The Impact of Haematopoietic Growth Factors on Supportive Care in Clinical Oncology: With Special Attention to Potential Tumour Cell Contamination in the Stem Cell Harvest

1998 ◽  
pp. 81-95
Author(s):  
C. P. Schröder ◽  
W. T. A. van der Graaf ◽  
P. H. B. Willemse ◽  
E. Vellenga ◽  
L. de Leij ◽  
...  
Keyword(s):  
Stem Cell ◽  
Growth Factors ◽  
Supportive Care ◽  
Clinical Oncology ◽  
Tumour Cell ◽  
The Impact ◽  
Cell Harvest

PET Evaluation Before Autografting Has a Strong Prognostic Impact in High-Risk, Relapsed Follicular Lymphoma Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1612-1612
Author(s):  
Loic Ysebaert ◽  
Jehan Dupuis ◽  
Michel Meignan ◽  
Anne Julian ◽  
Christian Recher ◽  
...  
Keyword(s):  
Stem Cell ◽  
Follicular Lymphoma ◽  
Conditioning Regimen ◽  
Tumor Burden ◽  
Prognostic Impact ◽  
High Tumor Burden ◽  
Richter Syndrome ◽  
The Impact ◽  
Cell Harvest

Abstract Abstract 1612 INTRODUCTION: in follicular lymphoma (FL) patients with high tumor burden (as defined by GELF criteria), R-CHOP is the standard upfront immunochemotherapy. Results from the PRIMA study suggest that a positive PET after induction therapy predicts for earlier relapses, even despite maintenance with rituximab (RTX) for two years [Trotman J, 2011]. For patients under 65y, who relapse after R-CHOP+/−RTX maintenance with high tumor burden, R-chemo+autografting is a recommended option. In a retrospective cohort of 43 relapsed FL pts in two French University Hospitals, we explored the role of such a strategy on outcome - in the era of new RTX based modalities - and also evaluated the impact of PET results before autografting. PATIENTS AND METHODS: Patients with relapsed FL after R-CHOP, with at least 1 GELF criteria at relapse (high tumor burden), and who received R-chemo before autografting were eligible. IWC+PETresponse criteria (Cheson 2007) were used, after R-CHOP frontline, and after salvage (before autografting). Patients with Richter transformation at relapse were excluded from this study. OS was calculated from date of salvage to date of death or last follow-up; progression-free survival (PFS) and time to next treatment (TTNT) were calculated from completion of salvage to date of FL relapse or next chemotherapy, respectively. RESULTS: 43 pts (60% males) younger than 65y were identified: they received either FCR-based (2 cycles of FCR, 1 cycle of R-DHAP then stem cell harvest, 2 last cycles of FCR, n=25) or R-DHAP-based (4 cycles of R-DHAP or DHAOx (oxaliplatin replacing cisplatin), and stem cell harvest, n=18). Characteristics at salvage: median age was 54 (range 28–62), with median GELF score of 1 (1–4). Thirty % had progression within 6 mo of R-CHOP (refractory);median PFS was 12mo (range 1–40mo) andmedian TTNT was 15mo. RTX maintenance in 12/43 pts did not significantly increased PFS (15 vs 9 mo, p=0.1). FLIPI1 was low in 39%, Int 36%, high 25% of pts, and FLIPI2 was low in 22%, Int 62.5%, high 15.5% of pts. 1/43 pt had CD20- relapse (who received RTX maintenance), and received FC without RTX. Results: response to FCR/R-DHAP included CR+CRu 68/72%, PR 24/28% respectively, PET evaluation was found negative in 23.5/36% respectively (p=ns). Median stem cell harvest (median 2 leukaphereses) was 4.37 vs 7.8.106 CD34+/kg in FCR vs R-DHAP pts (Mann-Whitney p=0.09), without failure (only one patient required plerixafor). Four patients did not receive the planned autologous transplant (2 failures after FCR (including one Richter transformation), 1 hepatitis before conditioning regimen, 1 withdrawal of consent). Conditioning regimen for the remaining 39 pts was BEAM in 16 (4 FCR+12 R-DHAP), Zevalin-BEAM in 23 pts (9 FCR+14 R-DHAP), including 9 pts who further received RTX maintenance post-autografting. At a median follow up of living pts of 18mo, 9 pts had relapsed, of which 8 needed additional therapy. At time of analysis (June 2011), 37 pts were alive. Causes for death included 1 pancytopenia and infection, 1 Richter syndrome, 1second cancer, 2 complications of allografting (received later on). Late complications were common: pancytopenia or prolonged grade III-IV neutropenia (>3mo) after procedure occurred in 5/43 pts (3 FCR, 2 R-DHAP, without evidence of MDS/AML in these cases), Richter syndrome occurred in 2 patients (1 death), second cancer in 3 pts (1 Hodgkin, 1 womb sarcoma, 1 lung cancer). On an intend-to-treat basis, 41 pts are evaluable. For FCR/R-DHAP pts, 2y PFS was 68/68%, 2y TTNT 80/70%, and 2y OS 73/100%, respectively (logrank p=ns). Two years TTNT tended to be higher in pts receiving Z-BEAM (55 vs 83%), or with PET negativity before autografting (70 vs 85%), both without reaching significance (logrank p=0.1). PET negativity before autografting was the only variable statistically associated with superior OS in our series (logrank p=0.0003). CONCLUSIONS: Our data suggest that PET negativity before consolidative autografting is an achievable and desirable goal in FL salvaged after R-CHOP. Disclosures: Ysebaert: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding.

FLT3 Signaling Enhances Stemness in Murine MLL-AF9 Acute Myeloid Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2980-2980
Author(s):  
Clare Sun ◽  
Christopher S. Seet ◽  
Jun Zhang ◽  
Yechen Xiao ◽  
Dewen You ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Growth Factors ◽  
Myeloid Leukemia ◽  
Tyrosine Kinase Receptor ◽  
Leukemia Stem Cell ◽  
Surface Phenotype ◽  
And Function ◽  
The Impact ◽  
Acute Myeloid

Abstract Abstract 2980 Acute myeloid leukemia (AML) is developmentally similar to normal hematopoiesis and driven by a subpopulation of leukemia stem cells (LSCs). LSCs are defined by their ability to self-renew and differentiate into more mature leukemia cells. These properties are influenced by the stem cell niche in which they reside. A number of key cytokines within this microenvironment have been identified, including CXCL12 and stem cell factor (SCF), while others have altered the lineage fate of leukemia by in vitro manipulation of growth factor conditions. Activating mutations in fms-like tyrosine kinase receptor-3 (FLT3) have suggested a role for FLT3 signaling in LSC development and function, but little is known about the role of wild type FLT3 and its ligand (FLT3-L) in the LSC niche. In our study, we examined the impact of different hematopoietic growth factors, specifically FLT3-L, on leukemia stem cell properties in a mouse model of MLL-rearranged AML. Murine CD117+ hematopoietic progenitor cells retrovirally transduced with the MLL-AF9 oncogene were selected and cultured in the presence of either FLT3-L or a combination of interleukin-3 (IL-3), interleukin-6 (IL-6), and SCF. We found that FLT3-L selectively expanded a population of CD117+/CD11blo/CD16/32lo cells with a common myeloid progenitor (CMP)-like surface phenotype. This population was present at a frequency of only 1.3% in cells cultured in IL-3/IL-6/ SCF, with remaining cells being mostly CD117+/CD11bhi/CD16/32hi of a granulocyte-macrophage progenitor (GMP)-like surface phenotype. Wright-Giemsa staining showed that cells expanded in FLT3-L also appeared small and morphologically primitive compared to IL-3/IL-6/ SCF cells. When myeloid growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-3 were added, FLT3-L expanded cells differentiated into a heterogeneous population of CD117+/CD11bhi/CD16/32hi and CD117−/CD11bhi/CD16/32hi cells, and regained the typical myelomonocytic blast morphology seen in MLL-AF9 AML. Flow cytometry with Hoechst 33342 and Pyronin Y staining showed that the cells expanded in FLT3-L were more quiescent, with 47.1% in G0 phase compared to only 1.5% in IL-3/IL-6/SCF expanded cells. Consistent with this, FLT3-L expanded cells showed increased resistance to daunorubicin in colony forming assays. Upon transplantation into lethally irradiated mice, cells expanded in FLT3-L produced leukemia at a remarkably higher frequency (8.7 log-fold using limiting dilution analysis) than cells expanded in IL-3/IL-6/SCF. To explain the differences observed, immunoblotting revealed selective upregulation of the canonical Wnt/β-catenin pathway in FLT3-L expanded cells. In AML, Wnt signaling has been shown to mediate leukemogenesis and LSC self-renewal and homing, and thus is a plausible mechanism for regulating the leukemia stem cell properties enhanced by FLT3-L. Our findings suggest a key role for FLT3 signaling in the development and function of LSCs in MLL-AF9 AML through upregulation of the Wnt/β-catenin pathway. Disclosures: No relevant conflicts of interest to declare.

Collection of Hematopoietic Stem Cells After Previous Exposure to Ittrium-90 Ibritumumab Tiuxetan (Zevalin) Is Feasible and Does Not Impair Autologous Stem Cell Transplantation Outcome in Follicular Lymphoma.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3019-3019
Author(s):  
Enrico Derenzini ◽  
Cinzia Pellegrini ◽  
Roberto Maglie ◽  
Vittorio Stefoni ◽  
Alessandro Broccoli ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Median Number ◽  
Disease Course ◽  
Disease Relapse ◽  
First Line ◽  
Cd34 Cells ◽  
The Impact ◽  
Cell Harvest

Abstract Abstract 3019 Background: Radioimmunotherapy (RIT) is an effective and manageable treatment option for those patients (pts) affected by follicular B-cell lymphoma (FL) who experience disease relapse. The results of RIT in the setting of first line consolidation are also very promising in terms of progression free and overall survival. On the other hand autologous stem cell transplantation (ASCT) is a suitable treatment option for relapsed FL patients. Although major concerns about the widespread use of RIT early in the disease course are the long term hematologic toxicity and the theoretical possible irreparable damage to bone marrow function with impairment of peripheral stem cell harvest, very few data are available about mobilization rates after Zevalin exposure. Methods: The aim of this monocentric study was to analyze the impact of prior Zevalin administration on peripheral blood stem cells (PBSC) mobilization and on the outcome of subsequent ASCT. Moreover the impact of different prior treatment regimens [Cyclophosphamide, Doxorubicin, Vincristine, Prednisone plus Rituximab (R-CHOP) or CHOP-like regimens vs Fludarabine, Mitoxantrone plus Rituximab (FM-R) vs Zevalin] and number of previous lines of therapy given earlier in the disease course, was prospectively evaluated in all FL patients (n=100) who underwent stem cell mobilization from January 2005 to March 2012. Results: At the time of mobilization, 68 pts had received R-CHOP or CHOP-like regimens, 20 pts FM-R, 12 pts RIT with Zevalin earlier in the disease course. Characteristics of pts such as age, weight and number of prior therapies, were well balanced in the 3 groups. Sixty one pts had received one prior therapy, 31 pts 2 therapies, 8 pts ≥ 3 lines of therapy. All pts received chemotherapy plus granulocyte colony stimulating factor (G-CSF) 5 μg/kg (n=94) or G-CSF alone (10 μg/kg) (n=6) as mobilization regimen. Mean CD34+ cells yield was 8.9 × 106/kg in the CHOP group, vs 5.8 × 106 CD34 + cells/kg in the FM-R group, vs 2.7 × 106 CD34 + cells/kg in the Zevalin group (p=0.05 CHOP vs FM-R; p<0.001 CHOP vs Zevalin; p<0.01 FM-R vs Zevalin; t test). The collection yield of 2.0 × 106 CD34 + cells/kg was reached in 98% (n=67) of pts in the CHOP group, vs 80% (n=16) in the FM-R group, vs 42% (n=5) in the Zevalin group. The number of previous treatments did not significantly affect PBSC harvest (1 vs 2 lines: p=0.1; 1 vs 3 lines: p=0.1; 2 vs 3 lines: p=0.3). Regarding the engraftment no differences were noted between the 3 groups and the median time to neutrophils (> 1000/μL) and platelets recovery (>20000/μL) was 10 and 11 days in all groups respectively. Only one pt in the CHOP group and one in the FM-R group did not undergo ASCT because of insufficient CD34+ harvest. Considering the Zevalin group (n=12), median age was 51 years (range 36–66). Seven pts received Zevalin as first line consolidation, 5 patients at disease relapse. Median number of prior therapies was 2 (range 1–4). Ten pts received chemotherapy plus G-CSF as initial mobilization regimen, 2 pts received G-CSF alone. Median time from RIT to mobilization was 13 months (4–60 months). Five pts (42%) reached the collection yield of > 2.0 × 106 CD34 + cells/kg with the first mobilization attempt. Considering the remaining 7 pts who failed (CD34+ cells below 10/mL before apheresis, or cell harvest below 2.0 × 106 CD34 + cells/kg), a surgical procedure was attempted in 4 pts, G-CSF + Plerixafor (240 μg/kg) in 3 pts. Remarkably the second harvest allowed 5 additional pts (3 pts after surgery, 2 pts after G-CSF + Plerixafor) to undergo ASCT. Finally ASCT was succesfully performed in 9 pts (75%). Median number of reinfused CD34+ cells was 2.3 × 106 CD34 + cells/kg (0.4–4.2). Three pts did not undergo ASCT, one because of disease progression, 2 pts because of insufficient CD34+ harvest. Conclusions: The type of previous therapy may significantly influence the mobilization rate in FL pts. Although mobilization was significantly impaired in pts previously treated with Zevalin compared to other chemotherapy regimens, stem cell harvest after RIT was feasible and the vast majority of patients retained the possibility to undergo ASCT with a second stem cell harvest, with no significant impact on engraftment. The use of Plerixafor seems to be particularly promising for those patients previously exposed to RIT who failed the first mobilization. Disclosures: No relevant conflicts of interest to declare.

scholarly journals VTD in comparison with VCD does not affect stem cell yields with G-CSF only mobilization

2020 ◽  
Vol 51 (1) ◽  
pp. 42-46 ◽  
Author(s):  
Matevz Skerget ◽  
Barbara Skopec ◽  
Matjaz Sever
Keyword(s):  
Stem Cell ◽  
Outcome Measures ◽  
Standard Of Care ◽  
National Registry ◽  
Newly Diagnosed ◽  
Treatment Groups ◽  
Cell Counts ◽  
Significant Difference ◽  
The Impact ◽  
Cell Harvest

AbstractTriplet induction regimens are standard of care for newly diagnosed transplant eligible multiple myeloma patients. The combinations of bortezomib and dexamethasone with either cyclophosphamide (VCD) or thalidomide (VTD) are widely used. There are no data available on the impact of the two regimens on stem cell harvest by using G-CSF only mobilization. In this study, we retrospectively analyzed data from our national registry. The outcome measures were mobilization failure, CD34+ cell counts on collection day, number of apheresis procedures, and the number of collected cells. Overall, 72 patients were treated with either VCD or VTD. The mobilization failure rates were 7% and 9% (p = 0.771) and the total number of collected stem cells were 7.0 × 106 and 6.7 × 106 per kg body weight (p = 0.710) for VCD and VTD, respectively. We found no statistically significant difference between the treatment groups in the outcome measures. The addition of thalidomide to bortezomib and dexamethasone (VTD) does not adversely affect stem cell harvest in patients mobilized with G-CSF only.

Lenalidomide Enhances Clonogenic Activity, Proliferation and Erythroid Lineage Commitment of CD34+ Progenitor Cells While It Is Cytotoxic to CD34- Accessory Cells.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1184-1184
Author(s):  
Prakash Vishnu ◽  
Athena Paulsen ◽  
Vivek Roy ◽  
Abba Zubair
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Growth Factors ◽  
Progenitor Cells ◽  
Bone Marrow Microenvironment ◽  
Lineage Commitment ◽  
Accessory Cells ◽  
Cd34 Cells ◽  
The Impact

Abstract Abstract 1184 Lenalidomide, a second generation immunomodulatory derivative of thalidomide, has demonstrated significant clinical benefit in myelodysplastic syndrome, multiple myeloma and B-cell malignancies. Its side effects include myelosuppression, particularly neutropenia, and impaired filgrastim induced stem cell mobilization in patients with myeloma. The precise mechanism of action of lenalidomide on hematopoietic and bone marrow microenvironment remains largely unknown. In this study, we investigated the effect of lenalidomide on survival, lineage commitment and differentiation of normal purified CD34+ hematopoietic stem cells. Mobilized peripheral blood progenitor cells (PBPCs) were obtained from a normal allogeneic stem cell donor with an informed consent, and were subjected to positive selection with the EasySep magnetic cell selection system to purify CD34+ cells (purity of 95%). Unsorted and CD34- accessory cells were used as controls. To assess the direct cytotoxic and proliferative effect of lenalidomide on purified CD34+ cells, lenalidomide (Celgene, NJ) was dissolved in DMSO and was diluted in culture medium to final concentration of 0.1, 1, 10, or 100 μM. Purified CD34+, CD34- and unsorted cells were plated in triplicates at a density of 2×104/mL in serum-free StemSpan® medium supplemented with growth factors and cytokines. 24 hours after plating the cells, lenalidomide or 0.1% DMSO as control was added. 72 hours following treatment, cells were counted with Beckman coulter counter and phenotypically analyzed using Accuri C6 flow-cytometer. The percentage of viable cells was determined using 7AAD staining. While no difference in viability was noted in the treated vs. untreated purified CD34+ cells, the viability of CD34- cells and unsorted cells was reduced to 30% and 40% respectively by lenalidomide. Contrary to our assumption, lenalidomide, in a dose dependant manner, induced proliferation of purified CD34+ cells. Maximal increase in proliferation was observed between 1mM and 10mM concentrations. The rate of growth plateaued beyond the 10mM concentration and 100mM concentration appeared to have no additional effect. At the peak of growth (10mM), the cell count nearly tripled. (Fig. 1) Lenalidomide appeared to be cytotoxic to CD34- and unsorted cells in a dose dependant manner. At 100mM concentration, the CD34- cell proliferation dropped by 4 fold and the unsorted cells by 7 fold. To examine the effect of lenalidomide on the clonogenic potential of purified CD34+ cells, 2,000 cells were seeded onto MethoCult® media (Stem cell technologies) supplemented with growth factors and cytokines. Cells were cultured in the presence of lenalidomide (0.1, 1, 10 and 100 μM) or 0.1 % DMSO as control. BFU-E, CFU-GM and CFU-mix were scored on day 14 with the use of an inverted microscope and standard morphological criteria. Significance of difference between groups was determined by student's t test for paired samples. Lenalidomide induced a significant increase in clonogenic activity of CD34+ cells (148 ± 27 colonies per 103 CD34+ cells, p = 0.01), most evident at the dose of 10 μM with enhanced formation of BFU-E (102 ± 23/ per 103 CD34+ cells, p = 0.01) but demonstrated no significant impact on CFU-GM (36 ± 14 per 103 CD34+ cells, p = 0.83) compared to control. (Fig. 2) This study demonstrates that lenalidomide has pronounced effects on both CD34+ and CD34- components of mobilized PBPCs. It enhances the proliferative and clonogenic potentials of CD34+ cells with lineage commitment towards erythroid differentiation. It also has cytotoxic activity towards CD34- cells. It is likely that neutropenia and impaired mobilization of stem cells in patients treated with lenalidomide is mediated via its impact on CD34- accessory cells in the bone marrow microenvironment. Further studies exploring the impact of lenalidomide on normal bone marrow stromal cells, T and NK cell mediated signaling are needed. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Effect of Early Post-Transplantation Tacrolimus Concentration on the Risk of Acute Graft-Versus-Host Disease in Allogenic Stem Cell Transplantation

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 613
Author(s):  
Nidhi Sharma ◽  
Qiuhong Zhao ◽  
Bin Ni ◽  
Patrick Elder ◽  
Marcin Puto ◽  
...  
Keyword(s):  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Tacrolimus Concentration ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
The Impact ◽  
Risk Of Relapse ◽  
Acute Graft

Acute graft versus host disease (aGVHD) remains a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT). Tacrolimus (TAC), a calcineurin inhibitor that prevents T-cell activation, is commonly used as a GVHD prophylaxis. However, there is variability in the serum concentrations of TAC, and little is known on the impact of early TAC levels on aGVHD. We retrospectively analyzed 673 consecutive patients undergoing allo-HSCT at the Ohio State University between 2002 and 2016. Week 1 TAC was associated with a lower risk of aGVHD II–IV at TAC level ≥10.15 ng/mL (p = 0.03) compared to the lowest quartile. The cumulative incidence of relapse at 1, 3 and 5 years was 33%, 38% and 41%, respectively. TAC levels at week 2, ≥11.55 ng/mL, were associated with an increased risk of relapse (p = 0.01) compared to the lowest quartile. Subset analysis with acute myeloid leukemia and myelodysplastic syndrome patients showed significantly reduced aGVHD with TAC level ≥10.15 ng/mL at week 1 and a higher risk of relapse associated with week 2 TAC level ≥11.55 ng/mL (p = 0.02). Hence, achieving ≥10 ng/mL during the first week of HCT may mitigate the risk of aGVHD. However, levels (>11 ng/mL) beyond the first week may be associated with suppressed graft versus tumor effect and higher relapse.

scholarly journals The patient advisor, an organizational resource as a lever for an enhanced oncology patient experience (PAROLE-onco): a longitudinal multiple case study protocol

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
M. P. Pomey ◽  
M. de Guise ◽  
M. Desforges ◽  
K. Bouchard ◽  
C. Vialaron ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Clinical Oncology ◽  
Patient Experience ◽  
Emotional Support ◽  
Social Care ◽  
Legal Issues ◽  
Care Services ◽  
Health And Social Care ◽  
Ethical And Legal Issues ◽  
The Impact

Abstract Background Quebec is one of the Canadian provinces with the highest rates of cancer incidence and prevalence. A study by the Rossy Cancer Network (RCN) of McGill university assessed six aspects of the patient experience among cancer patients and found that emotional support is the aspect most lacking. To improve this support, trained patient advisors (PAs) can be included as full-fledged members of the healthcare team, given that PA can rely on their knowledge with experiencing the disease and from using health and social care services to accompany cancer patients, they could help to round out the health and social care services offer in oncology. However, the feasibility of integrating PAs in clinical oncology teams has not been studied. In this multisite study, we will explore how to integrate PAs in clinical oncology teams and, under what conditions this can be successfully done. We aim to better understand effects of this PA intervention on patients, on the PAs themselves, the health and social care team, the administrators, and on the organization of services and to identify associated ethical and legal issues. Methods/design We will conduct six mixed methods longitudinal case studies. Qualitative data will be used to study the integration of the PAs into clinical oncology teams and to identify the factors that are facilitators and inhibitors of the process, the associated ethical and legal issues, and the challenges that the PAs experience. Quantitative data will be used to assess effects on patients, PAs and team members, if any, of the PA intervention. The results will be used to support oncology programs in the integration of PAs into their healthcare teams and to design a future randomized pragmatic trial to evaluate the impact of PAs as full-fledged members of clinical oncology teams on cancer patients’ experience of emotional support throughout their care trajectory. Discussion This study will be the first to integrate PAs as full-fledged members of the clinical oncology team and to assess possible clinical and organizational level effects. Given the unique role of PAs, this study will complement the body of research on peer support and patient navigation. An additional innovative aspect of this study will be consideration of the ethical and legal issues at stake and how to address them in the health care organizations.

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