Absolute Lymphocyte Count At Day+15 and +30 Post-ASCT As Predictors of Early and 1-Year Mortality for Patients with AL Amyloidosis Treated with a Single Autologous Stem Cell Transplant

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4518-4518
Author(s):  
Victor Hugo Jimenez-Zepeda ◽  
Donna Reece ◽  
Suzanne Trudel ◽  
Christine I. Chen ◽  
Norman Franke ◽  
...  
Keyword(s):  
Stem Cells ◽  
Overall Survival ◽  
Stem Cell ◽  
Immune System ◽  
Research Funding ◽  
Absolute Lymphocyte Count ◽  
Al Amyloidosis ◽  
Host Immune System ◽  
Princess Margaret Hospital

Abstract Abstract 4518 Absolute lymphocyte count (ALC) recovery after autologous stem cell transplantation has been identified as an independent prognostic factor for survival in several hematological malignancies, including multiple myeloma (MM), as well as in some solid tumours. Preclinical studies suggest a role of the host immune system in tumor control and tumor immunosurveillance. In human studies, T cells were shown to have suppressive effects on polyclonal immunoglobulin production in MM patients. These reports suggest an important role of the host immune system in the treatment of cancer. Thus, we set out to investigate if ALC at different time points before and after autologous stem cell transplantation (ASCT) is a predictor of survival in AL amyloidosis patients treated at Princess Margaret Hospital. Methods: Seventy-eight consecutive patients with documented symptomatic AL amyloidosis who underwent ASCT were identified from the Princess Margaret Hospital sysproteinemia database. This study was approved by the Ethics Committee of the Princess Margaret Hospital. The primary endpoint of the study was to assess the impact on overall survival (OS) based on ALC at day +15 and +30 post-ASCT in newly diagnosed AL amyloidosis patients who underwent a single ASCT. The Cox proportional hazard model was used to perform univariate analyses of possible prognostic variables for overall survival, after confirming the proportionality of each variable using time-dependent covariates. Results: A total of 78 patients with AL amyloidosis underwent ASCT from 01/2004 to 03/2010. Clinical characteristics are shown in Table 1. Patients received high-dose melphalan at 200 mg/m2 (24.4%), 140 mg/m2 (56.4%) or 100mg/m2 (19.2%) given intravenously on day -1 as per our risk-adapted approach, and stem cells were infused on day 0. At the time of this analysis, 60 patients were still alive and 29 (37%) had experience hematologic progression. Median progression-free survival (PFS) was 26.5 months (23–45) for all patients. The choice of ALC ≥1á0 × 109/L as the cut-off point was supported by the data because it yielded the greatest differential in survival, based on the chi-square χ2 = 100á4, P < 0á0001) analyzed at different cut-off points between the 25% and 75% quartiles from the log-rank test. An ALC of ≥ ≥1á0 × 109/L at day +15 and +30 post-ASCT significantly correlated with a better OS (mean OS of 170 versus 91 months and mean OS of 161 versus median of 33.4 months, respectively) (p=0.017 and p=0.0012) and PFS (median of 34.3 versus 16.4 months) (p=0.027). (Fig 1a-b). Early death and 1-year mortality were seen in 50% and 66.6% of cases with an ALC of <1á0 × 109/L at day +15 and +30 versus 0% and 12.5% in those patients with ALC ≥1á0 × 109/L (p=0.016 and 0.025, respectively). Multivariate analysis identified an ALC at day +15 and +30 as independent prognostic factors for OS while age > 60, B2-microglobulin > 460 μmol/L, LDH > 350 IU/L, CRP > 20mg/L, albumin < 35g/L, and creatinine>200 μmol/L were not associated with survival. In conclusion, ALC is a surrogate marker of the host immune system that correlates with better survival in AL amyloidosis patients undergoing a single ASCT. Immune reconstitution studies post-ASCT have demonstrated delayed recovery of T and B cells. However, normal numbers and function of NK cells have been documented as early as 2 weeks and these cells have been speculated as leading to a better outcome. Previously, it was reported that the number of infused NK cells along with the stem cells correlate with ALC day +15 recovery. The role of vaccination strategies and cellular therapies in AL amyloidosis should be investigated based on these findings. Disclosures: Reece: Otsuka: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Millinneum Pharmaceuticals: Research Funding; Merck: Consultancy, Honoraria, Research Funding. Chen:Roche: Honoraria; Johnson & Johnson, Lundbeck, Celgene: Consultancy; Johnson & Johnson, Celgene, GlaxoSmithKline: Research Funding. Tiedemann:Janssen: Honoraria; Celgene: Honoraria. Kukreti:Roche: Honoraria.

Mesenchymal Stem Cell Derived-Exosomes as Effective Factors in Reducing Cytokine Storm Symptoms of COVID-19

2021 ◽  
Vol 28 ◽  
Author(s):  
Amir Hossein Kheirkhah ◽  
Seyed Hossein Shahcheraghi ◽  
Malihe lotfi ◽  
Marzieh lotfi ◽  
Sanaz Raeisi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Immune System ◽  
Host Immune System ◽  
Cytokine Storm ◽  
Infection Transmission ◽  
Effective Factors ◽  
Different Types ◽  
Immune System Modulation

: Given that conventional therapies are ineffective for COVID-19, obtained exosomes from stem cells have been proposed as a sustainable and effective treatment. Exosomes are subsets with lengths between 30 and 100 nanometers, and they can be secreted by different cells. Exosomes are containing different types of miRNAs, mRNAs, and different proteins. The role of immune system modulation of exosomes of mesenchymal stem cells has been studied and confirmed in more than one study. Exosome miRNAs detect and reduce cytokines that cause cytokine storms such as IL-7, IL-2, IL-6, etc. These miRNAs include miR-21, miR-24, miR-124, miR-145, etc. The risks associated with treatment with exosomes from different cells are relatively small compared to other treatments because transplanted cells do not stimulate the host immune system and also has reduced infection transmission. Due to the ineffectiveness of existing drugs in reducing inflammation and preventing cytokine storms, the use of immune-boosting systems may be suggested as another way to control cytokine storm.

scholarly journals Age Distribution and Pattern of Myeloid Marrow Mutations in Patients (pts) with Higher-Risk Myelodysplastic Syndromes (HR-MDS) after Failure of Hypomethylating Agents (HMAs)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5257-5257
Author(s):  
Ghulam J Mufti ◽  
Lewis R. Silverman ◽  
Steven Best ◽  
Steve Fructman ◽  
Nozar Azarnia ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Overall Survival ◽  
Stem Cell ◽  
Research Funding ◽  
Somatic Mutations ◽  
Phase Iii ◽  
Elderly Subjects ◽  
Normal Peripheral Blood ◽  
Marrow Stem Cell

Abstract Background: The aging marrow stem cell demonstrates more somatic mutations when compared to younger marrow stem cells. These abnormalities have been noted in pts with MDS, as well as in patients with normal peripheral blood counts (Steensma et al, Blood 2015; Jaiswal et al, N Engl J Med 2014). Mutations are rarely detected in people <40 years of age, but increase each decade thereafter (Jaiswal et al, N Engl J Med 2014). Certain mutations (eg, DNMT3A, TET2, ASXL1, and SF3B1) are most prevalent in the oldest pts, and approximately 2% of pts with mutations associated with leukemia or lymphoma have age-related hematopoietic clonal expansion, which increases to 5-6% among patients ≥70 years of age (Xie et al, Nat Med 2014). In another study, 10% of elderly subjects had clonal hematopoiesis with somatic mutations and this number increased with increasing age (Genovese et al, N Engl J Med 2014). In a randomized, Phase III study with intravenous rigosertib (ONTIME) in patients with MDS failing HMA therapy, a much higher proportion of pts with bone marrow mutations was observed. The most frequent mutations were as follows: SRSF2 (28% of pts), TP53 (22%), ASXL1 (19%), SF3B1 (14%), and TET2 (14%) (Mufti et al, Blood 2014). Given that MDS is a disease of the elderly, and the importance of somatic mutations for diagnosis, prognosis, and (potentially) targeted therapy, we explored the correlation between age and type of somatic bone marrow mutation found in pts entered into ONTIME. Methods: We evaluated the bone marrow mutations in patients with MDS who were enrolled in ONTIME after failing to respond to a previous HMA. Bone marrow genomic DNA was isolated from single microscopic slides from 153 pts from ONTIME and subjected to sequence analysis of a "myeloid panel" comprising of 24 selected loci known to be frequently mutated in MDS and AML (Mufti et al, Blood 2014). We investigated these 24 myeloid abnormalities for their frequency in the identified age cohorts prior to study randomization to explore the correlation between age and the somatic mutation identified, specifically looking at pts older or younger than the mean age of pts with MDS in ONTIME (75 years). Results: Approximately 45% of patients had 1 mutation and an equal number had >1 (Figure 1). Table 1 shows the most frequent clonal myeloid mutations in ONTIME, based on age above and below 75 years (the median age in ONTIME).Table 3.Incidence (%) of Patients with Specific Mutations, Age Above and Below 75 YearsMutation< 75 years (N=60)≥ 75 years (N=51)Total (N=111)Fisher's Exact Test P-valueSRSF22729280.83TP532518220.37ASXL12018190.81SF3B11316140.79U2AF11212121.00TET21216140.59RUNX1814110.38DNMT3A812100.75In a separate analysis, the number of months from diagnosis of MDS and duration of prior HMA treatment did not appear to influence the pattern of mutations (Table 2). Table 2.Mutations by Months Since MDS Diagnosis and Duration of Prior HMAMutationNMonths from MDS Diagnosis median (range)Duration of HMA (mo) median (range)All analyzed pts11118.5 (0.1-116)8.9 (1.2-65)TP532414.9 (0.7-116)13.0 (1.2-36)SF3B11629.4 (7.5-63)13.0 (1.2-36)TET21522.6 (0.1-63)11.4 (2.0-36)SRSF23117.2 (6.6-116)6.4 (3.0-35)ASXL12115.7 (4.9-66)8.2 (2.8-44)DNMT3A1115.1 (7.4-36)6.5 (4.2-30)Conclusions: Somatic mutations are common in marrow stem cells from patients with HR-MDS. Over 45% of patients had 1 mutational abnormality, and 44% had >1. Of note, patients under and over the median age of pts with MDS had a similar mutational pattern, which was not influenced by either length of time since diagnosis of MDS or prior treatment with an HMA. In this analysis, the mutational genomic abnormalities in the MDS marrow stem cell were similar among younger and older patients with MDS, suggesting the underlying pathogenic mechanisms causing these abnormalities are also similar irrespective of patient age. Figure 1. Number of Mutations Per Patient Figure 1. Number of Mutations Per Patient Figure 2. Overall Survival in ONTIME by Number of Marrow Stem Cell Mutations Figure 2. Overall Survival in ONTIME by Number of Marrow Stem Cell Mutations Disclosures Mufti: Onconova Therapeutics Inc: Research Funding. Silverman:Onconova Therapeutics Inc: Honoraria, Patents & Royalties: co-patent holder on combination of rigosertib and azacitdine, Research Funding. Best:Onconova Therapeutics Inc: Research Funding. Fructman:Onconova Therapeutics Inc: Employment. Azarnia:Onconova Therapeutics Inc: Employment. Petrone:Onconova Therapeutics Inc: Employment.

scholarly journals IPO11 Regulates the Nuclear Import of BZW1/2 and Is Necessary for AML Cells and Stem Cells

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 22-23
Author(s):  
Boaz Nachmias ◽  
Veronique Voisin ◽  
Geethu Emily Thomas ◽  
Dilshad H. Khan ◽  
Rose Hurren ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Overall Survival ◽  
Stem Cell ◽  
Nuclear Import ◽  
Research Funding ◽  
Cell Function ◽  
Hematopoietic Cells ◽  
A Genome ◽  
Crispr Screen

While most patients with acute myeloid leukemia (AML) achieve remission with initial therapy, the majority relapse leading to poor overall survival. Relapse is frequently driven by a rare subset of leukemic stem cells (LSC). Understanding biological mechanisms that maintain LSCs will help identify new therapeutic strategies for this disease. To identify such vulnerabilities, we overlaid the results of a genome-wide CRISPR screen with the expression of genes enriched in functionally defined LSCs. Through our CRISPR screen, we identified 570 genes whose knockout reduced the growth and viability of OCI-AML2 cells. Essential genes for growth and viability by our CRIPSR screen were enriched in the LSC+ population. By overlaying the hits from our CRISPR screen with genes upregulated in LSCs, we identified IPO11, as a top hit, with 7.5-fold increase in the LSC+ fraction compared to the LSC- fraction. IPO11 is a member of the importin-β family of proteins and facilitates the import of protein cargo into the nucleus. Further analysis showed that IPO11 was upregulated in LSC+ (engrafting) vs. LSC- (non-engrafting) primary AML samples, CD34+ vs CD34- AML samples, undifferentiated progenitor vs. myeloid cluster AML samples, and relapse vs de novo AML. IPO11 was increased in AML cells compared to normal hematopoietic cells and increased IPO11 expression was associated with decreased overall survival in AML. By immunoblotting, IPO11 protein was increased in primary AML (n=4) compared to normal hematopoietic cells (n=4). To determine whether IPO11 is necessary for AML growth and viability, we knocked down IPO11 in OCI-AML2, TEX and NB4 leukemia cells with shRNA in lentiviral vectors. Knockdown of IPO11 reduced AML growth and viability by 80-90%. In contrast, knockdown of another importin-β family member, IPO5, that was not a hit in our CRIPSR screen, did not reduce AML growth and viability. Knockdown of IPO11 increased differentiation of AML cells as evidenced by the changes in gene expression, decreased chromatin accessibility, increased CD11b expression and increased non-specific esterase staining. Finally, knockdown of IPO11 reduced the engraftment of TEX cells and the low passage primary AML 8227 cells into immune deficient mice by over 90%. Importantly, IPO11 knockdown reduced engraftment of primary AML cells into mouse marrow. To identify novel cargos of IPO11, we performed proximity-dependent biotin labeling (BioID) coupled with mass spectrometry and identified proteins that interacted with IPO11. Among the top hits were BZW1 and BZW 2 (Basic leucine zipper and W2 domains 1 and 2). BZW1 and BZW2 are members of the bZIP super family of transcription factors. Knockdown of IPO11 reduced levels of BZW1 in the nucleus detected by immunoblotting and confocal microscopy. Commercial antibodies could not detect BZW2. To determine if the nuclear import of BZW1 and 2 were functionally important for the effects of IPO11 on AML stem cell function and differentiation, we knocked down BZW1 and BZW2. Dual knockdown of BZW1 and BZW2 (but not individual) mimicked the effects of IPO11 inhibition and decreased the growth and viability of AML cells. Changes in gene expression after BZW1/2 knockdown were similar to IPO11 knockdown with enrichment in myeloid-differentiated genes. By pathway analysis, we identified that IPO11 knockdown, as well as BZW1/2 knockdown decreased expression of MYC target genes, suggesting a mechanism by which these proteins regulate AML stem cell function. Thus, in summary, we identified IPO11 as an essential gene for the viability of AML cells and stem cells. This work highlights a previously unappreciated role of the protein import pathway in regulating AML stem cell function and highlights a potential new therapeutic target for AML. Disclosures Schimmer: Takeda: Honoraria, Research Funding; Novartis: Honoraria; Jazz: Honoraria; Otsuka: Honoraria; Medivir AB: Research Funding; AbbVie Pharmaceuticals: Other: owns stock .

Improved Stem Cell Transplant Related Mortality for AL Amyloidosis At a Single Transplant Center

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2016-2016
Author(s):  
Zandra K. Klippel ◽  
Barry Storer ◽  
William I. Bensinger ◽  
Leona Holmberg ◽  
Pamela S Becker ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Risk Stratification ◽  
Research Funding ◽  
Cardiac Involvement ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Entire Cohort

Abstract Abstract 2016 The role of AHSCT in AL amyloidosis is controversial. There is evidence that AHSCT offers long term disease control with high organ response rates, however, the only randomized phase III trial comparing transplant with conventional melphalan and dexamethasone therapy deemed transplant inferior. Better understanding of risk stratification for SCT candidacy has resulted in TRM rates are as low as 5.6% in some series. The goal of the current study was to evaluate the TRM rate for all consecutive patients who have undergone AHSCT for AL amyloidosis at institution. Special attention in evaluation of any detectable differences in TRM over the time period of this review was a major goal of this project. Retrospective review was performed of all patients with primary AL amyloidosis who have undergone AHSCT at our institution. The database captured patients from December 2001 and our study includes patients through February 2012. Patients who were diagnosed with secondary amyloidosis by the stem cell transplant service and/or referring oncologist were excluded. TRM was defined as death from any cause within 100 days post stem cell infusion. We then evaluated data from the entire cohort and divided it into two different time periods: 2001–2006 and 2007–2012. Thirty-nine patients had an initial AHSCT during the study period. Nine patients were enrolled in the SWOG 0115 trial which comprised tandem autoSCT using 100 mg/m2 of melphalan conditioning 3–6 months apart. Of those, 6/9 (66%) had both transplants. For purposes of this abstract we report on the data resulting from first transplantation only for patients in the SWOG 0115 trial. The median age at transplant for the entire cohort was 57.6 years old (39–74). Males represent 64% of the patients. Most of the patients had symptomatic involvement of one organ (48.7%) with 23% having more than 2 organs involved. There were 14 patients transplanted in the 2001–2006 period and 25 patients in the 2007–2012 period. Overall TRM for 2001–2012 was 5.1%. During the 2001–2006 period TRM was 14% (2/14 patients). No TRM occurred for patients transplanted from 2007–2012. Overall survival (OS) improved when separately comparing the two study periods. Overall survival was 64% at 3 years in the 2001–2006 cohort and 92% at 3 years in the 2007–2012 cohort. Patients in the 2007–2012 cohort include all patients enrolled to SWOG 0115. Sixty percent of patients reported for that period received <200mg/m2 melphalan for transplant conditioning. Eight of nine patients enrolled in SWOG 0115 received 100 mg/m2, one received 140mg/m2. Six patients treated on our institution's standard amylodosis SCT protocol received 140mg/m2 conditioning. The remaining ten patients received 200mg/m2 melphalan. Patients in the 2007–2012 period were more likely to receive induction treatment prior to transplant with novel regimens (72% vs 21% p=0.003). In addition, these patients were more frequently diagnosed with amyloid cardiac involvement. For purposes of this abstract amyloid cardiac involvement is defined according to whether or not the SCT team concluded on the basis of history, physical examination and available ancillary data (including echocardiography) that the patient had amyloidotic cardiac disease (40% vs 14% p=0.15). All patients had echocardiography pre-AHSCT. The mean Inter Ventricular Septum (mIVS) thickness was 14.5 mm in the 2007–2012 period vs. 11.7 mm in the 2001–2006 one p=0.004. Univariate analysis of risk factors affecting improved OS identified year of transplant (>2006; p=0.03), number of treatments pre-transplant (>1; p=0.04), and time from diagnosis to transplant (>4mo; p=0.05) as factors associated with improved survival. Number of organs involved (>1; p=0.06) showed a trend towards worse survival. In conclusion, our single institution data demonstrates a reduction in TRM over the past 5 years. Reasons for improvement in TRM are under investigation and may include better risk stratification, better supportive care (including frequent hospitalization for cardiac monitoring in high-risk patients) and improvement in pre-AHSCT performance status for those patients receiving induction therapy with novel agents. Figure: Comparison of overall survival of patients with AL amyloidosis after autologous stem cell transplant based on year of transplant. Figure:. Comparison of overall survival of patients with AL amyloidosis after autologous stem cell transplant based on year of transplant. Disclosures: Holmberg: Millenium: Research Funding; Otsuka: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Sanofi: Research Funding.

Long Term Survival Analysis after High-Dose Melphalan Chemotherapy Followed by Autologous Stem Cell Transplantation for Treatment of AL Amyloidosis: A Single Centre Experience.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5503-5503
Author(s):  
Jolanta B. Perz ◽  
Amin Rahemtulla ◽  
Chrissy M. Giles ◽  
Richard Szydlo ◽  
Jane F. Apperley
Keyword(s):  
Stem Cells ◽  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
High Dose ◽  
Al Amyloidosis ◽  
Term Survival ◽  
High Dose Melphalan

Abstract Introduction: AL amyloidosis (AL) is a clonal plasma cell disease with a median survival of 10–14 months without therapy. Phase II studies report remission rates in up to 50% of patients (pts) after high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT). We retrospectively analysed AL pts who underwent HDM and ASCT at the Hammersmith Hospital in London since 1996. Patients and methods: 19 pts (12 m, 7 f), median age 51 y (40 – 63 y) with lambda (14) or kappa (5) AL (2 pts with multiple myeloma stage IA) had the following leading organ involvements: 10 kidney, 3 cardiac, 3 liver or gut, 3 other. 12 pts had more than 2 involved organs. According to risk criteria for HDM (Comenzo and Gertz, 2002) 12 pts were high, 2 pts intermediate and 5 pts low risk. Stem cells were mobilised with Cyclophosphamide (4 g/m2) in 3 pts, Etoposide (1.6 g/m2) in 1 patient, G-CSF alone in 14 pts, 1 bone marrow harvest was performed. Melphalan dose was: 8 pts 200 mg/m2, 5 pts 140 mg/m2, 6 pts 100 mg/m2. The median number of infused stem cells was 3.45 x 106 CD 34+ /kg bw (1.96 – 11.3 x 106 CD 34+ /kg bw). Results: Treatment related mortality (TRM) was 26%. In 14 patients who survived longer than 100 days from ASCT 6 pts achieved a haematological remission (5 a complete remission, 1 a partial remission) but in 8 patients no remission was achieved: 2 pts received a second ASCT, 2 pts further chemotherapy, 2 pts required haemodialysis. The mean survival from HDM and ASCT is 58.1 months (SD 9.64 months, 95% CI 39.21 – 76.99). The 1 - year and 2 - years overall survival from HDM and ASCT was 73% and 62%, respectively. The overall survival dropped to 42% after 6 years and the main cause of death was progressive or relapsed AL. Conclusions: HDM and ASCT is feasible for patients with AL, however, TRM was high at 26% in a group of maily high risk patients. 62% of patients survived longer than 2 years, but disease relapse and deaths from relapsed or progressive disease occurred after longer than 2 years from HDM. Thus, new treatment strategies have to be investigated to treat disease progress and relapse in order to improve the long-term survival after HDM and ASCT in patients with AL.

Absolute Lymphocyte Count Predicts Overall Survival in T Cell Lymphomas.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3878-3878
Author(s):  
Deepti Behl ◽  
Kay M. Ristow ◽  
Svetomir Markovic ◽  
Thomas E. Witzig ◽  
Thomas M. Habermann ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Lymphocyte Count ◽  
Independent Predictor ◽  
Univariate Analysis ◽  
Absolute Lymphocyte Count ◽  
Sample Population ◽  
Host Immune System ◽  
T Cell Lymphomas

Abstract Background: Absolute lymphocyte count (ALC) recovery is an independent prognostic factor for survival for different hematological malignancies treated with autologous stem cell transplantation. Recently, we reported superior overall survival (OS) in patients with follicular lymphomas that presented with a higher ALC (ALC ≥ 1 x 109/L) at diagnosis. The role of ALC at diagnosis on survival in T cell lymphomas is not known. Methods: All patients evaluated at the Mayo Clinic for T cell lymphomas from October 1984 until April 2005 were analyzed in the study. The primary objective of the study was to assess the role of ALC at diagnosis and survival in T cell lymphomas. ALC at diagnosis was obtained from the standard complete blood cell count (CBC). Results: 223 patients with T cell lymphomas were included in the study. The histology included: peripheral T-cell lymphoma-unspecified (40%), anaplastic large cell (13%), angioimmunoblastic (10%), angiocentric (4%), intestinal T-cell (2%), and other (31%). The median follow-up was 18.6 months (range: 1 month – 229 months [19 years]). The sample population included 60% male and 40% females with a median age of 60 years (15–90 years). The median ALC at diagnosis was 1.2 x 109/L (range: 0.04–6.7 x 109/L). ALC as a continuous variable was identified as predictor for OS in the univariate analysis (HR= 0.690, 95%CI: 0.542–0.862, p < 0.0006). ALC ≥ 1 x 109/L was selected as the dichotomized value because it yielded the maximum difference in survival by c2 analysis looking at different cut-point from 0.6 to 1.7 x 109/L that were included between the 25% and 75% quartiles. Univariately, ALC ≥ 1 x 109/L was also identified as a predictor for OS (HR = 0.682, 95%CL= 0.578–0.804, p < 0.0001). Patients (N = 122) with an ALC ≥ 1 x 109/L experienced superior survival compared to patients (N = 101) with an ALC < 1 x 109/L [median OS: 76.3 vs 10.6 months, respectively; and 5 years OS estimates of 53% vs 23%, respectively, p < 0.0001]. When ALC ≥ 1 x 109/L was compared to the international prognostic index (IPI), ALC ≥ 1 x 109/L remained an independent predictor for survival in the multivariate analysis (HR = 0.779, 95%CL: 0.655–0.925, p < 0.004). Conclusion: This study demonstrates ALC as an independent predictor for OS in T cell lymphomas, suggesting that the host immune system affects survival in this group of patients.

Hepatic Response after High-Dose Melphalan and Stem Cell Transplantation for AL Amyloidosis Associated Liver Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2873-2873
Author(s):  
Saulius Girnius ◽  
David C. Seldin ◽  
Martha Skinner ◽  
Kathleen T. Finn ◽  
Vaishali Sanchorawala
Keyword(s):  
Stem Cells ◽  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
High Dose ◽  
Al Amyloidosis ◽  
Hepatic Involvement ◽  
High Dose Melphalan ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Immunoglobulin light chain (AL) amyloidosis is a plasma cell dyscrasia with extracellular protein deposition in various organ systems, including the liver. The natural history of AL amyloidosis with liver involvement has a poor prognosis, with median survival of only 8.5 to 9 months. High-dose melphalan chemotherapy and autologous peripheral blood stem cell transplantation (HDM/SCT) has been shown to result in durable hematologic response and prolonged overall survival in systemic AL amyloidosis. Patients were included who had hepatic involvement and received HDM/SCT from 1998 to 2006. Data was collected with the approval of the Institutional Review Board. Patients receiving HDM/SCT had to meet eligibility criteria to qualify for this aggressive treatment. Stem cells were mobilized using G-CSF alone. Intravenous melphalan was administered at 100–200 mg/m2 over 2 days in divided doses and stem cells were re-infused 24–72 hours after HDM. Liver response was determined by criteria set up by the Consensus Opinion from the 10th International Symposium on Amyloid and Amyloidosis. Sixty-nine patients qualified for this study, including 47 males and 22 females. The median age was 56 years (range, 37–75), median bilirubin was 0.5 mg/dL (range, 0.1 to 5.7), median alkaline phosphatase was 193 U/L (range, 59 to 1243) and the median liver size was 3 cm (range, 0–20cm) below the costal margin. Nine patients (13%) died from treatment-related mortality. The hematologic CR one year after treatment was achieved by 53% (31/58) of evaluable patients. The overall survival was 84% at 1 year and 49% at 5 years, by Kaplan-Meier estimates. Hepatic response occurred in 21% (10/47) at 1 year after HDM/SCT and 40% (12/30) at 2 years after HDM/SCT. In summary, hepatic involvement with AL amyloidosis does not increase treatment-related mortality from HDM/SCT. Hepatic response follows a hematological response and can occur as far as 2 years from HDM/SCT. Forty % of surviving evaluable patients showed remission of their hepatic disease from AL amyloidosis by 2 years.

Collection of Stem Cell Early In the Disease Course of Multiple Myeloma Is Associated with Early Engraftment.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4518-4518
Author(s):  
Francis Buadi ◽  
Angela Dispenzieri ◽  
Shaji Kumar ◽  
Martha Lacy ◽  
David Dingli ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Research Funding ◽  
Complete Response ◽  
Cell Transplant ◽  
Disease Course ◽  
And Storage ◽  
Stem Cell Collection

Abstract Abstract 4518 Introduction: Autologous stem cell transplant (PBSCT) is an integral part of the management of Multiple Myeloma (MM). Available data suggest that the timing of PBSCT has no effect on overall outcome. Some patients currently opt to delay their transplant, especially in this era of proteosome inhibitors and iMIDs. In such patients the best time for stem cell collection is unknown. We conducted a retrospective study looking at early stem collection and storage compared to stem cell collection at the time of transplant in patients who opt to be transplanted at a later date. Method: All patients who had PBSCT performed more than one year from the time of diagnosis were reviewed. Two groups of interest were then evaluated. Early collection (ET): those who had stem cells collected within 6 months of diagnosis, and Late collection (LT): those who had stem cells collected more than 1 year from diagnosis and within 3 months of PBSCT. Results: Table 1 shows some patient characteristics. 334 patients were identified, ET (85) and LT (249). Gender distribution, Durie Salmon stage, immunoglobulin subtype and cytogenetic abnormalities were similar in both groups. The LT group was older 60 yrs compared to ET 56.6 yrs, P=0.02. More patients in the ET (77%) group were mobilized with cyclophosphamide compared to LT (51%) p<0.0001. Stem cell yield was similar in both groups 9.26 × 10(6) CD34/kg in ET and 8.19 × 10(6) in LT, P=0.16. Median number of collections was 3 in both. More patients in the LT (67%) received Melphalan 200 mg/m2 conditioning compared to ET (59%) p=0.03. Neutrophil engraftment occurred at day + 11 ET and +12 (LT) p<0.0001. ET patients achieved platelet engraftment on day + 13 compared to + 15 (LT) p=0.002. Complete response rates were similar 30% (ET) and 34% (LT). Duration of response after PBSCT was not different 12.6 months (ET) and 11.6 months (LT). Median overall survival from diagnosis was 70.5 months (ET) and 74.5 months (LT) p=0.5. Similarly there was no difference in overall survival post PBSCT 33.5 month (ET) and 32.2 months (LT). Conclusion: Stem cell collection and storage early in the disease course of multiple myeloma results in early engraftment compared to stem cell collection at the time of transplant in patients who opt for a delayed transplant. More studies looking at cost analysis will however be need to determine the cost effectiveness of early versus late stem cell collection. Disclosures: Dispenzieri: Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Gertz:Celgene: Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Modified High-Dose Melphalan and Autologous Stem Cell Transplantation (mHDM/SCT) In the Treatment of AL Amyloidosis (AL) and/or High-Risk Myeloma (hM): Analysis of SWOG Trial S0115

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2004-2004
Author(s):  
Vaishali Sanchorawala ◽  
Antje Hoering ◽  
David C Seldin ◽  
Kathleen T Finn ◽  
Salli A Fennessey ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Research Funding ◽  
High Dose ◽  
Al Amyloidosis ◽  
Advisory Committees ◽  
High Dose Melphalan

Abstract Abstract 2004 Treatment of AL amyloidosis (AL) and myeloma (M) with high dose melphalan and autologous stem cell transplantation (HDM/SCT) is effective in inducing hematologic remissions and improving survival. However, the benefit of HDM/SCT in AL and host-based high-risk myeloma (hM) has not been explored in a multi-center study. We designed a trial of two cycles of modified high dose melphalan at 100 mg/m2 and autologous stem cell transplantation (mHDM/SCT) through SWOG 0115 (ClinicalTrials.govIdentifier: NCT00064337). The primary objective was to evaluate overall survival and additional objectives were to determine hematologic responses and tolerability of two cycles of mHDM/SCT in AL and hM in a multicenter study. Eligibility for patients with AL required evidence of tissue diagnosis of amyloidosis, underlying associated plasma cell dyscrasia, and adequate measures of performance status (Zubrod 0–2) and cardiopulmonary function (LVEF >45%, DLCO >50%). Eligibility for hM patients required age >70 years and/or serum creatinine of >2 mg/dL or calculated creatinine clearance of <50 mL/kg/min. Peripheral blood stem cells were collected following G-CSF alone with minimum yield of 7.0×106 CD34+ cells/kg required for participation in the trial. From 1/2004 to 11/2010, 70 eligible patients with AL (61 with AL and 9 with myeloma associated AL) and 27 with hM were enrolled at 17 centers in the US. The median age was 64 years (range; 33–79) and M:F ratio was 1.6:1. The median number of organs involved was 2 (range, 1–8). There were 22 patients (31%) with cardiac involvement. The median serum creatinine level was 1.7 mg/dL (range, 0.6–10.0) for patients with hM. There are 68 patients with AL and 25 patients with hM eligible for survival and 67 patients with AL and 25 patients with hM eligible for adverse event analysis at this time. The treatment-related mortality (TRM), defined as deaths within 100 days of registration (even without protocol-directed treatment) was 9% (n=9/97). TRM was 10% (n=7/70) for AL and 7% (n=2/27) for hM. TRM was 14% (n=3/22) for patients with AL and cardiac involvement. Grade 3 and higher non-hematologic adverse events by CTCAEv3.0 were experienced by 75% (n=50/67) of AL patients and 80% (n=20/25) of hM patients. The median overall survival is 68 months for AL with a median follow up for surviving patients of 40.6 months (range; 1.2–79). The median survival for hM patients has not been reached yet with a median follow-up of 34 months. The 5-year survival is 55% for AL and 54% for hM patients; and the median progression-free-survival is 43 months for AL and 31 months for hM. Hematologic responses, defined by the standard consensus criteria, were achieved by 39% (n=11/28) evaluable patients for AL and 57% (n=4/7) for hM following SCT. Clinical and organ responses were also evident at 1 year following HDM/SCT. Thirty % (n=3/10) patients with AL experienced cardiac response. In conclusion, this experience demonstrates that with careful selection of patients, mHDM for SCT in patients with AL amyloidosis and hM, even in the setting of a multicenter study, can lead to prolonged overall survival with acceptable TRM and morbidity. Disclosures: Holmberg: Celgene: Research Funding; Millennium-Takeda: Research Funding; Otsuka: Research Funding; Seattle Genetics: Research Funding; Genzyme: Research Funding; Genzyme: Research Funding; Merck: Research Funding; Genzyme: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Similar Survival with Deferred Versus Salvage Autologous Stem Cell Transplant in Light Chain Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4579-4579 ◽  
Author(s):  
Danny Luan ◽  
Koen Van Besien ◽  
Paul J Christos ◽  
Roger Pearse ◽  
Danielle Guarneri ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Light Chain ◽  
Research Funding ◽  
Small Sample ◽  
Renal Amyloidosis ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant

Background: Light chain (AL) amyloidosis is characterized by deposition of misfolded monoclonal immunoglobulin light chains leading to organ dysfunction. AL amyloidosis has traditionally been treated with agents used in multiple myeloma, primarily alkylators, proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and high-dose melphalan/autologous stem cell transplantation (ASCT). A retrospective study comparing patients with AL amyloidosis who underwent ASCT as frontline therapy ('upfront ASCT') to those undergoing ASCT following induction ('deferred ASCT') revealed that deferred ASCT was associated with prolonged overall survival (OS) compared to upfront ASCT (Afrough et al, Biol Blood Marrow Transplant, 2018). Given the number of effective new therapies for AL amyloidosis, the potential to delay ASCT after one or more lines of therapy ('salvage ASCT') is feasible. To our knowledge, transplant outcomes of AL amyloidosis patients undergoing deferred vs salvage ASCT following at least one relapse have not been reported. A retrospective chart review was conducted to compare AL amyloidosis patients receiving deferred vs salvage ASCT for progression-free survival (PFS) and overall survival (OS). The study was approved by the Institutional Review Board at Weill Cornell Medical College. Methods: Twenty-four patients with AL amyloidosis who underwent deferred or salvage ASCT between 2000-2018 were included in the analysis. Patients who underwent upfront ASCT without induction chemotherapy were excluded. Demographics and clinical parameters were extracted from the electronic medical record. PFS was calculated from date of ASCT to first relapse and OS was calculated both from date of diagnosis and date of ASCT to death. Patients were censored if lost to follow-up prior to experiencing the relevant event. PFS as well as OS of patients who underwent deferred vs salvage ASCT were compared. Log-rank tests were used to statistically evaluate differences between Kaplan-Meier PFS/OS curves. Cox proportional hazards models were used to calculate hazard ratios (HR) using deferred ASCT as the reference treatment. Results: Among the 24 patients included in this analysis, 13 underwent deferred ASCT with 1 prior line of chemotherapy (e.g., induction), and 11 underwent salvage ASCT with a median of 3 prior lines (Table 1). Ten patients had cardiac amyloidosis, 15 had renal amyloidosis, and 6 had multi-organ involvement. Induction regimens received in the deferred group are included in Table 1. Neither PFS nor OS was significantly different between patients receiving deferred vs salvage ASCT. After median follow-up of 2.9 years, median PFS in patients who received deferred ASCT was 6.5 years and not reached in those who received salvage ASCT (P=0.47), with a HR of 1.74 (95% CI, 0.38-7.85) (Figure 1A). Median OS from date of ASCT was not reached in either group after a median follow-up of 2.8 years (P=0.52), with a HR of 2.16 (95% CI, 0.19-24.04) (Figure 1B). Similarly, median OS calculated from date of diagnosis was not significantly different between deferred vs salvage ASCT (P=0.79) (Figure 1C). Conclusions: In this cohort of 24 AL amyloidosis patients, no significant differences in PFS or OS were seen between patients undergoing deferred ASCT following induction vs salvage ASCT following multiple lines of therapy. Unlike the superior OS seen with deferred vs upfront ASCT, our findings show that either deferred or salvage ASCT may be associated with comparable outcomes and suggest similar OS despite timing of transplant. However, it is important to note the small sample size and that none of our patients received daratumumab-based regimens which may have improved PFS/OS in either or both groups. There were also small differences between groups in use of maintenance (1 vs 3 patients in the deferred and salvage groups, respectively) and proportion of patients receiving higher doses of melphalan 200mg/m2 vs 140 mg/m2 (69% vs 55% in deferred and salvage groups, respectively). Nevertheless, the lack of difference seen in PFS and OS between the two groups suggests that eventual hematologic relapse and organ progression with death occur at similar time intervals despite timing of ASCT. This speaks to the point that in newly diagnosed AL amyloidosis as well as later in the disease, achieving deep responses to prevent organ progression and death regardless of timing of ASCT remains an important treatment goal. Disclosures Van Besien: Miltenyi Biotec: Research Funding. Coleman:Kite Pharmaceuticals: Equity Ownership; Pharmacyclics: Speakers Bureau; Merck: Research Funding; Gilead, Bayer, Celgene: Consultancy, Research Funding, Speakers Bureau. Niesvizky:Takeda, Amgen, BMS, Janssen, Celgene: Consultancy, Research Funding. Rosenbaum:Janssen: Research Funding; Honoraria Akcea: Other: Accordant Health.

Sign in / Sign up

Export Citation Format

Share Document