non-Hodgkin lymphoma who had MRD in the ovary harvested for OTC. The patient was diagnosed with aggressive B-cell lymphoma after gingival biopsy. The 18F-fluoro-2-deoxy-D-glucose positron emission tomography scan performed before OTC showed no viable lesions in either ovary. However, on histological evaluation, we detected infiltration of lymphoma cells in the ovary. Informed consent about MRD is required even if there is no evidence of MRD in the ovary before OTC. Patients whose cryopreserved ovaries have MRD may require the development of alternative assisted reproductive technologies such as in vitro growth or artificial ovary.
Subject(s)
Lymphoma, Non-Hodgkin , Ovary , Female , Humans , Young Adult , Adult , Gingiva , Neoplasm, Residual , Neoplasm Recurrence, Local , Lymphoma, Non-Hodgkin/diagnosis , CryopreservationABSTRACT
OBJECTIVE: CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy provides a durable response in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). The role of fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for early evaluation of response in patients with that immunotherapy was evaluated. SUBJECTS AND METHODS: Three separate 18F-FDG PET/CT examinations of 53 patients (29 males, 24 females; median 62 years old) with R/R DLBCL were conducted; before bridging therapy [time of decision (TD)], before CAR-T (tisagenlecleucel, n=37; lisocabtagenemaraleucel, n=16) infusion [time of CAR-T infusion (IT)], and one month (M1) after CAR-T infusion. Response was evaluated based on the Deauville 5-point scale and Lugano criteria. RESULTS: Among 21 patients (39.6%) with complete metabolic response (CMR) at IT-PET, 20 were able to continue CMR, while one showed progression at M1-PET. Among 32 patients (60.4%) with non-CMR at IT-PET, 12, 8, 4, and 8 showed CMR, partial metabolic response (PMR), (non-metabolic response (NMR), and progressive metabolic disease (PMD), respectively, at M1-PET as compared with IT-PET. Evaluations of M1-PET as compared with baseline TD-PET indicated 32, 7, 5, and 9 patients with CMR, PMR, NMR, and PMD, respectively. After a median 10.1 months, 26 patients showed progression and 13 had died from DLBCL. The 32 who achieved CMR showed significantly longer progression-free (P<0.0001) and overall survival (P<0.0001) periods as compared to the 21 non-CMR patients. CONCLUSION: Fluorine-18-FDG PET/CT findings obtained one month after CAR-T cell therapy showed accuracy for early response evaluation and prediction of progression in patients with R/R DLBCL.
Subject(s)
Fluorodeoxyglucose F18 , Immunotherapy, Adoptive , Lymphoma, Large B-Cell, Diffuse , Positron Emission Tomography Computed Tomography , Humans , Male , Female , Middle Aged , Lymphoma, Large B-Cell, Diffuse/diagnostic imaging , Lymphoma, Large B-Cell, Diffuse/therapy , Treatment Outcome , Aged , AdultABSTRACT
For successful chimeric antigen receptor T (CAR-T) cell therapy, CAR-T cells must be manufactured without failure caused by suboptimal expansion. In order to determine risk factors for CAR-T cell manufacturing failure, we performed a nationwide cohort study in Japan and analysed patients with diffuse large B-cell lymphoma (DLBCL) who underwent tisagenlecleucel production. We compared clinical factors between 30 cases that failed (7.4%) with those that succeeded (n = 378). Among the failures, the proportion of patients previously treated with bendamustine (43.3% vs. 14.8%; p < 0.001) was significantly higher, and their platelet counts (12.0 vs. 17.0 × 104 /µL; p = 0.01) and CD4/CD8 T-cell ratio (0.30 vs. 0.56; p < 0.01) in peripheral blood at apheresis were significantly lower than in the successful group. Multivariate analysis revealed that repeated bendamustine use with short washout periods prior to apheresis (odds ratio [OR], 5.52; p = 0.013 for ≥6 cycles with washout period of 3-24 months; OR, 57.09; p = 0.005 for ≥3 cycles with washout period of <3 months), low platelet counts (OR, 0.495 per 105 /µL; p = 0.022) or low CD4/CD8 ratios (Subject(s)
Lymphoma, Large B-Cell, Diffuse
, Receptors, Chimeric Antigen
, Humans
, Receptors, Chimeric Antigen/therapeutic use
, T-Lymphocytes
, Cohort Studies
, Japan/epidemiology
, Bendamustine Hydrochloride/therapeutic use
, Receptors, Antigen, T-Cell/therapeutic use
, Lymphoma, Large B-Cell, Diffuse/drug therapy
, Immunotherapy, Adoptive
, Risk Factors
ABSTRACT
OBJECTIVES: This study aimed to investigate real-world data of ixazomib plus lenalidomide and dexamethasone (IRd) therapy for patients with relapsed and refractory multiple myeloma (RRMM). METHODS: We retrospectively analyzed 122 patients treated with IRd at 16 centers from May 2017 to January 2019 by using the Kansai Myeloma Forum database. RESULT: At the start of IRd, the median age was 72 years, 66.7% of patients had IgG type, and the median number of prior therapies was 4, comprising bortezomib (85.4%) and lenalidomide (89.3%)-based regimens. Disease progression and adverse events accounted for treatment discontinuation in 46 and 32 patients, respectively. The median overall survival (OS) was not reached, and the median progression-free survival (PFS) was 11.9 months. Sensitivity to bortezomib did not affect the PFS, whereas lenalidomide-refractory patients had significantly lower PFS than lenalidomide-sensitive patients, who were comparable to TOURMALINE-MM1 study. The patients with IgG type had significantly better PFS and OS than those with non-IgG type. CONCLUSION: This study presents the largest real-world data of patients treated with IRd in Asia. However, in real clinical practice, the patient background is different from the TOURMALINE-MM1 study, and IRd showed poor efficacy, especially in the non-IgG type and lenalidomide-refractory patients with RRMM.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Multiple Myeloma/drug therapy , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers, Tumor , Boron Compounds/administration & dosage , Dexamethasone/administration & dosage , Female , Glycine/administration & dosage , Glycine/analogs & derivatives , Humans , Kaplan-Meier Estimate , Lenalidomide/administration & dosage , Male , Middle Aged , Multiple Myeloma/diagnosis , Multiple Myeloma/etiology , Multiple Myeloma/mortality , Neoplasm Staging , Prognosis , Retreatment , Retrospective Studies , Treatment OutcomeABSTRACT
OBJECTIVES: To determine the impact of the use of hydroxyethyl starch (HES) in granulocyte apheresis using Spectra Optia. BACKGROUND: Granulocyte transfusion (GT) is a therapeutic option for neutropenic patients with severe bacterial or fungal infections. Recent studies in emergency medicine have shown the potential risk of using HES, which is routinely used in granulocyte apheresis to increase yield by sedimenting red blood cells. We hypothesized that the use of a newer device (Spectra Optia) would spare the need for HES. METHODS: We retrospectively compared granulocyte apheresis with HES (HES group, n = 89) and without HES (non-HES group, n = 36) using Spectra Optia. RESULTS: The granulocyte yield was significantly higher in the HES group (7.3 × 1010 vs. 2.0 × 10, p < 0.01) and was attributed to the difference in collection efficiency (36% vs. 7.7%, p < 0.01). The absolute neutrophil count on the following morning of GT was significantly higher in the HES group than in the non-HES group (2460/µl vs. 505/µl, p < 0.01). There were no significant differences in the occurrence of adverse events between the HES and non-HES groups. The renal function was unchanged in both groups after apheresis. CONCLUSIONS: We demonstrated that the advantage of using HES remained unchanged in granulocyte apheresis using Spectra Optia.
Subject(s)
Blood Component Removal , Granulocytes , Humans , Leukocyte Transfusion , Retrospective Studies , StarchABSTRACT
PURPOSE: To determine the earliest optimal timing for assessment of early response following radioimmunotherapy in non-Hodgkin lymphoma patients using FDG-PET/CT. METHODS: FDG-PET/CT was performed prior to treatment (PET1), at 2 (PET2) weeks, and at 6 (PET3) weeks after 90Y-ibritumomab radioimmunotherapy in 55 patients. Response was evaluated based on the Deauville 5-point scale and Lugano criteria as well as semiquantitative analysis and compared with progression-free survival (PFS). RESULTS: PET 2 showed complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD) in 33, 13, 6, and 3 patients, respectively, while PET 3 in 41, 8, 3, and 3 patients, respectively. Mean SUVmax of 168 target lesions decreased over time (PET1, 2, 3; 5.58 ± 2.58, 1.87 ± 1.78, 1.75 ± 2.25, respectively). Progression or recurrence after a median of 12.6 months (range 2.6-72.0 months) was seen in 44 patients. Patients with CMR or metabolic response (CMR + PMR) on PET2 showed significantly longer PFS as compared to those who did not (p = 0.00028 and p = 0.029, respectively). A similar significant difference was observed based on PET3 (p = 0.00013 and p = 0.017, respectively). The same trend was observed when analyzing only the subgroup of patients with follicular lymphoma (N = 43/55) (p < 0.0001). CONCLUSION: Use of FDG-PET/CT findings with Lugano criteria for assessing early response to radioimmunotherapy after 6 weeks allowed for accurate evaluation and prognostic stratification, though scanning after 2 weeks was too soon to precisely evaluate response. KEY POINTS: ⢠The optimal timing of FDG-PET/CT to obtain a suitable tool for assessment of response after 90 Y-ibritumomab radioimmunotherapy of lymphoma has not yet been defined. ⢠Assessment after 6 weeks by FDG-PET/CT using the Lugano criteria accurately evaluates treatment response and prognosis. ⢠FDG-PET/CT performed 2 weeks after radioimmunotherapy is too early as it significantly misses objective responses.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Lymphoma, B-Cell/drug therapy , Positron Emission Tomography Computed Tomography/methods , Radioimmunotherapy/methods , Radionuclide Imaging/methods , Adult , Aged , Aged, 80 and over , B-Lymphocytes , Disease Progression , Female , Fluorodeoxyglucose F18/administration & dosage , Humans , Lymphoma, B-Cell/diagnostic imaging , Male , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Prospective StudiesABSTRACT
BACKGROUND: Human leukocyte antigen (HLA) mismatch and the administration of immunosuppressive agents are considered risks for human herpesvirus 6 (HHV-6) reactivation after stem cell transplantation (SCT). However, the incidence of HHV-6 reactivation in HLA-mismatched related SCT remains unknown. METHODS: We monitored plasma HHV-6 DNA loads weekly using real-time quantitative polymerase chain reaction for 5 weeks after SCT and compared serum IL-6 levels in HLA-mismatched SCT groups. RESULTS: Compared with detection in all 11 umbilical cord blood transplantation (CBT) patients (100%), plasma HHV-6 DNA was detected in only 3 of 42 haplo-SCT patients (7.1%) despite the use of methylprednisolone and antithymocyte globulin as graft-vs-host disease prophylaxis and a reduced-intensity conditioning regimen, respectively. Correspondingly, serum IL-6 levels in haplo-SCT patients were significantly lower than those in CBT patients. No HHV-6-associated encephalitis developed in either groups. CONCLUSIONS: Neither HLA disparity nor the use of methylprednisolone and antithymocyte globulin were risk factors for HHV-6 reactivation in our haplo-SCT patients. Rather than increasing risk, the administration of immunosuppressive agents potentially prevented HHV-6 reactivation after haplo-SCT by suppressing IL-6 production.
Subject(s)
Adrenal Cortex Hormones/therapeutic use , Cord Blood Stem Cell Transplantation/adverse effects , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation/adverse effects , Immunosuppressive Agents/therapeutic use , Roseolovirus Infections/diagnosis , Virus Activation/drug effects , Adolescent , Adult , Aged , Antilymphocyte Serum/therapeutic use , DNA, Viral/blood , Female , HLA Antigens/genetics , Herpesvirus 6, Human/physiology , Histocompatibility , Humans , Incidence , Interleukin-6/blood , Male , Methylprednisolone/therapeutic use , Middle Aged , Retrospective Studies , Transplantation Conditioning , Young AdultABSTRACT
Cord blood transplantation (CBT) is associated with delayed hematopoietic recovery and graft failure. To overcome these problems, we conducted a prospective, multicenter phase II study of intrabone marrow transplantation in which patients received reduced-intensity conditioning without anti-thymocyte globulin (ATG). The primary endpoint was the probability of full donor engraftment. Forty patients with hematologic malignancies were enrolled. Cord blood (CB) cells were injected without washing into 4 iliac bone sites (2 at each hemipelvis), at which approximately 6 mL of CB was administered at one site with local anesthesia. Full donor engraftment rate was 86.8%. The cumulative incidence of neutrophil and platelet engraftment was 86.4% and 85.5%, respectively. The median time to neutrophil (>0.5 × 109 /L) and platelet (2.0 × 109 /L) recovery was 17.5 and 44 days, respectively. The probability of severe acute graft-vs-host disease (GVHD) was 47.5%. The cumulative incidence of extensive chronic GVHD was 3.0%. The probability of relapse and non-relapse mortality was 30.4% and 28.0%, respectively. The survival rate at 3 years was 45.6%, although most patients were at an advanced stage. These results suggest that our intrabone marrow-CBT procedure without using ATG improves hematopoietic recovery and decreases the incidence of chronic GVHD, but does not decrease the incidence of acute GVHD.
Subject(s)
Bone Marrow Transplantation , Cord Blood Stem Cell Transplantation , Hematologic Neoplasms/therapy , Transplantation Conditioning , Adult , Aged , Blood Cell Count , Bone Marrow Transplantation/methods , Cause of Death , Cord Blood Stem Cell Transplantation/adverse effects , Cord Blood Stem Cell Transplantation/methods , Female , Graft Survival , Graft vs Host Disease/epidemiology , Graft vs Host Disease/etiology , Graft vs Host Disease/prevention & control , Hematologic Neoplasms/complications , Hematologic Neoplasms/diagnosis , Hematologic Neoplasms/mortality , Histocompatibility Testing , Humans , Incidence , Male , Middle Aged , Recurrence , Survival Rate , Time Factors , Tissue Donors , Transplantation Conditioning/adverse effects , Transplantation Conditioning/methods , Treatment OutcomeABSTRACT
Host Foxp3+CD4+ regulatory T cells (Tregs) have been shown to suppress graft-versus-host disease (GVHD) in experimental bone marrow transplantation (BMT) models; however, the detailed mechanism is unknown. To address this issue, we established a murine MHC-haploidentical BMT model (BDF1 (H-2b/d) â B6C3F1 (H-2b/k)), in which transplantation following conditioning with high-dose (13 Gy) or low-dose (5 Gy) total body irradiation corresponds to myeloablative stem cell transplantation (MAST) or reduced-intensity stem cell transplantation (RIST) BMT. All MAST recipients died of GVHD within 70 d, whereas RIST recipients developed almost no GVHD and survived for at least 3 mo. In this BMT model, we investigated the kinetics of immune cells in the mesenteric lymph nodes because GVHD was most prominent in the intestines. Host Tregs that survived after total body irradiation could proliferate transiently by day 4. Comparing the kinetics of immune cells among MAST, RIST, and anti-CD25 mAb-treated RIST, we found that the transiently surviving host Tregs were fully functional, closely contacted with host dendritic cells (DCs), and significantly restrained the maturation (CD80 and CD86 expression) of DCs in a dose-dependent manner. There was a positive correlation between the ratio of DCs to host Tregs and the extent of maturation of DCs. Host Tregs suppressed alloresponse mainly by contact inhibition. Host Tregs are already active in lymph nodes before transplantation and restrain the maturation of host DCs, thereby dampening the ability of DCs to activate allogeneic donor T cells and consequently reducing the magnitude of graft-versus-host reaction. Thus, host Tregs are negative regulators of host DCs that act in the peritransplantation period.
Subject(s)
Dendritic Cells/immunology , Graft vs Host Disease/immunology , Stem Cell Transplantation , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/transplantation , Adoptive Transfer , Animals , Bone Marrow Transplantation , CD4 Antigens/metabolism , Cell Differentiation , Cell Proliferation , Cells, Cultured , Dendritic Cells/cytology , Female , Forkhead Transcription Factors/metabolism , Lymph Nodes/cytology , Lymph Nodes/immunology , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Inbred DBA , T-Lymphocytes, Regulatory/cytology , Transplantation, HomologousABSTRACT
PURPOSE OF REVIEW: Inconsistent results regarding the clinical efficacy of granulocyte transfusions for the treatment or prophylaxis of life-threatening infections in neutropenic patients have been attributed to insufficient number of transfused neutrophils. Since the introduction of granulocyte colony-stimulating factor (G-CSF) to the granulocyte mobilization regimen in the 1990s, the number of transfused cells significantly increased, which directly translated to a significant increase in absolute neutrophil counts in the transfused patients. RECENT FINDINGS: For therapeutic granulocyte transfusions, neither of the two randomized controlled studies in the G-CSF era could demonstrate a clear clinical benefit. However, a number of small studies or case series have suggested its clinical efficacy, including one that demonstrated the clinical response against drug-resistant invasive fusariosis. For prophylactic granulocyte transfusions, there have been scarce reports in the G-CSF era. A pulmonary reaction is the most significant adverse event after granulocyte transfusions, although its reported frequency varies among studies. SUMMARY: Despite the expectation that the increased number of transfused neutrophils enables the clear demonstration of the clinical benefit, the role of therapeutic granulocyte transfusions remains controversial. Future directions may include: identifying the patient population who would benefit most from granulocyte transfusions; minimizing the risk of adverse events by identifying the risk factors and the prevention methods; and finding a way to prove the clinical benefit of granulocyte transfusions in therapeutic and prophylactic settings.
Subject(s)
Granulocytes/transplantation , Leukocyte Transfusion , Humans , Leukocyte Transfusion/adverse effects , Leukocyte Transfusion/methods , Neutropenia/etiology , Neutropenia/mortality , Neutropenia/prevention & control , Neutropenia/therapy , Treatment OutcomeABSTRACT
This prospective, multicenter phase I/II study of unmanipulated HLA-haploidentical reduced-intensity stem cell transplantation using a low dose of anti-T lymphocyte globulin (ATG) and steroid was conducted in 5 institutions in Japan. Thirty-four patients with hematologic malignancies who were in an advanced stage or at a high risk of relapse at the time of transplantation were enrolled. Among them, 7 patients underwent transplantation as a second transplantation because of relapse after the previous allogeneic stem cell transplantation. The conditioning regimen consisted of fludarabine, busulfan, and ATG (Fresenius, 8 mg/kg), and graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methylprednisolone (1 mg/kg). All patients except 1 (97.1%) achieved donor-type engraftment. Rapid hematopoietic engraftment was achieved, with neutrophils > .5 × 10(9)/L on day 11 and platelets > 20 × 10(9)/L on day 17.5. Treatment was started for ≥grade I GVHD, and the cumulative incidences of acute grade I and grade II to IV GVHD were 27.5% and 30.7%, respectively. The incidence of chronic GVHD (extensive type) was 20%. Fourteen patients (41.2%) had a relapse. The cumulative incidence of transplantation-related mortality at 1 year after transplantation was 26.5%. The survival rate at day 100 was 88.2%. The survival rates at 1 year for patients with complete remission (CR)/chronic phase (n = 8) and non-CR (n = 26) status before transplantation were 62.5% and 42.3%, respectively. In the multivariate analysis, non-CR status before transplantation was the only factor significant prognostic factor of increased relapse (P = .0424), which tended to be associated with a lower survival rate (P = .0524). This transplantation protocol is safe and feasible, if a suitable donor is not available in a timely manner. As the main cause of death was relapse and not GVHD, more intensified conditioning or attenuation of GVHD prophylaxis and/or donor lymphocyte infusion may be desirable for patients with non-CR status.
Subject(s)
Antilymphocyte Serum/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Busulfan/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Steroids/therapeutic use , Transplantation Conditioning/methods , Vidarabine/analogs & derivatives , Adult , Antilymphocyte Serum/administration & dosage , Antilymphocyte Serum/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Busulfan/adverse effects , Female , Humans , Japan , Male , Middle Aged , Prospective Studies , Recurrence , Steroids/adverse effects , Vidarabine/adverse effects , Vidarabine/therapeutic useSubject(s)
Chromosome Deletion , Multiple Myeloma/genetics , Multiple Myeloma/therapy , Plasmablastic Lymphoma/genetics , Plasmablastic Lymphoma/therapy , Smith-Magenis Syndrome , Adult , Biomarkers, Tumor , Biopsy , Chromosomes, Human, Pair 17 , Female , Humans , Immunohistochemistry , Multiple Myeloma/diagnosis , Plasmablastic Lymphoma/diagnosis , Positron Emission Tomography Computed Tomography , Tomography, X-Ray ComputedABSTRACT
Human leukocyte antigen (HLA)-haploidentical stem cell transplantation (haplo-SCT) is associated with a high incidence of cytomegalovirus (CMV) infection, probably originating from the delayed reconstitution of CMV-specific T cell immunity. There have been few reports on the presence of CMV-specific cytotoxic T lymphocytes (CMV-CTLs) after haplo-SCT. We have studied CMV-specific immune reconstitution by measuring the absolute number of CMV-CTLs using a flow cytometry method with HLA-A2-restricted NLVPMVATV peptide dextramers. We examined the association between reconstitution patterns of CMV-CTLs and the duration of CMV antigenemia in 15 patients who underwent first allogeneic SCT from HLA-haploidentical-related donors with HLA-A2. In seven and eight patients, CMV antigenemia consecutively resolved for more than 4 weeks (the CMV antigenemia 'resolved' group) and intermittently persisted (the CMV antigenemia 'persistent' group) during a 100-day observation period, respectively. The group of the seven patients, in whom levels of CMV antigenemia were reduced to zero, had a significantly lower maximum level of CMV antigenemia than the CMV antigenemia persistent group. In contrast, the CMV antigenemia persistent group had a significantly higher maximum level of CMV-CTLs, but the levels took longer to peak. Despite no difference in general lymphocyte recovery between the two groups, the CMV antigenemia resolved group had significantly higher median CMV-CTL counts than the CMV antigenemia persistent group at 6 weeks after onset of CMV infection. Flow cytometry analysis of CMV-CTLs is a convenient method of monitoring reconstitution of CMV-specific lymphocyte immunity following haplo-SCT.
Subject(s)
Cytomegalovirus Infections/diagnosis , Cytomegalovirus Infections/immunology , Cytomegalovirus/immunology , HLA Antigens/immunology , Hematopoietic Stem Cell Transplantation/adverse effects , T-Lymphocytes, Cytotoxic/immunology , Adult , Cytomegalovirus/isolation & purification , Cytomegalovirus Infections/mortality , Female , Follow-Up Studies , Haplotypes , Humans , Male , Middle Aged , Survival Rate/trends , T-Lymphocytes, Cytotoxic/virology , Transplantation, HomologousABSTRACT
Immune reconstitution after human leukocyte antigen (HLA)-mismatched (haploidentical) hematopoietic stem cell transplantation (haplo-HCT) can significantly influence long-term outcomes. The three possible HLA haplotypes after transplantation are: one carried by both the patient and the donor (shared HLA), one by donor only (donor-specific HLA), and one by patient only (host-specific HLA), and the donor T cells remain restricted to one of these three haplotypes. Understanding the presence of donor T cells restricted to each haplotype may provide more detailed insights into post-transplant immune response and potentially provide valuable information for the development of chimeric antigen receptor T cell or T cell receptor T cell constructs. In this study, patients or donors with HLA-A24 or HLA-A2 were tested with HLA-A*24:02- and A*02:01-restricted cytomegalovirus (CMV)-specific tetramers for detecting the respective HLA-restricted T cells. Sixty-four samples from 40 patients were assayed. More than half of the patients at day 90 and all patients by day 900 had shared HLA-restricted T cells. After day 90, half of the patients had donor-specific HLA-restricted T cells, but no host-specific HLA-restricted T cells were found. In the comparative analysis of the transplant types, shared HLA-restricted T cells were positive in all three categories: haplo-HCT (50%), 2-haplo-mis-HCT (75%), and spousal HCT (67%). Furthermore, donor-specific HLA-restricted T cells demonstrated positivity in haplo-HCT at 57% and in 2-haplo-mis-HCT at 60%, with a threshold of 0.01%. Donor-specific HLA-restricted T cells for spousal HCT were not examined due to the lack of an appropriate HLA combination for the tetramers. The presence of shared HLA-restricted T cells explains the host defense after HLA-haploidentical transplantation, while the presence of donor-specific HLA-restricted T cells may account for host defense against hematotropic viruses, such as CMV. However, this study failed to detect host-specific HLA-restricted T cells, leaving the host defense against epitheliotropic viruses unresolved, thus requiring further investigation.