scholarly journals Factors Affecting Natural Killer Cell Recovery after Autologous Stem Cell Transplantation in Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4895-4895
Author(s):  
Amany R. Keruakous ◽  
Raid Aljumaily ◽  
Daniel Zhao ◽  
Adam S. Asch ◽  
Carrie Yuen
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Count ◽  
Nk Cell ◽  
P Value ◽  
Cell Recovery ◽  
Factors Affecting ◽  
Exact Test ◽  
Induction Regimen

Abstract Introduction: Natural killer (NK) cells are large granular lymphocytes, very potent effector lymphocytes that can induce cytotoxicity against a vast array of tumors without the need for antigen sensitization or antigen presentation by MHC class I. NK cells are believed to play important role in immune surveillance for cancer, limiting neoplastic progression, and effectors of anti-tumor therapies -by introducing Abs that block NK cell inhibitory receptors yielding improved NK cell-mediated lysis- Retrospective studies demonstrated a significant correlation of NK cell recovery after autologous stem cell transplantation (ASCT) in multiple myeloma (MM) and disease outcomes. Higher absolute NK cell count one month after ASCT is associated with longer progression-free survival (PFS) and decreased risk of relapse. We aimed at investigating factors affecting NK cell recovery after ASCT in patients with multiple myeloma. Method: We designed a prospective cohort study, evaluating the potential factors that could affect NK cell recovery after ASCT. We included participants undergoing frontline ASCT for MM. We excluded participants with non-secretory myeloma or other malignancies that require active treatment, or with autoimmune disorders. All participants received conditioning regimen consisted of melphalan 200 mg/m2 on day -2. In patients older than 65 years old given 100mg/m2 for 2 days. Dose reduction to 140 mg/m2 for patients with serum creatinine > 2.0 mg/dL. Hematopoietic growth factor (peg-filgrastim 6 mg once subcutaneously) was given on day +1. Absolute NK cell count (CD3-, CD56+ cells) was determined using flow cytometric immunophenotyping of peripheral blood two-three months after ASCT. To determine variables that affected NK cell recovery after ASCT, absolute NK cell count was dichotomized to less than the lower limit of normal "NK < 76" and normal "NK > or equal 76" following institutional normal reference range which is consistent with ARUP NK cell enumeration reference. Statistical analysis was performed using Fisher-Exact test for categorical variable and Wilcoxon rank test for continuous variables. Results: We analyzed the results of fifteen patients treated with frontline ASCT for multiple myeloma. With a median age at diagnosis of 60 years, ranging from 47 - 70 years. Of which 53 percent females and 47 percent males. Patients' baseline characteristics are described in Table 1 Our data showed that 63 percent of patients with post-transplantation ALC > 1000 (5 of 8 patients), and 73 percent for ALC > 500, (8 of 11 patients), had normal absolute NK cell count; with a correlation coefficient of 0.3 (Pearson Correlation Coefficients), suggesting a moderate linear correlation between absolute NK cell count and ALC two-three months after ASCT. Patients' gender, age at ASCT, and comorbidity index (SORROR score) did not differ between the two groups of patients, P-value= 0.6193, 0.8454, 0.1721, respectively. Additionally, disease burden at the time of diagnosis, presence of CRAB criteria, involved free light chain and monoclonal immunoglobulins; all did not differ between the two cohorts. (Table 2) Medications received before ASCT did affect the absolute NK cell count with a higher proportion of normal absolute NK cell count, and higher mean absolute NK cell in the cohort received double-class (PI plus IMiDs) when compared to triple-class (PI plus IMiDs plus Anti-CD 38 mAb) therapy before transplantation (mean NK cell count 125 and 53 Cell/μL, respectively), with marginal statistical significance P-value= 0.0667 (Fisher's Exact Test). Discussion: Our study showed that the addition of anti-CD38 mAb to myeloma induction regimen, associated with compromised NK cell recovery. Casneuf et al reported similar findings, in daratumumab-treated myeloma patients, total and activated NK-cell counts reduced rapidly in peripheral blood after the first dose, remained low throughout treatment, and recovered after treatment ended. Similar reductions were observed in the bone marrow. Conclusion: Medications received before transplantation potentially affect NK cell recovery in multiple myeloma patients. Although, the addition of anti-CD38 mAb to the myeloma induction regimen is associated with deeper response, its impact on immune reconstitution needs to be investigated on a larger sample size. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals What are the factors affecting survival after autologous stem cell transplantation in patients with multiple myeloma?

2020 ◽  
Vol 14 (1) ◽  
pp. 57
Author(s):  
Serife Solmaz ◽  
Celal Acar ◽  
Ahmet Seyhanlı ◽  
OmurGokmen Sevindik ◽  
Ozden Piskin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Factors Affecting

Early Response to Botezomib Combined Chemotherapy Can Be Helpful for Prediction of Progression Free Survival in Patients with Multiple Myeloma Who Were Ineligible for Stem Cell Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5138-5138
Author(s):  
Ho Sup Lee ◽  
Yang Soo Kim ◽  
Kihyun Kim ◽  
Jin Seok Kim ◽  
Hyo Jung Kim ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Progression Free Survival ◽  
Initial Response ◽  
Early Response ◽  
P Value ◽  
Combined Chemotherapy ◽  
Response Group

Abstract Abstract 5138 Background: Response to treatment has been associated with improved survival in multiple myeloma (MM). The use of novel agents changed achievement of CR rates compared with conventional chemotherapy. The purpose of our study is to show influence of early response after treated with bortezomib combined chemotherapy to survival in patients with newly diagnosed MM who are ineligible for stem cell transplantation. Methods: We assessed response at least forth cycles before next chemotherapy by international myeloma working group response criteria. The median duration from starting chemotherapy to initial response date was 2.3 month (range; 0.9 – 3.7 months). The enrolled cases were all received bortezomib combined chemotherapy as front line therapy. We divided into good response group (A group) which were included showing more than very good partial response (VGPR) and poor response group (B group) which were partial response (PR) or less than PR. Endpoints were comparision of progression free survival (PFS) and overall survival (OS) between A and B groups. Results: We retrospectively analyzed 129 patients registered data for our study from the Korean Multiple Myeloma Working Party (KMMWP) performed a nationwide registration of MM patients. In our results of initial response, 16 patients were in CR (12.4%), 50 were in VGPR (38.8%), 40 were in PR (31.0%), 14 were in SD (10.9%), and 9 were in PD (7.0%). However, in results of best responses, 46 patients were in CR (35.7%), 31 were in VGPR (24.0%), 32 were in PR (24.8%), 11 were in SD (8.5%) and 9 were in PD (7.0%). 3 years PFS of A group and B group were 55.6% and 18.4%, respectively (p-value < 0.001). 3 years OS of A and B group were 65.3% and 52.9%, respectively (p-value 0.078). Conclusion: Early response at least forth cycles before next chemotherapy might be helpful for prediction of PFS in patients who were ineligible stem cell transplantation. Disclosures: No relevant conflicts of interest to declare.

Bortezomib Plus Dexamethasone As Induction Treatment Followed by Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma: A Study From India

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4584-4584 ◽  
Author(s):  
Shyam Aggarwal ◽  
Anshul Bhalla ◽  
S.L Khatri ◽  
Anand Simar S ◽  
Manorama Bhargava ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Peripheral Blood ◽  
Progressive Disease ◽  
Peripheral Blood Stem Cell ◽  
Blood Stem Cell ◽  
Induction Regimen ◽  
Stem Cell Collection ◽  
Blood Stem Cell Transplantation

Abstract Abstract 4584 Background and Objectives – Multiple myeloma (MM) is an incurable hematological malignancy, afflicting 25000 patients each year in India. Complete remission in myeloma is a surrogate marker for improved survival. The objective of induction regimen, using novel agents such a bortezomib, and Autologous Peripheral Blood Stem Cell Transplantation (APBSCT) is to increase the number of patients achieving CR. Here, we report a retrospective evaluation of the efficacy and response rates of induction with Bortezomib (Velcade) plus Dexamethasone (VD Regimen) followed by APBSCT and its effect on stem cell collection and final outcome of the transplant. Methods – Ten patients with symptomatic MM who had received VD induction before stem cell collection were evaluated. VD Induction comprised of Bortezomib (1.3 mg/m2) and Dexamethasone (40 mg) administered on days 1, 4, 8, 11 for four 21-day cycles. Peripheral blood stem cell collection technique involved administration of granulocyte stimulating factor (G-CSF); 300 mg/kg administered twice daily for 5 days. Adequate number of stem cells was collected in nine patients by a single harvest. One patient required apharesis twice for adequate stem cell collection. These cells were cryo-preserved. High dose Melphalan (200 mg/m2) was given followed by stem cell transfusion. Results – The median CD34-positive stem cell count was 5.6 × 106/kg. All the patients engrafted post transplant. The median time for engraftment i.e. Absolute Neutrophil Count (ANC) > 500/mL was 10 days and Platelet Count > 50000/mL was 16 days. The median length of hospital stay was 21 days. They were successfully managed for fever and infections with antibiotics, antifungals and supportive treatment. Irradiated blood (median - 4 units) and platelet apharesis (median – 3 units) were given. Response was assessed according to International Myeloma Working Group uniform response criteria. After induction with VD protocol, the overall response rate (ORR) was 90%. 2 patients (20%) had a complete response (CR), 7 patients (70%) had very good partial response (VGPR) and 1 patient (10%) had progressive disease. Post – APBSCT, the patient with progressive disease achieved VGPR and 6 out of 7 patients (85.7%) with VGPR achieved CR making the total responses as 8 CRs and 2 VGPRs. Thus, ORR was 100%, including 80% CR rate and 20% VGPR rate. All patients were put on maintenance therapy, 6 patients were on thalidomide (50 mg/day) and 4 patients received lenalidomide (10 mg/day) therapy. In the analysis, the median progression-free survival (PFS) was not reached at 22 months. The median overall survival (OS) was not reached after a median follow-up of 25 months, and the 2-year OS rate was 70%. Three patients (30%) had a relapse post-APBSCT, after 5 months, 9 months and 18 months respectively. Two patients (20%) expired, one due to myeloma and the other due to unrelated cause. All three patients with renal insufficiency experienced improvement in renal function and did not require dialysis post-APBSCT. Two patients (20%) developed neuropathy and two patients (20%) developed Herpes Zoster infection due to bortezomib therapy. Conclusions – The induction regimen of bortezomib plus dexamethasone is effective and well tolerated in symptomatic myeloma patients. It significantly improves post-induction and post-transplantation CR and VGPR rates and does not affect stem cell mobilization and collection procedure. Disclosures: No relevant conflicts of interest to declare.

scholarly journals NK Cell Reconstitution After Autologous Hematopoietic Stem Cell Transplantation: Association Between NK Cell Maturation Stage and Outcome in Multiple Myeloma

2021 ◽  
Vol 12 ◽  
Author(s):  
Ane Orrantia ◽  
Iñigo Terrén ◽  
Gabirel Astarloa-Pando ◽  
Carmen González ◽  
Alasne Uranga ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Nk Cells ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Nk Cell ◽  
Cell Maturation ◽  
Hematopoietic Stem

Autologous hematopoietic stem cell transplantation (autoHSCT) is a standard of care for transplant-eligible patients with multiple myeloma (MM). Among factors that influence outcome after autoHSCT, it has been suggested that the number of natural killer (NK) cells plays an important role. However, the impact that different NK cell subsets and their phenotype could have in disease progression after autoHSCT are less clear. For this reason, we have phenotypically and functionally characterized NK cells during immune system reconstitution after autoHSCT in 54 MM patients. Shortly after leukocyte recovery, an extensive redistribution of NK cell subsets occurs in these patients. In addition, NK cells undergo a profound phenotypic change characterized, among others, by their increased proliferative capacity and immature phenotype. Importantly, MM patients who showed lower frequencies of the mature highly differentiated NKG2A-CD57+ NK cell subset at +30 and +100 days after autoHSCT experienced superior progression-free survival and had a longer time to the next treatment than those with higher frequencies. Our results provide significant insights into NK cell reconstitution after autoHSCT and suggest that the degree of NK cell maturation after autoHSCT affects the clinical outcome of MM patients treated with this therapeutic strategy.

The Impact of Immunosuppressive Therapy on an Early Quantitative Reconstitution of NK Cells after Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4946-4946
Author(s):  
Sebastian Giebel ◽  
Joanna Dziaczkowska ◽  
Iwona Wylezol ◽  
Jerzy Wojnar ◽  
Malgorzata Krawczyk-Kulis ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Nk Cells ◽  
Nk Cell ◽  
The Other ◽  
Cell Recovery ◽  
Hematopoietic Stem ◽  
Preparative Regimen ◽  
The Impact

Abstract In a previous study we demonstrated that in case of KIR-ligand incompatibility, NK cells may mediate graft-versus-leukemia effect resulting in improved outcome in a setting of unrelated donor-hematopoietic stem cell transplantation (URD-HSCT). This effect, however, varies and depends on the preparative regimen including the use of pre-transplant antithymocyte globulin (ATG) as an in vivo T-depletion. On the other hand, the impact of ATG on NK cell recovery has not been determined so far. The goal of this study was to analyze the influence of various immunosuppressive modalities used for acuteGVHD prophylaxis or treatment on the early NK cell reconstitution after allogeneic HSCT. METHODS: We analyzed the number of peripheral blood NK cells with the use of flow cytometry on day +30 (+/−2) after alloHSCT. NK cells were defined as CD3-CD56+ cells. Eighty alloHSCT recipients were included in the study; 43 patients were given transplant from an HLA-identical sibling (sibHSCT) whereas in 37 cases the donor was an unrelated vulunteer. ATG (6–10 mg/kg) as a part of preparative regimen was used on days −3, −2, −1 in case of URD-HSCT, but not sibHSCT. Besides, acuteGVHD prophylaxis consisted of Cyclospirin A (3 mg/kg) since day −1 and short-course Methotrexate (three or four doses). For patients transplanted before year 2002 (38/80 analyzed cases) - prednisolone 0.5 mg/kg since day +1 until day +28 was additionally administered. Metylprednisolone (2 mg/kg) was used as a first-line therapy of acuteGVHD. RESULTS: We did not find any difference regarding the number of NK cells on day +30 after alloHSCT between patients given pre-transplant ATG and those in whom no form of T-depletion has been administered: 130 (11–841) x106/L vs. 116 (65–841) x106/L (p=NS). In contrast, the use of steroids for acuteGVHD prophylaxis was associated with significant impairment of the quantitative NK cell reconstitution: 106 (10–694) x106/L vs. 211 (32–890) x106/L NK cells on day +30 (p=0.004). The incidence of acuteGVHD as well as the use of steroids for acuteGVHD treatment had no impact on the number of circulating NK cells. None of the other factors analyzed including the number of methotrexate doses, source of stem cells, the number of CD34+ cells transplanted, and age was found to influence an early NK cell recovery. CONCLUSIONS: Although ATG used as a part of pre-transplant conditioning regimen circulates and remains active for several weeks after alloHSCT, it does not seem to have any impact on an early NK cell quantitative reconstitution. In contrast, prolonged administration of low-dose steroids may impair the NK cell recovery. Since NK cells are considered a potential tool for a cellular therapy of hematologic and other malignancies, our findings should be taken into account when planning this kind of treatment in the context of allotransplantation. In addition, our results support the earlier hypothesis that the preparative regimens containing ATG may enable elucidation of a potential benefit from KIR-ligand incompatibility.

Total Lymphocyte and Natural Killer (NK) Cell Count Day 30 Post-Transplant Strongly Predict Transplant Outcome after T Cell Depleted Allogeneic Stem Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2993-2993
Author(s):  
Bipin N. Savani ◽  
Stephan Mielke ◽  
Katayoun Rezvani ◽  
Agnes Yong ◽  
Nancy Hensel ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Count ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Nk Cell ◽  
Transplant Outcome ◽  
Post Transplant

Abstract One hundred and fifty-seven patients with leukemia (80 CML, 48 AML/MDS, 29 ALL) received a T cell depleted myeloablative allogeneic stem cell transplantation (SCT) from an HLA-matched sibling between 09/1993–09/2005. Conditioning consisted of TBI (12–13.6 Gy) + cyclophosphamide (96) or cyclophosphamide and fludarabine (61). The stem cell source was G-CSF mobilized peripheral blood stem cell (PBSC) in 129 and bone marrow in 28 patients. T cell dose with graft ranged from 0.2 – 2 × 105/kg CD3+ cells. GVHD prophylaxis was with low dose cyclosporine (level 100–200 ng/ml) in 103 and standard dose in 54. Patients without ≥ grade II acute GVHD received 1–2 donor lymphocyte infusion of 107 CD3+ cells/kg between days 45 and 100. Absolute lymphocytes on day 30 (LC30) was available in 154 patients (3 patients died before day 30) and 54 day +30 post-transplant samples were available for lymphocyte subset analysis. Median lymphocyte count on day +30 (LC30) was 400/μl, (range 10–3295) and 150/μl, (range 6–1005) for CD56+, CD16+ CD3− NK cells (NK30). Statistical analysis was performed on SPSS14 software. Median age of the group was 34 years (range 10–56). 78 patients had standard risk (SR) disease in first remission or first chronic phase of CML. The remaining 79 had high risk (HR) disease. At the time of analysis 85 patients are (51.5±4%) are alive with median follow-up of surviving patients 1392 days (range 147–4208). Only 9 patients (3 above median LC30) developed aGVHD before day+30. Patients with ≥ median LC30 had significantly better transplant outcome: survival 71±5 vs. 36 ±5.5%, p<0.0001; DFS 71±5 vs. 31±5 %, p<0.0001; NRM 10±3.5 vs. 38 ±6%, p<0.0001; relapse 22±5 vs. 51±7.5%, p=0.004; ≥ II aGVHD 34 ±5 vs. 51±6%, p=0.05. In multivariate analysis only disease risk and LC30 emerged as independent prognostic factors: LC30 above 400/μl was associated with improved survival (RR 4.3), DFS (RR 4.5), less relapse (RR 10.3), NRM (RR 3.3) and aGVHD (RR 2.3). LC30 impacted on outcome of both HR and SR disease groups (Figure). LC30 and NK30 were highly correlated (r2– 0.45, p<0.0001) and NK30 above 150/μl was also associated with improved transplant outcome: In multivariate analysis of this subset of 54 patients, SR disease and NK30 emerged as the only independent factors with better outcome for NK30 >150/μl: higher survival (RR 3), and DFS (RR 3), less relapse (RR 4.8), less NRM (RR 3) and less aGVHD (RR 5.3). This study does not define whether LC30 is a surrogate for NK cell count or whether both are a surrogate for some other undetected prognostic factor. However the inverse relationship between NK count and aGVHD suggests an NK-mediated effect through elimination of host antigen presenting cells as has been described in mismatched SCT but also in HLA identical SCT by Cook et al (Blood2004, 103, 1521) Prospective studies to correlate transplant outcome with NK cell recovery and function after HLA identical SCT are indicated. Figure Figure

NK-92 Therapy Is Well Tolerated, Has Minimal Toxicity and Shows Efficacy in a Phase I Trial of Patients with Relapsed/Refractory Hematological Malignancies Relapsing after Autologous Stem Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4297-4297 ◽  
Author(s):  
Brent Williams ◽  
Bertrand Routy ◽  
Neal denHollander ◽  
Xing-Hua Wang ◽  
Amelie Chaboureau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Phase I ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Phase I Trial ◽  
Hematological Malignancies ◽  
Nk Cell ◽  
Cell Lymphoma

Abstract Background Autologous NK cell adoptive immunotherapy has potential to treat a variety of malignancies, but is limited by patient-specific variations in numbers and quality of expanded cells. In contrast, allogeneic NK cell lines can overcome many of these limitations. The NK line, NK-92 can be manufactured under Good Manufacturing Practice (GMP) compliant conditions, and infused into patients, as demonstrated in two prior phase I trials for solid tumours. Here, we report the findings of a phase I trial of NK-92 with the highest cell dosing regimen tested to date, in patients with relapsed/refractory hematological malignancies. Methods We conducted a single-center, non-randomized, non-blinded, open-label, Phase I dose-escalation trial of irradiated NK-92 cells in adults with refractory hematological malignancies who relapsed after autologous stem cell transplantation. The objectives were to determine, safety, feasibility and evidence of activity against refractory hematological malignancies. Inclusion criteria included measurable disease, adequate organ function and ECOG performance status of < 2. Exclusion criteria were pregnancy, concurrent treatment within 28 days with other experimental therapy, known HIV, HBV or HCV infection and malignant CNS disease. Patients were treated at one of three dose levels (1x109 cells/m2, 3x109 cells/m2 and 5x109 cells/m2), given on day 1, 3 and 5 for a planned total of six monthly cycles. NK-92 cells were obtained from Conkwest, and a frozen working cell bank was established at Princess Margaret Cancer Centre and stored in liquid nitrogen. Clinical-grade NK-92 cells were then manufactured under GMP conditions by expanding a cryopreserved vial of NK-92 in Vuelife culture bags using GM1 medium. Release criteria of NK-92 for infusion included negative mycoplasma testing, day 7 culture sterility, endotoxin <0.05 EU/mL, and additionally, a negative stat gram stain and cell viability of >70%. The final NK-92 cell product was resuspended in GM2 medium (Plasma-Lyte-A medium), irradiated with 10 Gy and infused fresh intravenously over one hour. Results Twelve patients with hematological malignancies who relapsed after undergoing stem cell transplantation for relapsed/refractory disease were enrolled with the following diagnoses: multiple myeloma (5), diffuse large B-cell lymphoma (4), Hodgkin lymphoma (2) and mantle cell lymphoma (1). There were 9 males and 3 females and median age was 60 (range: 42-67) years. Patients had received 2-5 chemotherapy regimens before autologous stem cell transplantation and some also received additional chemotherapy after autotransplant and prior to receiving NK-92 infusions. The number of cycles of NK-92 administered ranged from 1-6, with 10 patients coming off study because of disease progression, and one patient proceeding to allogeneic stem cell transplantation. The only toxicity was infusion-related fever and chills (grade II) in one patient, and none had evidence of cytokine release syndrome. A patient with relapsed, refractory Hodgkin lymphoma had a complete response and remains in remission more than five years after NK-92 therapy. An additional three patients experienced transient responses. There were no significant alterations in hemoglobin, platelets, white cell count, creatinine or liver function tests in patients receiving NK-92 infusions. While six patients developed anti-HLA antibodies, none developed a T-cell immune response as determined by the mixed lymphocyte response of patient lymphocytes against NK-92. Conclusion NK-92 can be administered after autologous stem cell transplantation at very high doses with virtually no toxicity to patients with relapsed/refractory hematological malignancies. This is the first trial of NK-92 which includes patients with multiple myeloma. Surprisingly, most patients did not mount cellular immune responses against NK-92, despite receiving very large numbers of NK cells, up to a total of 150x109 cells. We conclude that high dose NK-92 therapy is safe and has the potential to induce long term survival in select patients. We propose that NK-92 can serve as a standardized off-the-shelf cellular treatment for malignancies and could provide a platform for gene-modified targeted cell therapy. Disclosures Keating: Conkwest: Other: Research funding unrelated to clinical trial.

Phase II Pethema Trial of Alternating Bortezomib and Dexamethasone As Induction Regimen Before Autologous Stem-Cell Transplantation in Younger Patients With Multiple Myeloma: Efficacy and Clinical Implications of Tumor Response Kinetics

2007 ◽  
Vol 25 (28) ◽  
pp. 4452-4458 ◽  
Author(s):  
Laura Rosiñol ◽  
Albert Oriol ◽  
Maria Victoria Mateos ◽  
Anna Sureda ◽  
Pedro García-Sánchez ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Tumor Response ◽  
Negative Impact ◽  
M Protein ◽  
Minor Response ◽  
Induction Regimen

PurposeThis is the first study in which bortezomib and dexamethasone were administered on an alternating basis as up-front therapy in multiple myeloma (MM). We investigated the efficacy and kinetics of response to each drug and safety.Patients and MethodsPatients with newly diagnosed MM who were less than 66 years old were treated with bortezomib at 1.3 mg/m2on days 1, 4, 8, and 11 (cycles 1, 3, and 5) and dexamethasone 40 mg orally on days 1 through 4, 9 to 12, and 17 to 20 (cycles 2, 4, and 6), followed by autologous stem-cell transplantation (ASCT). Responses were evaluated by modified European Bone Marrow Transplantation criteria. Random effects models were used to analyze the tumor response kinetics.ResultsForty patients were enrolled. Partial response (PR) or greater was 65% (12.5% complete response [CR], 10% very good PR [VGPR], and 42.5% PR) plus 17.5% minor response. Time to response was rapid, with 82% serum M-protein reduction achieved within the first two cycles. The M-protein decrease was similar with dexamethasone and with bortezomib (P = .48). Chromosome 13 deletion, t(4;14), and t(14;16) did not have a negative impact on response. Toxicity was low, with no grade 3 to 4 peripheral neuropathy and no grade 2 to 4 thrombocytopenia. The response rate after ASCT was 88%, with 33% CR (negative immunofixation) plus 22% VGPR.ConclusionBortezomib alternating with dexamethasone is a highly effective induction regimen with low toxicity. The kinetic study has shown a high degree of heterogeneity in response and rapid effect from both agents, supporting the use of a short induction regimen before ASCT in MM.

Oligoclonal T Cells Associated with Gvhd Following Allogeneic Stem Cell Transplantation Conditioned with Thymoglobulin and Reduced Intensity Total Body Irradiation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4662-4662
Author(s):  
Masoud Manjili ◽  
Catherine H Roberts ◽  
Maciej Kmieciak ◽  
Madhu S Gowda ◽  
Andrea Ferreira-Gonzalez ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Count ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Recovery ◽  
Reduced Intensity

Abstract Abstract 4662 Patients undergoing unrelated donor stem cell transplantation following reduced intensity regimens are prone to acute graft vs host disease (GVHD). In vivo T cell depletion with rabbit anti-thymocyte globulin (r-ATG, Thymoglobulin, Genzyme inc. Cambridge MA) is consistently associated with reduced risk of acute GVHD however poor T cell reconstitution seen with current schedules results in a high incidence of opportunistic infections and relapse. We report data on immune reconstitution in patients participating in an ongoing clinical trial testing a novel conditioning regimen for allogeneic GCSF-mobilized blood stem cell transplantation. Patients were randomized to receive conditioning with either 7.5 or 5.1 mg/kg of r-ATG in divided doses between days -9 and -7, followed by 450 cGy total body irrradiation (TBI) in 3 fractions on day -1 and 0. GVHD prophylaxis was with tacrolimus (day -3 to 120) and mycophenolate mofetil (day 0-30). So far 10 heavily pre-treated (median number of prior therapies 4, prior autologous SCT n=5) patients have been transplanted; 6 from unrelated donors (1 bone marrow), 3 from matched related donors and 1 from an HLA-A mismatched sibling. Diagnosis includes MM (4), NHL (3), and CLL/PLL (3). Median patient age is 57 years. No patients have developed acute GVHD in the first 90 days. All patients achieved prompt engraftment of neutrophils and have demonstrated sustained complete myeloid donor chimerism (median <1% recipient DNA) at 3-6 months post transplant. NK cell recovery is prompt (mean±SD absolute CD56+ cell count 177±85/μL at day 30) and sustained (184±116 at day 90). T cell subset recovery is modest (absolute CD3+ cell count 861±934/μL at day 90) with predominantly cytotoxic T cells (CD3+/4+ cell count 143±116 and CD3+/8+ cell count 708±837). T cell chimerism at day 90 is mixed with either donor ('10% recipient DNA, n=5) or recipient dominance (>10% recipient DNA, n=3). Patients demonstrating dominant donor T cell chimerism at day 90 went on to develop either delayed onset acute GVHD (n=2/8 evaluable) or chronic GVHD (n=2/8) after withdrawal of immunosuppression. Patients demonstrating mixed T cell chimerism with recipient dominance did not develop chronic GVHD; one of these patients has relapsed, following an HLA-A mismatched SCT from his brother, and though he had predominantly recipient derived T cells, his granulocytes were completely donor derived indicating graft tolerance. T cell receptor beta locus was examined by RT-PCR for oligoclonality in all the donor-recipient pairs at baseline, day 90 and at onset of GVHD. Patients with GVHD demonstrated high level of expression of TCR V beta 23 and 24 (n=1/4), 11 (n= 1/4), 18 (n= 1/4), or 11 and 18 (n= 1/4) exclusively, in addition to TCR V beta 14, 16, 17, 22. The latter loci were also expressed in patients who had no GVHD with mixed T cell chimerism; this group of patients also expressed TCR V beta 4 (n=2/2), 13 and 19 (n=1/2) exclusively. All but one of the patients expressed the majority of TCR V beta loci at day 90 (with the exceptions noted above) indicating early polyclonal T cell recovery following transplantation. Asymptomatic CMV and EBV reactivation requiring therapy developed in one patient each. No patients have developed invasive fungal infections. In conclusion conditioning with Thymoglobulin and reduced intensity TBI results in stable myeloid engraftment in patients receiving unrelated and alternative donor transplants. In this small group of patients, GVHD appears to be associated with emergence of oligoclonal T cell populations which in the future may be selectively depleted ex vivo to allow engraftment without risk of chronic GVHD. Disclosures: McCarty: Celgene: Honoraria; Genzyme: Honoraria. Toor:Genzyme: Research Funding.

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