Incidence of Febrile Episodes During Stem Cells Mobilization After High Dose Cyclophosphamide Chemotherapy and G-CSF (filgrastim or lenograstim) Administration in Multiple Myeloma Patients: Preliminary Final Results.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4560-4560
Author(s):  
Enrico Orciuolo ◽  
Gabriele Buda ◽  
Emerenziana Marturano ◽  
Elisa Mauro ◽  
Giuseppe Milone ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Conflicts Of Interest ◽  
Treatment Plan ◽  
High Dose ◽  
Absolute Count ◽  
Functional Block ◽  
Grade 3 ◽  
Febrile Episodes

Abstract Abstract 4560 Introduction The G-CSF, primary regulator of granulopoiesis, has shown its efficacy in reducing duration of neutropenia after chemotherapy or myelosuppressive therapy. In these situations G-CSF, accelerating the granulocytous reconstitution, may enable a significant reduction of the incidence, duration and severity of infection. Commercially formulations of rHu-G-CSF include lenograstim, a glycosylated form, and filgrastim, a non-glycosylated form. Glycosylation of the molecule contribute to pharmacokynetis advantages and to higher affinity to specific receptor. Additionally, lenograstim exposed neutrophils maintain unchanged all their functions in vitro, while filgrastim exposed neutrophils present functional defects due to higher adhesivity, cytoscheletric alterations and a more immature phenotype. Aim On these bases, we hypotized that lenograstim may prevent febrile episodes (FE) and reduce their lasting in patients with chemotherapy derived neutropenia more efficiently than filgrastim. Primary endpoint is the incidence of FE (ClinicalTrials.gov ID: NCT00932217). Patients and methods starting from April 2005, 180 multiple myeloma patients achieving high dose cyclophosphamide for stem cells mobilization were enrolled in 11 Italian Centers. Treatment plan consisted in: high dose cyclophosphamide (3 or 4 g/sqm) on day 1, G-CSF (random 1:1 on the base of a generated random list: filgrastim or lenograstim) 30 MU/day from day +4 to +9, 60 MU/day from day +10 to the achievement of an optimal CD34+ cell count for staminoapheresis. FE, significant if equal or higher than 38 °C for at least 2 different determinations, were recorded till day +30. Results 176 of 180 patients received scheduled treatment and are eligible for final analyses. All 176 patients underwent post-chemo grade 4 neutropenia and G-CSF was administered starting from day +4. FE were recorded in 26 pts, 16 in the filgrastim arm (89 total patients) and 10 in the lenograstim arm (87 total patients). The global fever incidence was 14.77%, 17.98% with filgrastim and 11.49% with lenograstim. However, to demonstrate functional block of filgrastim exposed neutrophils, FE have been related to neutrophil absolute count. Related to the neutropenia grade, 8 FE are recorded with filgrastim (8.99%) and 1 FE with lenograstim (1.15%) with absolute neutrophil count >500/μL (grade 3) (chi square test with Yates' correction: p=0.0436); this difference is still evident when neutrophils are >1000/μL (grade 2), with 7 episodes with filgrastim (7.87%) versus 1 (1.15%) with lenograstim. Conclusions Lenograstim is associated with a reduced global incidence of FE in multiple myeloma patients undergoing to high dose cyclophosphamide and stem cells mobilization when compared to filgrastim. Additionally, excluding the time frame when neutrophils are not yet recovered (neutrophils <500/μL; grade 4 neutropenia) and G-CSF effects may not be demonstrated, filgrastim treated patients present, when compared to lenograstim treated patients, an higher FE incidence at neutrophil absolute count recovery (both with grade 3 and grade 2 neutropenia), confirming the functional block of filgrastim exposed neutrophils described in vitro. On the contrary, lenograstim allows to recovery normally functional neutrophils as demonstrated by the very low incidence of FE (1.15% with neutrophils >500/μL) in treated patients. Disclosures: No relevant conflicts of interest to declare.

Incidence of Febrile Episode During Stem Cell Mobilization (SCM) After High Dose Ciclophosphamide Chemotherapy (HD-CTX) and G-CSF (filgrastim or lenograstim) Administration in Multiple Myeloma (MM) Patients: II Interim Evaluation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4135-4135
Author(s):  
Enrico Orciuolo ◽  
Gabriele Buda ◽  
E. Mauro ◽  
E. Marturano ◽  
Domenico Pastore ◽  
...  
Keyword(s):  
Treatment Plan ◽  
Febrile Episode ◽  
High Dose ◽  
Functional Capabilities ◽  
Random List ◽  
Secondary Endpoints ◽  
Cell Mobilization ◽  
Grade 3 ◽  
Febrile Episodes

Abstract Introduction: Clinical use of G-CSF in pts with high grade chemotherapy induced neutropenia does not conduce to a reduction of the incidence of febrile episodes (FE). This paradox may be explained by the acquisition of a defective chemotaxis by neutrophils (PMN) exposed to filgrastim (Fil), due to a higher adhesivity and cytoscheletric alterations. Lenograstim (Leno), a glicosilated form of G-CSF, is able to stimulate PMN production, manteining in vitro all the functional capabilities. On these bases, we hypotized that Leno may prevent FE and reduce their lasting in pts with chemotherapy derived neutropenia. Patients and methods: starting from April 2005, 105 MM pts achieving HD-CTX for SCM were enrolled in 12 Centers. Treatment plan consisted in: HD-CTX (3 or 4 g/sqm) on day 1, G-CSF (random: Fil or Leno) 30 MU/day from day +4 to +9, 60 MU/day from day +10 to the achievement of an optimal CD34+ cell count for staminoapheresis. Random, 1:1, was effectuated on the base of a generated random list. FE, significant if equal or higher than 38 °C for at least 2 different determinations, were recorded till day +30. Primary endpoint is the incidence of FE; secondary endpoints are the duration of FE, efficacy in the CD34+ cell mobilization, time to mobilization. Results: 105 pts were enrolled. All pts underwent post-chemo grade 4 neutropenia and G-CSF was administred starting from day +4. FE were recorded in 23 pts, 14 in the Fil arm (53 total pts) and 9 in the Leno arm (52 total pts). The global fever incidence was 21.9%, 26.4% with Fil and 17.3% with Leno, with a 9.1% difference. Average days with fever are 4.00 with Fil and 3.67 with Leno. Related to the neutropenia grade, 8 FE are recorded with Fil and 1 FE with Leno with absolute PMN count &gt;500/μL (grade 4); 7 episodes with Fil vs 1 with Leno when PMN are &gt;1000/μL (grade 3–4). CD34+ SCM occurs in after an average time of 10.3 day with Fil and 9.8 day with Leno, with an higher absolute count with Leno when compared to Fil: 131.9 CD34+/μL (range 40–640) vs 111.6 (range 40–616) CD34+/μL. Conclusions: Leno is associated with a reduced incidence (17.3% vs 26.3%) of FE in MM patients undergoing to HD-CTX and SCM when compared to Fil. FE are recorded with Fil even in presence of PMN confirming the functional block by Fil on PMN documented in vitro. CD34+ mobilization occurs shorter and with higher efficiency with Leno when compared to Fil. On these evidences, patients’ enrollment will continue to 180 to validate these results.

The Optimal Timing for Stem Cell Collection After Induction Therapy for Patients with Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2252-2252
Author(s):  
Aziz Nazha ◽  
Dan T. Vogl ◽  
Una O'Doherty ◽  
Patricia Mangan ◽  
Kathleen Cunningham ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
Conflicts Of Interest ◽  
Optimal Timing ◽  
High Dose ◽  
Cell Transplant ◽  
Cd 34 ◽  
The Mean ◽  
Stem Cell Collection

Abstract Abstract 2252 Introduction: High dose chemotherapy and stem cell transplant remains an integral part of the therapy for Multiple Myeloma patients under age of 70. The collection of sufficient number of stem cells for one or more transplant is however sometimes a challenge. Moreover, the optimal timing for stem cell collection after induction chemotherapies is controversial. The standard recommendation is for stem cell collection after 4–6 cycles of non-alkylator regimen, however studies to support this practice are limited. Material and Method: We conducted a retrospective analysis of 366 patients who were diagnosed with multiple myeloma and mobilized at the Hospital of University of Pennsylvania between January 2002 and December 2008. Patients who did not meet the initial inclusion criteria were those who had induction regimens containing an alkalytor agent or whose regimens were not well documented and were excluded from futher analysis (85). Every 4 cycles of any non-alkalytor agent was considered to be one treatment session for the purpose of this analysis. 245 patients received 1 or 2 treatment sessions and 36 received &gt; 2. All patients were mobilized with either Cyclophosphamide/G-CSF (CY/G-CSF), Plerixafor/G-CSF (AMD/G-CSF), or G-CSF alone. Result: The mean number of collected CD 34+ cells (CD 34+) was 9.22 × 106 CD34+/Kg in the patients who received 1 or 2 sessions and 6.87 × 1106 CD34+/Kg in the patients who received &gt; 2 sessions (P= 0.005). The number of the patients who collected &gt; 6 × 106 CD34+/Kg was 63%(153/246), 53%(19/36) respectively, (p= 0.005). The patients who mobilized with either CY/G-CSF or AMD/G-CSF collected higher number of CD34+ than the patients mobilized with G-CSF alone in both groups. (Table 1, 2.) The mean number of collected stem cells was 7.14 × 106 CD34+/Kg in the patients who received more than 2 sessions of different regimens and 6.26 × 106 CD34+/Kg in the patients who received &gt; 2 sessions of the same regimen. Conclusion: The patients who mobilized after fewer than 8 cycles of non-alkylator agents (2 sessions) collected a higher number of CD 34+ than those with greater than 8 cycles. CY/G-CSF or AMD/G-CSF are similar and superior to G-CSF alone in the more heavily treated patients. The patients who received multiple sessions of the same regimen have similar outcome compared to those who received multiple different regimens suggesting that the duration of the treatment may impact stem cell collection more than the content of the regimen. Prospective studies in this regards are warranted. Disclosures: No relevant conflicts of interest to declare.

Hematopietic Stem Cells with Defects in the NF-κB Alternative Pathway Show a Deficient Repopulation Capacity

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1269-1269
Author(s):  
Lucia Fernandez ◽  
Africa Gonzalez ◽  
Carmen Sanchez-Valdepeñas ◽  
Luis Madero ◽  
Roland M Schmid ◽  
...  
Keyword(s):  
Stem Cells ◽  
Blood Cells ◽  
Conflicts Of Interest ◽  
Alternative Pathway ◽  
High Dose ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Deficient Mice ◽  
Marrow Cells

Abstract Abstract 1269 Hematopoietic stem cells (HSCs) maintain the production of all blood cells through the lifespan of an organism, and regenerate the whole hematopoietic system after stressful episodes such as high dose chemotherapy or upon transplantation. The functions of HSCs in these 2 situations, steady-state and under stress, are controlled by a variety of molecules, which may provide different contribution to each process. We investigated whether the NF-kB alternative pathway might have a role in HSCs functions, using mice deficient for two components of this pathway: NF-kB-inducing kinase (NIK) or p52. The activation of NIK is generally known as the alternative (or non-canonical) NF-kB pathway, and drives the post-translational processing of p100 to mature p52, which results in the translocation to the nucleus of p52-containing complexes such as p52/RelB. Apart from the already reported defects in B-cell maturation, both NIK- and p52-deficient mice did not present major disturbances in blood cells numbers. The absolute numbers of marrow cells were not different among the knocked-out and the wild-type mice. We first studied the compartment of marrow cells known to be enriched for HSCs, either lineage-depleted Sca1-positive ckit-positive cells (LSK), or CD150 positive CD48 negative cells. The proportions of marrow cells with the immunophenotype of HSCs in either NIK-deficient or p52-deficient mice were similar to those in control mice. The amount of clonogeneic progenitor cells in the marrow was assessed in standard CFU-GM cultures, and gave no differences in output in any of the mice studied. We set up in vitro liquid cultures with murine stem cell factor and human interleukin-11, and determined the cellular production weekly. Cultures started with NIK-deficient marrow cells produced significantly less numbers of cells and CFU-GM, compared with those started with wild type marrow. This deficit in hematopoietic capacity was further confirmed in a more stringent assay of HSC function, the in vivo competitive repopulation assay. Equal numbers of lineage-depleted (Lin-) CD45.2 marrow cells of either NIK-deficient, p52-deficient or wild-type mice, were mixed with Lin- CD45.1 marrow cells of syngeneic mice, and transplanted into lethally irradiated CD45.1 recipients. Four months after transplant, the chimeric status and the hematopoietic lineage repopulation of CD45.2 cells was assessed in peripheral blood (PB). NIK- or p52-deficient HSCs repopulated the B-, T- and myeloid-lineages but at significantly lower levels when compared to wild type HSCs. Total donor CD45.2 cells and total CD45.2 LSK cells were also significantly lower in the marrows of mice transplanted with NIK- or p52-deficient HSCs versus those of controls. We used the marrows of the repopulated mice for secondary transplants, and confirmed the defect in the repopulating capacity of NIK- and p52-deficient HSCs. Our results suggest that the NF-kB alternative pathway plays a role in the function of HSCs, and this role may be important under stress conditions. Disclosures: No relevant conflicts of interest to declare.

The More Effective and the More (bio) Similar: Plerixafor and Filgrastim XM02 (tevagastrim) As First Line PBSC Mobilization Strategy in Patients with Multiple Myeloma and Lymphomas Candidate to ABMT

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2994-2994
Author(s):  
Daniele Laszlo ◽  
Giovanna Andreola ◽  
Aleksandra Babic ◽  
Mara Negri ◽  
Cristina Rabascio ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Conflicts Of Interest ◽  
Median Number ◽  
High Dose Chemotherapy ◽  
European Medicines Agency ◽  
High Dose ◽  
First Line ◽  
Adequate Number ◽  
Cd34 Cells

Abstract Abstract 2994 Patients affected by hematologic malignancies might benefit from high dose chemotherapy followed by peripheral stem cells (PBSC) transplant. Chemotherapy in combination with G-CSF is effective in mobilizing stem cells but often toxic, might require prolonged hospitalization and extensive supportive care. Moreover a high proportion of patients, ranging from 11 to 53%, fail to collect an adequate number of stem cells with this approach. In this setting plerixafor, a CXCR4 chemokine antagonist, has shown to increase the number of circulating CD34+ cells in cancer patients when used alone or with G-CSF and to be able to rescue patients unable to mobilize with traditional regimens. Recently, several forms of biosimilar nonglycosylated recombinant human G-CSF have been clinically developed and approved by the European Medicines Agency for the same indications as the reference filgrastim product on the basis of comparable quality, efficacy, and safety. Biosimilars also provide a more cost-effective strategy and their use in clinical setting may provide cost savings in their indicated uses. From December 2010 to July 2011, 16 patients, median age 55 (19–67), affected by Non-Hodgking Lymphoma (6), Hodgking Disease (2) and MM (8), received a combination of biosimilar version of G-CSF (Tevagrastim) and plerixafor in order to mobilize PBSC as first line strategy. Tevagrastim was self-administered (10μg/kg/die) for 3 days; on day 4 patients were admitted to the hospital, circulating CD34+ cells counted and if >20 cells/μl, plerixafor was administered (0.24mg/kg) 12 hours before the scheduled apheresis. There were 7 males and 9 females, median lines of previous chemotherapy was 1(1–4). Median number of circulating CD34+ cells on day 4 was 16 (8–42). Plerixafor was administered to all but 1 patients who had already 42 CD34+ cells/μl on day 4. On day 5, after plerixafor administration median number of circulating CD34+ cells had raised to 68/μl (18–138). All the patients underwent leukapheresis and were able to collect an adequate number of CD34+ cells necessary for the transplantation procedure with a median number of 5.2 ×106 (2.2–10.6) CD34+cells/kg in a median number of 1 procedure (1–2). For patients with Multiple Myeloma, 6/8 patients were able to collect a median of 5.8×106 CD34+/kg (4.2–10.6) in a single procedure. No major side effect was observed. So far, 7/16 patients underwent high dose chemotherapy followed by PBSC transplant. Engraftment occurred in all patients with a time to ANC>500 of 12 (9–13) and of PLT>20.000 of 13 (9–19) days. The combination of tevagrastim and plerixafor is safe and effective in mobilizing PBSC and allows a collection of a more than adequate number of cells in most of the patients in a maximum of 2 apheresis procedure, even in patients with MM who need to collect a double amount cells. Disclosures: No relevant conflicts of interest to declare.

TM-233 Exerts Anti-Myeloma Activity and Overcomes Bortezomib-Resistance In Human Multiple Myeloma Cells By Targeting NF-κB and JAK/STAT Dual-Signaling Pathways

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4427-4427
Author(s):  
Morihiko Sagawa ◽  
Tatsuki Tomikawa ◽  
Tomoe Anan ◽  
Takayuki Tabayashi ◽  
Reiko Watanabe ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Signaling Pathways ◽  
Conflicts Of Interest ◽  
Subcutaneous Administration ◽  
Cellular Growth ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Grade 3

Although the introduction of bortezomib and immunomodulatory drugs (IMiDs) has led to improved outcomes in patients with multiple myeloma (MM), the disease remains incurable. Bortezomib, a proteasome inhibitor, is widely used in the treatment of MM and has resulted in marked therapeutic effects; however, this therapy is often complicated by peripheral neuropathy (PN), of which grade ≥3 PN is dose-limiting toxicity and can necessitate cessation of therapy. Subcutaneous administration of bortezomib can reduce the incidence of PN; however, among cases of PN that still occur, 24% are grade 2 PN and 6% are grade 3 PN. These data suggest that the incidence of PN higher than grade 2 is not attenuated by the subcutaneous delivery of bortezomib. In addition, patients often become refractory to bortezomib after long-term use. In an effort to identify potent and well-tolerated agents, clinical trials of novel agents (e.g., carfilzomib, pomalidomide, and monoclonal antibody against CS-1) are being conducted both in patients with newly diagnosed MM and in those with relapsed/refractory disease. We previously reported that 1’-acetoxychavicol acetate (ACA) obtained from the rhizomes of the plant Languas galanga induces cell death of MM cells in vitro and in vivo through inhibition of NF-κB-related functions (Cancer Res, 2005; 65: 4417). Subsequently, we developed several ACA analogs based on quantitative structure-activity relationship (QSAR) analysis to develop more potent NF-κB inhibitors, and successfully synthesized a novel benzhydrol-type analog of ACA, named TM-233, that exerted potent growth inhibition against various MM cells (U266, RPMI8226, and MM-1S cells) in a dose- and time-dependent manner when compared with ACA (Chem Pharm Bull., 2008; 56: 1490). Further, TM-233 inhibited constitutive phosphorylation of JAK2 and STAT3 and down-regulated the expression of anti-apoptotic Mcl-1 protein. TM-233 directly bound and activated the transcription of the Mcl-1 gene promoter. Mcl-1 is the downstream molecule of STAT3; therefore, these results suggest that TM-233 induces cell death in MM cells with down-regulated Mcl-1 via modulation of the JAK/STAT pathway. In addition, we examined the DNA-binding activity of NF-κB in TM-233-treated MM cells and found that NF-κB was inhibited by TM-233. Further, Western blotting showed that TM-233 rapidly decreased the nuclear expression of NF-κB but increased the accumulation of NF-κB in the cytosol, suggesting that TM-233 inhibits the translocation of NF-κB from the cytosol to the nucleus. Immunohistochemical analysis confirmed that the p50/RelA dimer of NF-κB was located in the cytosol and not in the nucleus in TM-233-treated MM cells. We then examined the effects of TM-233 on bortezomib-resistant MM cells. Bortezomib-resistant MM cell lines (i.e., KMS-11/BTZ and OPM-2/BTZ) were established by limiting dilution. We found that these cells have a unique point mutation, G322A, in the gene encoding the proteasome β5 subunit (Leukemia 2010; 24: 1506). TM-233, but not bortezomib, inhibited cellular growth and induced cell death in KMS-11/BTZ and OPM-2/BTZ cells in a time- (0-48 hours) and dose- (0-5 μM) dependent manner. Furthermore, the combination of low-dose TM-233 (less than 2 μM) and bortezomib (10 nM) significantly induced cell death in bortezomib-resistant MM cells via inhibition of NF-κB activity. These results indicate that TM-233 could overcome bortezomib resistance in MM cells by acting via different mechanisms from those of bortezomib. In conclusion, TM-233 induced cell death in MM cells, and this effect was mediated through the JAK/STAT and NF-κB dual-signaling pathways. These data indicate that TM-233 might be a more potent and more specific NF-κB inhibitor than that of original compound (ACA), and might be able to overcome bortezomib-resistance in MM cells. Therefore, further studies investigating clinical approaches, including combination therapy, are warranted. Disclosures: No relevant conflicts of interest to declare.

Bortezomib Added to the Standard Mobilization Regimen of G-CSF and High-Dose Cyclophosphamide Is a Safe and Effective Combination for a High Yield Stem Cell Collection While Promoting Further Tumor Mass Reduction in Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2953-2953 ◽  
Author(s):  
Jessica L. Stern ◽  
Brian Di Carlo ◽  
Michael W. Schuster ◽  
Tsiporah B. Shore ◽  
John G. Harpel ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
Alkylating Agents ◽  
Pegylated Liposomal Doxorubicin ◽  
Stem Cell Mobilization ◽  
High Dose ◽  
Cell Mobilization ◽  
Grade 3 ◽  
Stem Cell Collection

Abstract Standard stem cell mobilization regimens for multiple myeloma patients include G-CSF alone or in combination with high dose cyclophosphamide. Given the known in vitro and in vivo synergy between alkylating agents and proteosome inhibitors, we sought to optimize the potential for concurrent cytoreduction by adding bortezomib to the mobilization regimen. Five evaluable patients, whose prior therapy consisted of six cycles of a 21-day treatment with bortezomib/dexamethasone +/− pegylated liposomal doxorubicin, were mobilized. They received IV push bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11 in combination with high-dose cyclophosphamide at 3mg/m2 and MESNA on day 8. G-CSF was given for 10 consecutive days starting on day 9. One patient began this regimen in nCR, two were in PR, and two were in CR by urine and serum immunofixation and bone marrow evaluation. Stem cells were easily harvested from each of the five patients. The number of CD34+ cells collected far exceeded the amount normally mobilized with cyclophosphamide and/or G-CSF alone, with four out of 5 patients collected in a single day. The two patients who began the mobilization cycle in PR continued to respond positively. Their protein levels dropped an additional 8.9 and 14.6 percent respectively during the last cycle. The patient who began mobilization in nCR achieved a CR by the end of treatment. Some expected toxicities associated with high dose cyclophosphamide and G-CSF occurred. All patients experienced grade 3 and 4 cytopenias, however, they recovered and were able to continue on to transplant. Serious adverse events of grade 3 chest pain (non-cardiac), grade 4 pneumonia, and grade 4 febrile neutropenia also occurred. Bortezomib in addition to high dose cyclophosphamide followed by G-CSF is a novel, well-tolerated and efficacious combination for stem cell mobilization in patients with multiple myeloma. This regimen not only yields a high number of stem cells within a short collection time, but may further cytoreduce disease as well. Stem Cell Collection Patients Days Required for Collection CD34+ Stem Cells (million/kg) 1 1 21.2 2 1 47.4 3 1 22 4 1 17.9 5 4 40.6

Bortezomib-Containing Regimens for Multiple Myeloma Maintenance Therapy: a Meta-Analysis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3473-3473
Author(s):  
Yucai Wang ◽  
Wenwen Zhang ◽  
Fang Yang ◽  
Xiaoxiang Guan ◽  
Neil Kothari ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Maintenance Therapy ◽  
Conflicts Of Interest ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
High Dose ◽  
Vascular Events ◽  
Cardiac Disorders ◽  
Grade 3

Abstract Objective: To evaluate the efficacy and safety of bortezomib-containing regimens in maintenance therapy of multiple myeloma through meta-analysis of randomized controlled trials (RCTs). Patients and methods: PubMed, Web of Science and ASH databases were searched for RCTs that investigated the treatment outcomes (progression-free survival [PFS] and overall survival [OS]) of maintenance therapy with bortezomib-containing regimens in patients with multiple myeloma. Study endpoints included PFS, OS, and grade 3 or 4 adverse events. Pooled hazard ratios (HRs) for survival outcomes and risk ratios (RRs) for dichotomous data with 95% confidence interval (CI) were calculated using Comprehensive MetaAnalysis (v2). Results: Three RCTs comprising 1396 patients were included in this meta-analysis. Compared with maintenance therapy without bortezomib and/or no maintenance therapy, bortezomib-based maintenance therapy regimens significantly prolonged PFS (HR = 0.66, 95% CI = 0.58 - 0.76, P < 0.001) and OS (HR = 0.74, 95% CI = 0.62 - 0.88, P = 0.001) in multiple myeloma patients. In patients who received high-dose chemotherapy followed by autologous stem cell transplantation (ASCT), bortezomib-based maintenance therapy increased both PFS (HR = 0.73, 95% CI = 0.61 - 0.86, P < 0.001) and OS (HR = 0.76, 95% CI = 0.61 - 0.95, P = 0.016). For transplant ineligible patients, maintenance therapy with bortezomib-containing regimen also increased PFS (HR = 0.58, 95% CI = 0.47 - 0.71, P < 0.001) and OS (HR = 0.70, 95% CI = 0.52 - 0.92, P = 0.012). However, bortezomib-based maintenance therapy increased the risks of grade 3 or 4 adverse events including thrombocytopenia (RR = 1.37, 95% CI = 1.01 - 1.87, P = 0.046), infections (RR = 1.29, 95% CI = 1.02 - 1.64, P = 0.035), cardiac disorders (RR = 2.01, 95% CI = 1.17 - 3.47, P = 0.012), and vascular events (RR = 2.02, 95% CI = 1.15 - 1.45, P= 0.015). Conclusions: Bortezomib-based maintenance therapy results in significant improvement in PFS and OS in multiple myeloma patients, but may increase the risk of developing some grade 3 or 4 adverse events, such as thrombocytopenia, infections, cardiac disorders, and vascular events. Further studies are needed to corroborate the above findings given the limited data on proteasome inhibitor based maintenance therapy for multiple myeloma. Disclosures No relevant conflicts of interest to declare.

scholarly journals Differential Expression of MicroRNA-19b Promotes Proliferation of Cancer Stem Cells by Regulating the TSC1/mTOR Signaling Pathway in Multiple Myeloma

2018 ◽  
Vol 50 (5) ◽  
pp. 1804-1814 ◽  
Author(s):  
Ni Wang ◽  
Xiaohua Liang ◽  
Weijian Yu ◽  
Shihang Zhou ◽  
Meiyun  Fang
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Cancer Stem Cells ◽  
Real Time ◽  
Caspase 3 ◽  
In Silico Analysis ◽  
Luciferase Assay ◽  
Downstream Target ◽  
Induced Apoptosis

Background/Aims: MiR-19b has been reported to be involved in several malignancies, but its role in multiple myeloma (MM) is still unknown. The objective of this study was to explore the biological mechanism of miR-19b in the progression of MM. Methods: First, we performed real-time polymerase chain reaction (PCR) and Western blot to study the expression of miR-19b, tuberous sclerosis 1 (TSC1), and caspase-3 in different groups. MTT assay was performed to explore the effect of miR-19b on survival and apoptosis of cancer stem cells (CSCs). Computation analysis and luciferase assay were utilized to confirm the interaction between miR-19b and TSC1. Results: A total of 38 participants comprising 20 subjects with MM and 18 healthy subjects as normal controls were enrolled in our study. Real-time PCR showed dramatic upregulation of miR-19b, but TSC1 was evidently suppressed in the MM group. MiR-19b overexpression substantially promoted clonogenicity and cell viability, and further inhibited apoptosis of CSCs in vitro. Furthermore, miR-19b overexpression downregulated the expression of caspase-3, which induced apoptosis. Using in silico analysis, we identified that TSC1 might be a direct downstream target of miR-19b, and this was further confirmed by luciferase assay showing that miR-19b apparently reduced the luciferase activity of wild-type TSC1 3´-UTR, but not that of mutant TSC1 3´-UTR. There was also evident decrease in TSC1 mRNA and protein in CSCs following introduction of miR-19b. Interestingly, reintroduction of TSC1 abolished the miR-19b-induced proliferation promotion and apoptosis inhibition in CSCs. Conclusion: These findings collectively suggest that miR-19b promotes cell survival and suppresses apoptosis of MM CSCs via targeting TSC1 directly, indicating that miR-19b may serve as a potential and novel therapeutic target of MM based on miRNA expression.

scholarly journals The Molecular Basis of Long First Remissions in Normal Karyotype AML Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3827-3827
Author(s):  
Francesca Ferraro ◽  
Christopher A Miller ◽  
Amy Abdalla ◽  
Nichole Helton ◽  
Nathan Salomonis ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Somatic Mutations ◽  
Conflicts Of Interest ◽  
Normal Karyotype ◽  
High Dose ◽  
Intermediate Risk ◽  
The Mean ◽  
Cebpa Mutations

Currently, it is not clear why some patients with acute myeloid leukemia (AML) can be "cured" with chemotherapy alone; are they living with small amounts of disease that is held in check by immunologic (or other) mechanisms, or is their disease really eradicated? The percentage of cytogenetically normal AML patients who have long (>5 years) first remissions (LFRs) after chemotherapy alone is low (about 9.1% in patients <60 years and 1.6% in >60 years1). For this reason, most intermediate risk patients are offered allogeneic transplantation to decrease their risk for relapse. To better understand mechanisms of chemotherapy sensitivity in AML, we performed an analysis of the mutation landscape and persistence, using samples from 8 normal karyotype LFR patients (without CEBPA mutations) who received standard "7+3" induction and high dose cytarabine consolidation as their only therapy. The mean age at diagnosis was 43.5 years, and the mean follow up in first remission is 7.6 years; none of these patients has relapsed to date. For each case, we performed enhanced exome sequencing at diagnosis (235x coverage of the entire exome, and ~1008x coverage of recurrently mutated AML genes). Each case had at least one documented AML driver mutation, with a median of 29 somatic mutations in the exome space. We created probes for 225 mutations (mean 28 per case), and performed error-corrected sequencing (Haloplex) for all available remission samples. The mean depth of Haloplex coverage was 1607x, and each sample had at least one AML-specific mutation assayed, with a sensitivity of 1 cell in 1,750 (0.06%). 7/8 patients demonstrated complete clearance of all mutations in all remission samples tested, which was confirmed with digital droplet PCR for 5 cases, with a sensitivity of detection of 1 cell in 100,000. In one case, we detected a persistent ancestral clone harboring DNMT3AR882H, which can be associated with long first remissions for some patients2. Strikingly, the founding clone in all 8 cases had one or more somatic mutations in genes known to drive cell proliferation (e.g. MYC, FLT3, NRAS, PTPN11, Figure 1 top panel). These are usually subclonal mutations that occur late during leukemic progression, suggesting that the presence of a "proliferative hit" in the founding clone might be important for chemotherapy clearance of all the AML cells in a given patient. To support this hypothesis, we analyzed the mutational clearance of 82 AML cases with paired diagnosis and day 30 post-chemotherapy bone marrow samples. We observed that, whether present in the founding clone or in subclones, mutations in MYC, CEBPA, FLT3, NRAS, and PTPN11 cleared after induction chemotherapy in all samples, while other mutations were often persistent at day 30 (e.g. DNMT3A, IDH1, IDH2, NPM1, TET2; Figure 1 bottom panel). Compared to other published sequencing studies of AML, MYC and NRAS mutations were significantly enriched in this small cohort (MYC p= 0.002, and NRAS p= 0.034), with MYC enrichment being particularly striking (37.5% versus 1.8%). All MYC mutations were canonical single base substitutions occurring in the highly conserved MYC Box 2 domain at the N-terminus of MYC (p.P74Q or p.T73N). Overexpression of MYCP74Q in murine hematopoietic progenitors prolonged MYC half life (89 min vs. 44 min for wild type), and enhanced cytarabine sensitivity at all concentrations tested (range 10-1000 nM, p=0.0003), both in vitro and in a MYC-driven leukemia model in vivo. MYC expression measured with flow cytometry in the blasts of the LFR samples was significantly higher (p=0.045) compared to unfavorable risk (complex karyotype) or other intermediate risk categories, but similar to good risk AML (biallelic CEBPA mutations, core binding factor fusion-associated AML, and AML with isolated NPMc), suggesting that activation of the MYC pathway may represent a shared feature of chemosensitive patients. Taken together, these data suggest that some intermediate patients who are effectively "cured" with chemotherapy alone may not have persistent subclinical disease, nor retained ancestral clones that could potentially contribute to relapse. Importantly, these patients often have mutations driving cell proliferation in the founding clone, indicating that the presence of specific mutations in all malignant cells may be critical for complete AML cell clearance with chemotherapy. 1. Blood Adv. 2018 Jul 10; 2(13): 1645-1650 2. N Engl J Med 2018; 378:1189-1199 Disclosures No relevant conflicts of interest to declare.

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