Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL

Blood ◽  
2014 ◽  
Vol 123 (21) ◽  
pp. 3255-3262 ◽  
Author(s):  
Christian H. Geisler ◽  
Mars B. van t’ Veer ◽  
Jesper Jurlander ◽  
Jan Walewski ◽  
Geir Tjønnfjord ◽  
...  
Keyword(s):  
High Risk ◽  
Low Dose ◽  
Progression Free Survival ◽  
Free Survival ◽  
Younger Patients ◽  
Post Hoc Analysis ◽  
Key Points ◽  
Post Hoc ◽  
Treatment Related Mortality ◽  
Related Mortality

Key Points Frontline FCA increases progression-free survival in CLL and, in a post hoc analysis, also survival in younger patients. With the low-dose approach, no increase in treatment related mortality is seen.

Decitabine As Induction Therapy For Median-To-High-Risk Myelodysplastic Syndromes(MDS) and Acute Myeloid Leukemia(AML) Before Allogeneic Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5044-5044
Author(s):  
Jin Zhou ◽  
Wu Depei ◽  
Chengcheng Fu ◽  
Aining Sun ◽  
Huiying Qiu ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Relapse Rate ◽  
Low Dose ◽  
Survival Advantage ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potentiallycurative therapy for patients with MDS and AML, especially with refractory and relapsed disease. The leading cause of the failure of Allo-HSCT lies in that critical organ disfunction and related complications are common in elderly patients .There’s no matched donor available and high relapse rate were additional risk factors for higher mortality of Allo-HSCT. Decitabine is the only demethylation drugs approved in China for treatment of median-to-high-risk MDS. Treatment with decitabine before Allo-HSCT could reduce tumor burden, keep the disease stable, and allow patients enough time to select a suitable donor. 46 patients with MDS (n=14)and AML (n=32)were admitted in hematological Dept. of First Affilated Hospital of Soochow University who all received treatment with decitabine alone or combined with chemotherapy followed by allo-HSCT between September 2009 andFebruary 2013. Disease classifications of 46 patients (median age 39ys, range 9-54ys) were as follows: RCMD (n=3), RAEB-1(n=2), RAEB-2 (n=9), refractory and relapsed acute leukemia (n=28) and MDS-AML (n=7). All MDS patients were median risk 2 according to IPSS. 57.1% MDS and 68.8% AML patients have chromosomal abnormalities. Patients were treated with decitabine 20mg/m2 for 3-5d alone (n=14) or plus CAG chemotherapy (n=32) prior to modified BuCY condition regimen. Acute graft-versus-host disease (GVHD) prevention regimen were cyclosporine-A (CsA) plus low-dose methotrexate (MTX) for allo-HSCT from HLA-identical sibling donor, anti-thymocyteglobulin (ATG), CsA,Mycophenolate mofetil(MMF) and low-dose MTX for HLA matched allo-HSCT from unrelated donor and HLA haplo-identical allo-HSCT from related donor. The overall response rate and complete remission rates of decitabine treatment before transplantation were 85.7%, 71.4% in MDS patients and 78.1%, 53.1% in AML patients respectively. 91.3% patients obtained successful engraftment. After a median follow-up of 8 months (2-33 months), the overall survival (OS) rate was 76.1%. Treatment-related mortality was 16.8% within 100 days. The incidences of acute and chronic GVHD among evaluable patients were 5.4% and 29.7%. Cumulative relapse rate was 39.1% after transplantation. The 33-months DFS rates and OS rates were 62.5% and 90% in patients who had achieved complete remission treated with decitabine induction prior to transplantation, while median DFS and OS were only 5 ms (p=0.008)and 12.4 ms(p=0.0004)in patients who had not. The survival advantage had nothing to do with the HLA typing and donor. Decitabine induction is an effective therapy to bridge time to HSCT in MDS and AML patients with low treatment-related mortality. Its Improving therapeutic efficacy before transplantation will allow people obtain survival advantage post transplantation. Disclosures: No relevant conflicts of interest to declare.

Pharmacokinetic Dose Guidance of IV Busulfan with Fludarabine with Allogeneic Stem Cell Transplantation Improves Progression Free Survival in Patients with AML and MDS; Results of a Randomized Phase III Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 892-892 ◽  
Author(s):  
Borje S Andersson ◽  
Marcos J de Lima ◽  
Rima M Saliba ◽  
Elizabeth J Shpall ◽  
Uday Popat ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Research Funding ◽  
Progression Free Survival ◽  
Fixed Dose ◽  
Free Survival ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Abstract 892 The myeloablative, reduced toxicity regimen, IV Busulfan (Bu) and fludarabine (Flu), is effective conditioning for allogeneic stem cell transplantation for treatment of patients with AML and MDS. We performed a prospective randomized study to optimize the antileukemic cytoreduction of this regimen, testing the hypothesis that pharmacokinetically (PK-) guided IV Bu-dosing to an average daily AUC of 6,000 μMol-min yields improved leukemia-free survival compared with a fixed IV Bu dose of 130 mg/m2, which gives a median AUC of approximately 5000 μMol-min. The study was approved by the M.D. Anderson Cancer Center IRB and all patients provided informed consent. 139 patients were in a first or second complete remission (CR), 86 were not in remission, including patients with marrow remission but with incomplete hematologic recovery (CRi) or with active disease. Median age was 50 years (range 13–65). 51% received a transplant from a related donor and 49% had unrelated donors. 28% patients received bone marrow and 72% PBPC grafts. Disease characteristics are summarized in the following table. Median follow-up of surviving patients was 25 months (2–66). The patients receiving PK guided busulfan dosing had significantly better progression free survival at 3 years than the fixed dose group, 56% (45–66%) vs. 42% (32–52%) P=0.03, as well as lower cumulative incidence of progression 23% (16–34%) vs. 35% (27–46%) p=0.03. Overall survival at 3 years for the two groups was 57% (46–68%) vs 47% (36–57%) p=0.2. The greatest effect was seen in patients not in remission at the time of transplant. The cumulative incidence of disease progression for the PK Guided and Fixed dose groups was 20% and 25% in patients transplanted in remission (P=0.5), and 29% and 50% for patients transplanted not in remission (P=0.03). Major outcomes are summarized in the following table. There was no significant difference in toxicity pattern, incidence of acute GVHD or treatment related mortality between the PK-guided/adjusted and fixed- dose groups. In multivariate analysis, poor risk cytogenetics and flt3 mutation was associated with inferior PFS. In conclusion, administration of higher dose intravenous busulfan using pharmacokinetic dose guidance targeting an AUC of 6000 μMol-min combined with fludarabine improved progression free survival in patients undergoing allogeneic stem cell transplantation for treatment of AML and MDS, without increasing the risks for serious toxicity and treatment-related mortality. Disclosures: Andersson: Otsuka: Consultancy, MD Anderson Cancer holds a patent on busulfan. Off Label Use: Busulfan for conditioning for AML. Popat:Otsuka: Research Funding. Jones:Otsuka: Membership on an entity's Board of Directors or advisory committees. Nieto:Otsuka Corp: Research Funding. Kebriaei:Otsuka: Research Funding. Worth:Otsuka Corp: Research Funding. Champlin:Otsuka Corp: Research Funding; NCI CA55164: Research Funding.

scholarly journals Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma

Blood ◽  
2016 ◽  
Vol 128 (9) ◽  
pp. 1174-1180 ◽  
Author(s):  
Hervé Avet-Loiseau ◽  
Rafael Fonseca ◽  
David Siegel ◽  
Meletios A. Dimopoulos ◽  
Ivan Špička ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Poor Prognosis ◽  
Progression Free Survival ◽  
Risk Profile ◽  
Risk Status ◽  
Free Survival ◽  
The Poor ◽  
Key Points ◽  
Risk Patients

Key Points KRd has a favorable benefit-risk profile compared with Rd, regardless of baseline cytogenetic risk status, in patients with relapsed MM. KRd improves but does not abrogate the poor prognosis associated with high-risk cytogenetics in patients with relapsed MM.

Non-Myeloablative Umbilical Cord Blood Transplantation (UCBT): Low Transplant-Related Mortality in 59 High-Risk Adults.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 825-825 ◽  
Author(s):  
Juliet N. Barker ◽  
Daniel J. Weisdorf ◽  
Todd E. Defor ◽  
John E. Wagner
Keyword(s):  
High Risk ◽  
Progression Free Survival ◽  
Low Grade ◽  
Free Survival ◽  
Neutrophil Recovery ◽  
Prior Therapy ◽  
Cell Dose ◽  
Co Morbidity ◽  
Related Mortality

Abstract Conventional allogeneic HSC transplantation is limited by lack of rapidly available, HLA-matched donors & excess transplant-related mortality (TRM) in high-risk adults. Therefore, we investigated the combined use of unrelated donor UCB, utilizing 2 units to augment graft cell dose, with non-myeloablative (NMA) conditioning in adults with advanced or high-risk hematologic malignancy. From 10/01 to 3/04, 59 consecutive adults [median age 49 years (range 19–60), median weight 78 kg (range 53–114)] received NMA UCB UCBT. Patients were eligible if: age >45 years (n=43; 73%); &/or extensive prior therapy (n=25; 42%, inc. 14 prior transplants); &/or serious co-morbidity (n=18; 31%). Patients received cyclophosphamide 50 mg/kg (day-6), fludarabine 200 mg/m2 (40 mg/m2 days−6 to −2), & 200 cGy TBI (day-1), with cyclosporine-A to at least day 100 & mycophenolate mofetil to day 30. Twelve patients without recent chemotherapy also received ATG during conditioning. Patients received either single (n=14) or double (n=45) UCB units with a median total infused cell dose of 3.4 x 107 NC/kg (range 1.1–5.7). Of the 104 units used, 61 were 4/6, 35 were 5/6 & 8 were 6/6 HLA-A,B,DRB1-antigen matched with the recipient. Of 58 evaluable patients, neutrophil recovery to >0.5 x 109/l occurred at a median of 8 days (range 5–32) with a cumulative incidence of sustained donor engraftment of 89% (95%CI: 81–97). In patients with sustained donor engraftment the median BM chimerism was 85% (range 8–100) at day 21, 100% (range 72–100) at day 100, & 100% (range 87–100) at 1 year after transplant. Four patients had primary graft failure & 2 had secondary graft rejection. Of the 44 patients with a prior autograft or chemotherapy within 3 months prior to UCBT, 43 (98%) achieved sustained engraftment as compared to 9/14 (64%) patients who had no chemotherapy or whose chemotherapy was at least 4 months prior to UCBT. The cumulative incidences of grade II–IV & III–IV acute GVHD were 63% (95%CI: 49–77) & 25% (95%CI: 14–36) at day 100, & chronic GVHD was 28% (95%CI: 16–40) at 1 year. TRM was 19% (95%CI: 9–29) at day 180, & relapse/progression was 33% (95%CI: 20–46) at both 1 & 2 years. Regression of relapsed or persistent disease has been seen in patients with MDS (n=2), CML (n=1), intermediate and low grade NHL/CLL (n=11), Hodgkins disease (n=1) & myeloma (n=1). With a median follow-up of 16 months (range 4–30), the probability of overall & progression-free survival was 52% (95%CI: 39–65) & 37% (95%CI: 24–50) at 1 year, & 44% (95%CI: 30–58) & 37% (95%CI: 24–50) at 2 years, with no difference in outcome between single & double unit recipients. Notably, day 180 TRM in patients aged >45 years was 14% (95%CI: 4–24), & in those with extensive prior therapy was 24% (95%CI: 8–40). Serious co-morbidity, however, was associated with a higher day 180 TRM of 44% (95%CI: 20–68)(p<0.01). Despite HLA disparity & NMA conditioning, NMA UCBT is associated with prompt neutrophil recovery, a high incidence of sustained engraftment & relatively low TRM in older or extensively pre-treated adults. Further, a graft-vs-malignancy effect is suggested in both myeloid & lymphoid malignancies. Extended follow-up confirms that the progression-free survival is reasonable given the high-risk nature of this patient population. This approach allows transplantation to be offered to many adults who would otherwise be ineligible based on lack of donor &/or inability to tolerate conventional conditioning.

Low-Dose Decitabine Combined with Modified Bucy Is More Effective Conditioning Regimen for High-Risk Patients with Acute Myeloid Leukaemia/Myelodysplastic Syndrome

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5750-5750
Author(s):  
Xiaowen Tang ◽  
Jing Cao ◽  
Xiaojing Shi ◽  
Ling Ge ◽  
Aining Sun ◽  
...  
Keyword(s):  
High Risk ◽  
Low Dose ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Hematologic Malignancies ◽  
Advanced Stage ◽  
Free Survival ◽  
Risk Patients ◽  
Disease Free ◽  
Related Mortality

Abstract Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment options to hematologic malignancies. However, majority of patients with refractory or resistant AML/MDS can not achieve remission before transplantation. It is necessary to design a safe and effective conditioning regimen to reduce tumour burden, improve remission rates, decrease transplantation-related mortality, and improve disease-free survival (DFS) in patients with advanced acute myloid leukemia(AML) and myelodysplastic syndrom(MDS). One of the promising drugs of epigenetics is decitabine (DAC), which has a significant effect on a variety of hematologic malignancies including MDS and advanced AML. Furthermore, decitabine can not only up-modulate the tumor-associated antigen express on surface of leukemia cells to increase graft-versus-leukemia (GVL) effect but also can reduce the incidence of graft-versus-host disease (GVHD) by increase the number of regulatory T Cells (Tregs). Objective: To investigate the security and efficacy of conditioning regimen containing low-dose decitabine combined with modified BUCY regimen for advanced AML/MDS patients, explore the role of immunomodulatory activity post transplantation and compared this regimen with conventional modified BUCY regimen. Methods: Between January 2012 and March 2015, a total of 156 patients were enrolled in this retrospective study. In which, there were 46 patients who received a conditioning regimen of low-dose DAC and a modified BUCY regimen(DAC group) followed by allo-HSCT, and the second cohort consisted of 110 who only received a conventional modified BUCY regimen(Con group). Comparing the baseline of two groups, there were no significant difference except there were more advanced stage patients in DAC group(63% vs 32.7%,p=0.007). A modified BUCY conditioning regimen include semustine (250 mg/m2/d) for 1 d(-10d), cytarabine (2 g/m2 q12 h) for 2 d (-9 d to -8 d), busulfan (0.8 mg/kg/6 h) for 3 d (-7 d to -5 d), and cyclophosphamide (1.8 g/m2/d) for 2 d (-4 d to -3 d). Meanwhile, patients in the DAC group received the DAC treatment for 3 to 4 d with a total of 100 mg/m2 before modified BUCY regimen. Results: In DAC group, all patients engrafted successfully, including 29/46(63%) non-remission (NR) patients. However, there were seven patients presented graft failure in Con group. The transplantation-related mortality (TRM) rate was significantly lower in DAC group(0% vs 13.6%, p=0.019). The median time of neutrophil recovery was 12(10-21)d vs 12(10-23)d, and platelet recovery was 13(10-35)d vs 14(9-40)d, respectively in DAC and Con group, and there were no significant differences. With the median follow-up of 277.5(39-985)d and 221(3-1237)d in two groups, the cumulative relapse rate(RR) was 38.2% vs 36.8% (p=0.951). The incidence rate of aGVHD was lower in DAC group(26.7% vs 46.8%, p=0.034), while there were no diference in the incidence rate of cGVHD(68.4% vs 70.7%, p=0.598). Compared with Con group, the estimated 2-year overall survival (2yr-OS) rate and 2 year disease-free survival (2yr-DFS) rate were both higher in DAC group(2yr-OS:45.6% vs 75.3%, p=0.007, Fig 1; 2yr-DFS:39.1% vs 51.5%, p=0.076). Furtheremore, for patients in advanced stage before transplant, the estimated 2yr-OS was 37.2% vs 72.7%(p=0.009) and 2yr-DFS rate was 38.5% vs 49.8%(p=0.051), respectively. For AMLs, the estimated 2yr-OS rate in DAC and Con group was 75.0% vs 43.0%(p=0.034), and for advanced stage AMLs, the estimated 2yr-OS rate was 66.1% vs 29.7%( p=0.031). Regarding the early relapse rate(RR) of 6 months post transplant, DAC group were less than that of Con group(11.5% vs 35.3%, p=0.124). Conclusion: 1. Low-dose decitabine combined with modified BUCY is a safe and effective conditioning regimen for high-risk patients with AML/MDS with low toxicity and well tolerance. 2. 100% NR patients of DAC group achieved complete remission with full donor chimerism at d30. 3.Comparing with Con group, patients in DAC group had ralative lower incidence of aGVHD, TRM and RR but relative higher estimated 2-yr OS and DFS, especially for advanced stage patients. Disclosures No relevant conflicts of interest to declare.

Prevention of active multiple myeloma (MM) using IL-1 receptor antagonist (IL-1ra) and low-dose dexamethasone (Dex) and monitoring the high sensitivity C-reactive protein (hsCRP)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8105-8105
Author(s):  
J. A. Lust ◽  
M. Q. Lacy ◽  
S. R. Zeldenrust ◽  
A. Dispenzieri ◽  
M. A. Gertz ◽  
...  
Keyword(s):  
High Risk ◽  
Low Dose ◽  
Plasma Cells ◽  
Progression Free Survival ◽  
High Sensitivity ◽  
Myeloma Cell ◽  
Cell Labeling ◽  
Bone Lesions ◽  
Minor Response ◽  
Free Survival

8105 Background: IL-6 is the central myeloma growth factor and we have shown that abnormal production of IL-1beta in the myeloma microenvironment stimulates the generation of paracrine IL-6. A Phase II trial was completed using IL-1ra, which inhibits paracrine IL-6 production, and low dose Dexamethasone (Dex), which decreases IL-1 levels through myeloma cell apoptosis, in patients with smoldering/indolent MM (SMM/IMM). These patients are at the greatest risk for progression to active MM and most likely to benefit from anti- cytokine therapy. Methods: Patients that had ≥ 10% bone marrow plasma cells and/or an IgG or IgA M-spike ≥ 3 g/dL and did not require immediate chemotherapy were eligible. A total of 47 patients received 100 mg of IL-1ra SQ qd for 6 months unless clinical progression occurred. Responding patients were allowed to continue on therapy with IL-1ra alone. Low dose Dex (20 mg qweek) was added after 6 months of IL-1ra in non-responding patients. The primary endpoint was progression-free survival (PFS). Results: The 47 patients were at high risk for progression to active MM with 98% having ≥ 10% plasma cells, 89% generating IL-1 levels consistent with myeloma (≥ 1.0), and 32% having bone lesions. All 47 patients received IL-1ra initially and 25/47 subsequently received IL-1Ra/Dex. For the group of 47 patients, the median overall progression-free survival was 37.5 months. Three patients achieved a minor response (MR) to Anakinra alone; 5 pts achieved a PR and 4 patients an MR after addition of Dex. Seven patients had a decrease in the plasma cell labeling index (PCLI; a marker of myeloma cell growth) on Anakinra alone which paralleled a decrease in the high sensitivity CRP (a marker of serum IL-6 levels). The median PFS for patients without (n=12) and with (n=35) a ≥ 15% decrease in their baseline hsCRP was 6 months and > 3 yrs, respectively (p=0.002). Conclusions: In SMM/IMM patients at high risk for progression to active myeloma, treatment with IL-1 inhibitors (IL-1ra ± Dex) results in an increased PFS in patients that demonstrate a ≥15% reduction in the baseline CRP compared to those that do not respond. No significant financial relationships to disclose.

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