The benefit of early admission of allogeneic stem cell transplantation (SCT) recipients to the intensive care unit (ICU) as soon as they develop organ injury is unknown. We performed a retrospective ...study on 92 patients admitted to the ICU to determine the impact of time from organ injury to ICU admission on outcome. The number of organ injuries prior to ICU admission was associated with an increased in-hospital mortality (OR 1.7, 95% CI 1–2.7,
p
= 0.04). Time between first organ injury and ICU admission was also associated with an increased in-hospital survival (OR 1.4, 95% CI 1.1–1.8,
p
= 0.02). A score combining these two covariates—the number of organ injuries/day (sum of days spent with each individual organ injury)—further improved the prediction of hospital survival. Patients with more organ injuries/day had significantly higher in-hospital mortality rate even after adjustment for refractory acute GVHD and the SOFA (OR 1.3, 95% CI 1–1.7,
p
= 0.02). Early ICU admission of allogeneic SCT recipients to the ICU as soon as they develop organ injury is associated with decreased in-hospital mortality.
Hepatobiliary complications are frequent in the context of allogeneic hematopoietic cell transplantation (allo-HCT) and contribute largely to the morbidity and mortality after transplantation. Within ...the framework of the ninth workshops of practice harmonization of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held in Lille in September 2018, diagnostic approaches and treatments of hepatobiliary dysfunctions prior to and following transplantation were reviewed according to the analysis of published studies.
Acute and chronic renal failures are very common after allogeneic HSCT. These complications have a real impact on mortality and morbidity of transplant recipients. Within the framework of the ninth ...workshops of practice harmonization of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held in Lille in September 2018, various causes and mechanisms of renal failure, diagnostic work-up, treatment and recommendations to limit renal failure after transplantation are reviewed. Recommendations to adjust medications to avoid renal failure are also proposed in this article.
Azacitidine (AZA) is the current standard of care for high-risk (ie, International Prognostic Scoring System high or intermediate 2) myelodysplastic syndrome (MDS), but most patients will experience ...primary or secondary treatment failure. The outcome of these patients has not yet been described.
Overall, 435 patients with high-risk MDS and former refractory anemia with excess blasts in transformation (RAEB-T) were evaluated for outcome after AZA failure. The cohort of patients included four data sets (ie, AZA001, J9950, and J0443 trials and the French compassionate use program).
The median follow-up after AZA failure was 15 months. The median overall survival was 5.6 months, and the 2-year survival probability was 15%. Increasing age, male sex, high-risk cytogenetics, higher bone marrow blast count, and the absence of prior hematologic response to AZA were associated with significantly worse survival in multivariate analysis. Data on treatment administered after AZA failure were available for 270 patients. Allogeneic stem-cell transplantation and investigational agents were associated with a better outcome when compared with conventional clinical care.
Outcome after AZA failure is poor. Our results should serve as a basis for designing second-line clinical trials in this population.
Objective The impact of reducing immunoglobulin dosage while switching from intravenous to subcutaneous replacement therapy was evaluated. Methods Sixty-five patients with primary ...hypogammaglobulinemia on stable intravenous replacement therapy were included in a monocentric longitudinal trial. IgG trough levels were measured at baseline and during 1 year following the switch to the subcutaneous route. Results Mean IgG trough level after 12 months of subcutaneous therapy was increased by 5.4% (8.37-8.82 g/l, p = 0.3), while immunoglobulin dosage had been reduced by 28.3% (151-108 mg/kg/week, p < 0.0001). For the patients with the lowest serum IgG level upon intravenous infusions, serum IgG level rose by 37% (5.33-7.33 g/l, p = 0.003), while mean immunoglobulin dosage was reduced by 36% (170-109 mg/kg/week, p = 0.04). Conclusion The present study shows that sustained serum IgG levels can be achieved after switching towards subcutaneous replacement despite using reduced immunoglobulin doses.
Background: MDS or AML occurring during the course of MPD carry a very poor prognosis and current treatments, with the exception of allogeneic SCT, have very limited efficacy. AZA significantly ...improves survival in higher risk MDS (ASH 2007, abstr n° 817) and in some AML, but its use has not been extensively reported so far in MDS and AML post MPD.
Methods: The French health agency (AFSSAPS) designed a still ongoing pt named program (ATU) of AZA in higher risk MDS and poor risk AML. 17 pts with MDS or AML post MPD, included in this program in 5 centers (Paris-Avicenne, Paris St Louis, Paris-Cochin, Tours and Toulouse), before April 08 and having completed ≥ 1 cycle of AZA (75 mg/m2/d during 7 days per 28 d cycle) are analysed here. Response was evaluated according to IWG 2006 criteria for MDS and IWG-AML 2003 criteria for AML.
Results: median age was 68y (range 38–83), M/F: 7/10. The initial MPD was Polycythemia Vera (PV) in 6 pts, Essential Thrombocytopenia (ET) in 7 pts, primary myelofibrosis (MF) in 2 pts and unclassified in 2 pts. Median interval from diagnosis to progression was 10 years (range 7 months-22 years). 10/16 (62%) pts had JAK2-V617F mutation. Treatment of MPD had consisted of HU in 7 pts, pipobroman in 4 pts, both in 4 pts, imatinib in 1 pt and Interferon Alfa in 1 pt. At the time of inclusion, WHO classification was AML in 8 pts, and MDS in 9 pts (RAEB-2 in 8pts, RAEB-1 in 1pt) Karyotype was normal (n=2), isolated −7/7q- (n=3), isolated del 5q (n=1), + 8 (n=2), isolated −17 (n=1), t1;7 (n=2), complex (n=3) including −7 (3), −5(2) and +8(1), and a failure (n=3). Before AZA, 2 pts had received intensive chemotherapy (1 CR, 1 failure) followed by allo SCT in 1 of them (who subsequently relapsed).
The median number of cycles of AZA administered was 4 (range 1–9). 2 pts received only 1 cycle due to early death (from aspergillosis and unknown cause). The overall response rate (ORR, including CR, PR, CRi) was 10/17 (59%). In the 15 pts who received more than 1 cycle, 4/8 MDS achieved CR (including one cytogenetic CR) and 2/8 achieved PR. RBC and platelet transfusion independence were achieved in 4/8 and 6/8 respectively (resp). In AML, 1/7 pts achieved CR and 3/7 achieved CRi. 2 of the 10 responders relapsed (after 5 and 12 months resp) and the other 8 remained responders after 1+ to 12 + months (median 3.5). 9/10 responders were still alive after 2 to 16 months (median 5.5). Interestingly, in 3 pts with a very long history of MPD (15, 16 and 22 years) treated with HU or pipobroman, who at progression had MDS and cytopenias, response to AZA was associated to recurrence of MPD (2 TE and 1 PV) requiring restart of cytoreductive therapy in 2 of them.
Conclusion: 5 AZA gives encouraging results in MDS or AML occurring in the course of MPD with an overall response rate of 59%. An update, with cases recently included in the program, will be presented.
Abstract 1773
Poster Board I-799
Patients aged ≥ 80 years account for as many as 30 to 35% of MDS in large registries (Rollison Blood 2008; Germing Ann Hematol 2008). Those patients (pts), when they ...have high risk MDS, are rarely candidates for chemotherapy (CT), even at low dose like low-dose araC, due to the risk of myelosuppression, and generally receive best supportive care (BSC) only, with very poor survival. Azacytidine (AZA) improves survival in higher-risk MDS pts, including RAEB-t and in pts aged > 75, with more limited myelosuppression than CT (Lancet Oncol 2009).
An AZA compassionate program (ATU) was opened in France between Dec 2004 and Dec 2008 for higher risk MDS, and for AML not candidates or refractory to intensive chemotherapy (IC). We retrospectively analyzed the outcome of MDS (including RAEB-t and CMML) pts ≥ 80 years from the 42 centers with complete patient (pt) reporting, and having received ≥ 1 cycle of AZA.
The study population included 41 pts (M/F: 22/19; median age 83y, range 80-91) WHO diagnosis was RMCD in 2, RAEB-1 in 12, RAEB-2 in 16, and RAEB-t in 8, CMML in 3; IPSS cytogenetic risk favorable (fav) in 16, intermediate (int) in 10, and unfavorable (unfav) in 9 (karyotype failure/not done in 6); IPSS was int-1 in 8, int-2 in 18 and high in 13, undetermined in 2. Six pts had previously been treated unsuccessfully with low-dose AraC.
With a median follow-up of 12 months, pts had received a median of 4 cycles (1-12) of AZA, at FDA/EMEA-approved schedule (75 mg/m2/d x7d/4 w) in 54% or a less intensive schedule (5d/4w, or <75 mg/m2/d) in 46%. Dose reduction was more frequent than in pts < 80y (30%, p=0.04).
Febrile neutropenia was reported in 36% pts, 67% of whom required hospitalization. Both rates were comparable to those observed in pts < 80 years (p=0.2 and p=0.5, respectively), and were not lower in pts treated by less intensive AZA dosing (p=0.7; and p=0.6 respectively). 5 pts (12%) died before completion of 4 cycles, compared to 10% below the age of 80y (p=0.7).
According to IWG 2006 criteria, the overall response rate (ORR) was 34%, including CR in 6 pts (15%), PR in 2 (5%), marrow CR (mCR) in 3 (7%), stable disease (SD) with HI in 3 (7%), SD without HI in 9 (21%), progression in 12 (29%), and AZA discontinuation before 4 cycles in 6 (16% including 5 deaths, 1 SAE). The ORR did not significantly differ from that of pts < 80y (45% p=0.6).
Median OS was 17.1 months and 1-y and 2-y OS were and 59.7% and 49.8% respectively, not significantly different from OS of pts < 80y (median OS: 15 months, p=0.27). The number of patients was too small to analyze prognostic factors of response to AZA and survival.
Although this cohort of higher risk MDS aged 80 or greater obviously included a selected population of relatively “fit” very old persons, our results suggest that treatment with AZA in this age group is associated with significant overall response rates and OS rates at 1 or 2 years. There was no clear evidence of increased toxicity such as a higher hospitalization rate for infection or increased death rate before 4 cycles, when compared to similar patients aged less than 80.
Fenaux:Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.
Abstract 1054
Poster Board I-76
Limited options are available in AML refractory to or relapsing after intensive chemotherapy (IC), especially in elderly patients (pts). Azacytidine (AZA) prolongs ...survival when used as first line treatment of higher-risk MDS and WHO AML with 20-29% BM blasts (Lancet Oncol 2009). Its role in relapsed/refractory AML, especially with baseline BM blasts > 30%, has not been evaluated in large patient (pt) series.
An AZA compassionate program (ATU) was opened in France between Dec 2004 and Dec 2008 for higher risk MDS, and for AML not candidates or refractory to IC. We retrospectively analyzed the outcome of WHO AML (including RAEB-t) included in this program in the 42 centers with complete pt reporting, and who had received ≥ 1 cycle of AZA after relapse or failure of IC.
184 pts were included. Median age was 64 years, 58 pts had prior MDS, 14 had RAEBt at diagnosis, and 16 had therapy-related AML. Cytogenetics (MRC classification) was favorable (fav) in 2, intermediate (int) in 115 (including normal karyotype (NK) in 75), unfavorable (unfav) in 53, and failed in 14 pts. 65 pts had failed to achieve CR (51 after 1, and 14 after ≥2 courses of induction IC), 91 pts were in 1st relapse (median CR duration: 11 months), 28 were in 2nd or subsequent relapse. 20 pts previously had received alloSCT (14 in 1st CR, 5 in 2d CR, 1 refractory).
Median follow-up was 15 months. The median number of AZA cycles was 3 (1-28) at FDA/EMEA-approved MDS schedule (75 mg/m2/d x7d/4 w) in 75% and less intensive (5d/4w, or <75 mg/m2/d) in 25% pts, with concomitant valproic acid (VPA) in 33%.
Febrile neutropenia occurred in 67% pts, requiring hospitalization in 41%. Overall response rate (ORR) (Cheson et al. JCO 2003 criteria) was 11%: CR: 13 (7%), CRi: 5 (3%), PR: 1 (1%). 44 pts died before completing 4 cycles, and AZA was stopped before 4 cycles in another 52 pts (lack of response: n=43, severe infection: n=3, pt decision: n=5, allo SCT: n=1). The remaining 69 pts failed to achieve response after 4 cycles. In the 13 pts with CR, 6 (43%) were in persistent CR after a median follow-up of 7 months. In total, 9 pts received alloSCT after AZA: 2 CR, 7 refractory. Median OS was 7.8 months (1y OS: 29.1%). In univariate analysis, age, prior MDS, disease status (1st, ≥2nd relapse, refractory), WBC count at diagnosis, addition of VPA, and CR1 duration for pts in 1st relapse, did not influence ORR or OS. Only normal karyotype at onset of AZA improved ORR and OS (ORR: 18% vs 7%, p=0.04; 1y-OS: 44.4% vs 15.9%, p=0.001).
We next restricted our analysis to the 141 pts with refractory AML (defined as failure of ≥2 IC cycles in pts <60y and ≥1 IC cycle in pts ≥60y) or in first relapse. 102 of them were aged ≥ 60y (median age 68y; 40 refractory, 62 in 1st relapse; median 1st CR duration: 12 months, range 2 - 54). Their ORR was 13% (CR 9%, CRi 4%). 1y OS was 29.4%, and median OS 8.9 months. OS was not influenced by previous MDS (n=32) or disease status (relapse/refractory). OS was improved in pts with NK (1y OS 42.5% vs 17.3%, p=0.02).
The remaining 39 pts were aged < 60y (median age 52y); 10 of them were refractory, and 29 in first relapse (including 12 with unfav karyotype and 10 having failed 1 IC cycle after 1st relapse). Only 1 pt obtained CR and 1 PR (ORR: 6%), and median OS was 6.9 months (1y OS: 30%).
In this high-risk population of relapsed/refractory AML, AZA resulted in significant responses and OS in AML pts refractory to one cycle of intensive chemotherapy (IC) or in untreated first relapse after IC, who were generally elderly pts. Results were more limited in pts with refractory disease after 2 induction cycles or first relapse resistant to one cycle of IC (who were generally younger). Those results warrant further studies of AZA in combination to other active agents in this population, particularly in elderly patients.
Off Label Use: Azacytidine (FDA and EMEA approved in higher-risk MDS and RAEBt) used in WHO AML (including with marrow blasts > 30%). Fenaux:AMGEN: Research Funding; CELGENE: Research Funding.
PDF
