Prognostic Factors of Infections and Effect of Primary Anti-Infectious Prophylaxis in MDS Patients Treated with Azacitidine (AZA): A Prospective Study

Abstract Background: Hypomethylating agents, especially AZA, have become the reference first line treatment of high-risk MDS. Myelosupression, although less important than with chemotherapy, is however observed, leading to potentially life threatening infections. A retrospective study found unfavorable (unfav) cytogenetics and low platelet counts to be predictive factors of infections in high risk MDS and AML patients (pts) receiving AZA (Merkel and al, Am j Hemat 2012). However, prognostic factors of infections, and whether infection prophylaxis would be useful in this situation, has not been prospectively evaluated. Methods: Between June 2011 and March 2013, 120 high-risk MDS pts were included in a randomized phase II trial seeking the most promising drug association with AZA by comparison with AZA alone in higher risk MDS (including AML with 20 to 30% marrow blasts and CMML with > 10% marrow blasts) (NCT01342692). Pts received AZA (75mg/m²/dx7d every 4 weeks) alone (N=40), with Valproic acid (N=40) or with Lenalidomide (N=40) (10mg/dx14d every 4 weeks). G-CSF was not used. Infectious events (IE) (diagnosed as such by the treating physician), hospitalizations for sepsis and pts receiving antimicrobial prophylaxis were reported at each cycle. Predictive factors of the occurrence of IE were analyzed. Results: 75 (62.5%) pts developed 259 IE, including 61 requiring hospitalization in 46 pts (61.3% of infected patients). The number of IE and of infected patients were similar in the 3 study arms. 39 pts died during the study, 12 of them because of infection, none of whom had responded to AZA (4 progressions, 4 failures and 4 deaths before evaluation). IE were more common during the first two cycles of therapy, with 86 (31.3%), 52 (23.5%) 45 (18.9%), 26 (15%), 15(19.2%) and 24 (19.7%) IE during cycles 1, 2, 3, 4, 5, and 6, respectively. Fever of unknown origin (FUO) (39.6%) and pneumonia (28.8%) were the most common type of infections followed by ENT (9.9%), urinary tract (8.1%), skin (5.4%), dental (4.5%) and intra-abdominal (3.6%). 6,3% were bacteriemia. Among the 26 microbiologically documented IE, 13 were CG+ (4 staph aureus, 4 enteroccus species, 4 coag neg staph and 1 other), 9 were BG- (6 E Coli, 1 pseudomonas and 2 others) and 3 were viral (HSV1, influenza B, Hepatitis E) and only one patient had documented invasive fungal infection (asp fumigatus). Overall, 23 (19%), 22 (18%), 10(8%) pts received bacterial (Levofloxacine), fungal (posaconazole) and viral (Valaciclovir) prophylaxis resp. Predictive factors of IE were unfav karyotype (79.5% infections vs. 50.8% in pts with fav or int karyotype; p=0.005) and platelets (PLT) < 20 G/L (92.3% infections vs. 58.9% for platelets > 20 G/L; p=0.03). In multivariate analysis, only unfav karyotype was predictive of IE (p=0.01). Other baseline parameters (including ANC, IPSS, age, sex, Hb level, and BM blast %) and bacterial, fungal or viral prophylaxis had no significant predictive value on the occurrence of IE. In multivariate analysis, predictive factors of pulmonary infection were anemia at baseline (p=0.04) and unfav karyotype (p<0.001), while prophylaxis had no significant impact. Infected pts had significantly more hospitalizations and deaths than non-infected pts (p<0.0001 and p=0.028 resp.). In multivariate analysis, unfav karyotype (p<0.001) and PLT <20 G/L (p=0.05) were significantly predictive of hospitalization for infection, while baseline Hb <10g/dL (p=0.02), and unfav karyotype (p=0.03) were predictors of fatal infection. Conclusion: 62.5% of the 120 pts developed infections during AZA treatment, mainly during the first 2 cycles, and 10% of the pts died from infection. Only one invasive fungal infection was documented. Unfav karyotype was strongly predictive of IE, hospitalization for infection and fatal infections. Other significant predictive factors were baseline anemia for pulmonary infection and fatal infection, and thrombocytopenia for hospitalization for infection, while ANC was not a significant factor. Moreover, prophylaxis was not associated with a decrease of IE in our study, but the small number of pts who received it precludes any conclusion. Disclosures Ades: celgene: Research Funding; Novartis: Research Funding. Fenaux:Novartis: Research Funding; celgene: Research Funding; Janssen: Research Funding.

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Varying Importance of Prognostic Factors in Subgroups of Myelodysplastic Syndromes Defined by Blast Count, Cytogenetic Risk Group, or WHO Classification.

Blood ◽

10.1182/blood.v114.22.2776.2776 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2776-2776

Author(s):

Andrea Kuendgen ◽

Corinna Strupp ◽

Kathrin Nachtkamp ◽

Barbara Hildebrandt ◽

Rainer Haas ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

High Risk ◽

Research Funding ◽

Risk Group ◽

Univariate Analysis ◽

Risk Groups ◽

High Risk Group ◽

Intermediate Risk ◽

Blast Count

Abstract Abstract 2776 Poster Board II-752 Introduction: We wondered whether prognostic factors have similar relevance in different subpopulations of MDS patients. Methods: Our analysis was based on patients with primary, untreated MDS, including 181 RA, 169 RARS, 649 RCMD, 322 RSCMD, 79 5q-syndromes, 290 RAEB I, 324 RAEB II, 266 CMML I, 64 CMML II, and 209 RAEB-T. The impact of prognostic variables in univariate analysis was compared in subpopulations of patients defined by medullary blast count, namely <5%, ≥5% (table), ≥10%, and ≥20% (not shown), as well as 3 subpopulations defined by the cytogenetic risk groups according to IPSS (table). Multivariate analysis of prognostic factors was performed for cytogenetically defined subgroups and WHO-subtypes. Results: Strong prognostic factors in all blast-defined subgroups were hemoglobin, transfusion dependency, increased WBC, age, and LDH. However, all variables became less important in patients with ≥20% blasts (RAEB-T) and increased WBC was rare. Platelet count and cytogenetic risk groups were relevant in patients with <5%, ≥5%, and ≥10% marrow blasts, but not in RAEB-T. Marrow fibrosis was important in patients with <5% or ≥5% blasts, but not ≥10%. Gender and ANC <1000/μl were significant only in patients with a normal blast count. Furthermore, we looked for the effect of the karyotypes, relevant for IPSS scoring (-Y, del5q, del20q, others, del7q/-7, complex), and found a comparable influence on survival, irrespective whether patients had < or ≥5% marrow blasts. In subpopulations defined by cytogenetic risk groups, several prognostic factors were highly significant in univariate analysis, if patients had a good risk karyotype. These included hemoglobin, sex, age, LDH, increased WBC, transfusion need, and blast count (cut-offs 5%, 10%, and 20%). In the intermediate risk group only LDH, platelets, WBC, and blasts were significant prognostic factors, while in the high risk group only platelets and blast count remained significant. Multivariate analysis was performed for the cytogenetic risk groups and for subgroups defined by WHO subtypes. The analysis considered blast count (</≥5%), hemoglobin, platelets, ANC, cytogenetic risk group, transfusion need, sex, and age. In the subgroup including RA, RARS, and 5q-syndrome, LDH, transfusion, and age in descending order were independent prognostic parameters. In the RCMD+RSCMD group, karyotype, age, transfusion, and platelets were relevant factors. In the RAEB I+II subgroup, the order was hemoglobin, karyotype, age, and platelets, while in CMML I+II only hemoglobin had independent influence. In RAEB-T none of the factors examined was of independent significance. Looking at cytogenetic risk groups, in the favorable group, several variables independently influenced survival, namely transfusion, blasts, age, sex, and LDH (in this order). Interestingly, in the intermediate and high risk group, only blast count and platelets retained a significant impact. Conclusion: Univariate analysis showed prognostic factors (except ANC) included in IPSS and WPSS are relevant in most subgroups defined by marrow blast percentage. However, they all lose their impact if the blast count exceeds 20%. Regarding cytogenetic risk groups, several prognostic factors lose their influence already in the intermediate risk group. This underscores the prognostic importance of MDS cytogenetics. Multivariate analysis showed MDS subpopulations defined by WHO types also differ with regard to prognostic factors. In particular, CMML and RAEB-T stand out against the other MDS types. Disclosures: Kuendgen: Celgene: Honoraria. Hildebrandt:Celgene: Research Funding. Gattermann:Novartis: Honoraria, Participation in Advisory Boards on deferasirox clinical trials. Germing:Novartis, Celgene: Honoraria, Research Funding.

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Classical Empiric Antifungal Therapy Vs. D-Index Guided Early Therapy Using Micafungin for Persistent Febrile Neutropenia (CEDMIC trial): A Randomized Controlled Trial from Japan FN Study Group

Blood ◽

10.1182/blood-2018-99-111154 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 816-816

Author(s):

Shun-Ichi Kimura ◽

Yoshinobu Kanda ◽

Masaki Iino ◽

Takahiro Fukuda ◽

Emiko Sakaida ◽

...

Keyword(s):

High Risk ◽

Febrile Neutropenia ◽

Fungal Infection ◽

Antifungal Therapy ◽

Invasive Fungal Infection ◽

Research Funding ◽

Controlled Trial ◽

Pharmaceutical Research ◽

Randomized Controlled ◽

Neutropenic Patients

Abstract Introduction: Empiric antifungal therapy (EAT) is recommended for persistent or recurrent febrile neutropenia based on an old randomized controlled trial, but such treatment is apparently overtreatment for the majority of patients. On the other hand, preemptive therapy triggered by positive blood tests for fungal antigens and/or imaging study findings was shown to increase the incidence of invasive fungal infection, and thus, a risk-based approach is important. The D-index, which is defined as the area over the neutrophil curve during neutropenia and hence reflects both the duration and depth of neutropenia (Figure 1A), enables real-time monitoring of the risk of invasive fungal infection. Previous studies showed that the cumulative D-index (c-D-index), which was calculated as cumulative D-index from the onset of neutropenia (Figure 1B), had high negative predictive values for invasive mold infection or pulmonary infection with cutoff values of 5,800 or 5,500 in high-risk neutropenic patients [J Clin Oncol 2009; 27: 3849-54. Biol Blood Marrow Transplant 2010; 16: 1355-61]. Methods: We investigated a novel approach, called D-index-guided early antifungal therapy (DET) and compared it to EAT in high-risk neutropenic patients. In the EAT group, empiric antifungal therapy was started for persistent (>=4 days) or recurrent febrile neutropenia. For patients with persistent or recurrent febrile neutropenia in the DET group, preemptive antifungal therapy was applied until c-D-index reached 5,500, but antifungal agent was initiated after c-D-index exceeded 5,500, even if there was no significant finding in serum fungal makers or imaging studies, to prevent excessive invasive fungal infection. Micafungin at 150 mg/day was administered as EAT or DET in this study. We randomized 423 patients who underwent chemotherapy or hematopoietic stem cell transplantation for hematological malignancies, in which predicted period of neutropenia exceeded 7 days, into the EAT group or the DET group, and 413 were eligible for intent-to-treat analyses (201 patients in the EAT group, 212 patients in the DET group). The prophylactic use of fluconazole or itraconazole was allowed. Primary endpoint was the development of proven/probable invasive fungal infection. Results: Backgrounds of the patients were similar between the 2 groups (Table 1). Invasive fungal infection (proven/probable/possible) was observed in 12 patients (6.0%) of the EAT group and 5 patients (2.4%) of DET group, respectively. Proven/probable invasive fungal infection was identified in 5 patients (2.5%) of the EAT group and 1 patient (0.5%) of DET group, which fulfilled the predetermined criteria of non-inferiority of the DET group. Regarding the pathogens, the EAT group included 1 case of candidemia and 4 cases of invasive pulmonary aspergillosis, and the DET group included one fusariosis. The survival rate of the EAT and DET group was 98.0% vs. 98.6% at day 42 and 96.4% vs. 96.2% at day 84, respectively. During the observation period, 31 patients died due to disease progression (n=19), infection (n=5) or other causes (n=7). Causes of infection related mortality included Pseudomonas aerginosa infection (n=2), fusariosis (n=1), toxoplasmosis (n=1) and septic shock by unknown pathogen (n=1). The frequency of micafungin use was significantly lower in the DET group than the EAT group (32.5% vs. 60.2%, P<0.001). Similar results were obtained in per-protocol set analyses. Conclusions: DET successfully reduced the use of antifungal agents without increasing invasive fungal infection or mortality compared to EAT. This randomized controlled study revealed the feasibility of DET in high-risk neutropenic patients. Disclosures Kimura: Astellas: Honoraria; Pfizer: Honoraria; Sumitomo Dainippon Pharma: Honoraria; MSD: Other: Investigator in the institute; Nippon Kayaku: Honoraria; Celgene: Honoraria; Kyowa Hakko Kirin: Honoraria; Takeda: Honoraria. Kanda:Chugai: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Ono: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; CSL Behring: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Tanabe-Mitsubishi: Research Funding; Novartis: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Dainippon-Sumitomo: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Taisho-Toyama: Research Funding; Taiho: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria. Fujiwara:Shire: Consultancy; Pfizer: Consultancy; Chugai: Consultancy; Kirin: Consultancy; Kyowa-Hakko: Consultancy; Astellas: Consultancy. Suzumiya:Celltrion: Research Funding; Taiho: Research Funding, Speakers Bureau; SymBio: Research Funding; Toyama Chemical: Research Funding; Takeda: Research Funding, Speakers Bureau; Eisai: Research Funding, Speakers Bureau; Chugai-Roche: Research Funding, Speakers Bureau; Kyowa Hakko Kirin: Research Funding, Speakers Bureau; Zenyaku Kogyo: Consultancy; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Pfizer: Research Funding; Sumitomo Dainioppon: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Ono: Speakers Bureau; Ohtsuka: Speakers Bureau; Shire Japan: Speakers Bureau. Takamatsu:Taisho Toyama Pharmaceutical: Research Funding; TAIHO Pharmaceutical: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Ono Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; Kyowa Hakko Kirin: Research Funding; Chugai Pharma: Research Funding; Takeda Pharmaceutical: Research Funding; Celgene: Honoraria. Tamura:Astellas Phrma: Research Funding; Eisai: Speakers Bureau; Kyowa Hakko Kirin: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau.

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Allotransplants for Patients 65 Years or Older with High-Risk Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2018-99-112749 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4667-4667

Author(s):

Paul Lin ◽

Lauren Westfall Veltri ◽

Katy Rezvani ◽

Betul Oran ◽

Sairah Ahmed ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

High Risk ◽

Myeloid Leukemia ◽

Research Funding ◽

Risk Group ◽

Morphological Evidence ◽

Consolidation Chemotherapy ◽

Medical Event ◽

History Of

Abstract Outcome of persons >65 years with acute myeloid leukemia (AML) is poor. Allogeneic transplant can cure some of these patients but is associated with substantial transplant-related mortality (TRM) and high relapse risk. We analyzed 185 consecutive patients >65 years with high-risk AML between 2010 and 2015 who had measurable residual disease (MRD) and molecular risk assessments and who received myeloablative conditioning (MAC, n=42) or reduced-intensity conditioning (RIC, n=143) and a transplant from an HLA-identical sibling (n=66) or a 10/10 loci HLA-matched unrelated donor (MUD, n=119) in order to identify patients who would benefit from allotransplant. MRD was assessed by flow cytometry in bone marrow samples. AML cytogenetic and molecular risk were defined using the 2017 European Leukemia Net genetic risk stratification. The patients who were MRD-negative at time of transplant had a better 2-year cumulative incidence of relapse (CIR 17.6%) and a 2-year overall survival (OS, 69.4%) as compared to the patients in remission but MRD-positive (55.6% CIR, 21.5% OS) or the patients who had morphological evidence of leukemia prior to transplant (48.7% CIR, 19.9% OS), (p<0.0001). Multivariate analysis for 2-year CIR showed that having detectable leukemia at time of SCT (defined as MRD-positive or morphological evidence of leukemia) (HR=14.5, CI=3.4-61.4, p<0.0001), having received <3 cycles of chemotherapy prior to SCT (HR=1.8, CI=1.1-2.8 p=0.01), and high-risk genetics were independent predictors of relapse. However, high-risk genetics only had a deleterious effect on outcomes for MRD-negative patients (HR=9.4, CI=2.0-43.6, p=0.004), and did not affect the outcome of patients with detectable leukemia (HR=1.1, CI=0.7-1.9, p=0.61). Patients who received RIC (Flu-Mel-RIC or Bu-Flu-RIC) or MAC (Bu-Flu-MAC) had similar proportion of MRD-negative patients (p=1.0). However, MRD-negative patients who received Flu-Mel-RIC had a superior OS than patients who received Bu-Flu-RIC (adjusted HR=1 vs 5.3, p=0.02) or patients who received Bu-Flu-MAC (HR=1 vs 5.093, p=0.04), which is explained by a significantly lower relapse rate in patients receiving Flu-Mel-RIC (adjusted HR=1 vs 4.8, p=0.03) and a significantly lower TRM as compared to patients receiving Bu-Flu-MAC (adjusted HR= 5.1, p=0.01). Patients who had major medical complications (MMC), defined as a medical event requiring admission to the intensive care unit for ventilatory or inotropic support or a medical event that prolonged the patient hospitalization for more than 2 weeks, during induction or consolidation chemotherapy preceding the transplant, had a higher day +100 mortality (30.6% vs 6.0%, p<0.0001), 2-year TRM (55.6% vs 16.8%, p<0.0001) and lower 2-year OS (8.3% vs 44.6%, p<0.0001). Multivariate analysis for 2-year OS showed that history of delayed hematological recovery during induction or consolidation chemotherapy prior to transplantation (HR=1.5, CI=1.0-2.3, p=0.04), high risk genetics (HR=1.8 CI:1.2-2.6, p=0.006), donor-recipient HLA-DRβ3/4/5-DP mismatch (HR=2.2, CI=1.3-3.6, p=0.001), history of cardiovascular disease (HR=1.7, CI=1.1-2.6, p=0.02) were independent predictors for OS. Other variables such as secondary leukemia, CMV sero-status, FEV1 or creatinine clearance prior to SCT, sex mismatch, ABO group mismatch, donor type, or stem cell source did not have a significant impact on OS or TRM. Outcomes were also similar between patients transplanted in CR1 or in ≥ CR2 or in CR or CRi. We sought to identify those patients who may clearly benefit from a SCT. To that end, we classified patients according to the MRD status prior to transplantation and the presence or absence of the other prognostic factors identified in the multivariate analysis. As seen in the Figure, the High risk group which includes patients with detectable leukemia and >1 additional adverse prognostic factors (or a MMC), had a 2-year OS of 7.7% (CI=3.1-17.8). In comparison, the Low risk group which includes MRD-negative patients with ≤3 other prognostic factors (and no MMC), had a 2-year OS of 76.2% (CI=63.3-85.6). Finally, the Intermediate risk group which constituted the remaining patients, had a 2-year OS of 32.2% (CI=22.1-44.3, p<0.00001). These data indicate the possibility to identify persons >65 years with high-risk AML likely to benefit from an allotransplant. Figure. Figure. Disclosures Rezvani: Affirmed GmbH: Research Funding. Oran:ASTEX: Research Funding; Celgene: Consultancy, Research Funding; AROG pharmaceuticals: Research Funding. Shpall:Affirmed GmbH: Research Funding. Champlin:Otsuka: Research Funding; Sanofi: Research Funding.

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Donor Type, Chronic Gvhd Subtype , and the Severity of Chronic Gvhd at the Time of Initiation of Chronic Gvhd Treatment Affect Failure-Free Survival in the Patients with Chronic Gvhd

Blood ◽

10.1182/blood.v126.23.3139.3139 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3139-3139

Author(s):

Jieun Uhm ◽

Elizabeth Shin ◽

Marc Poch Martell ◽

Fotios V. Michelis ◽

Auro Viswabandya ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

High Risk ◽

Research Funding ◽

Chronic Gvhd ◽

Overlap Syndrome ◽

Unrelated Donor ◽

Free Survival ◽

Unrelated Donors ◽

Severe Grade

Abstract Introduction: Chronic graft versus host disease (cGVHD) is one of the major complications after allogeneic hematopoietic cell transplantation (allo-HCT). Several prognostic factors have been proposed to predict the outcomes of cGVHD including progressive type onset, extensive skin involvement, thrombocytopenia and NIH global score (NIH GS). Most studies have been focusing on the factors at the diagnosis of cGVHD without consideration of baseline characteristics prior to allo-HCT. We attempted to evaluate the prognostic factors for the outcomes of cGVHD treatment including the characteristics at the start of cGVHD treatment as well as prior to HCT. Method: We retrospectively reviewed 668 consecutive patients who underwent allo-HCT between 2004 and 2012 at the Princess Margaret Cancer Centre, Toronto, Canada, among whom 277 patients diagnosed as cGVHD and received systemic corticosteroids as a frontline cGVHD therapy. Chronic GVHD was classified and graded using the NIH consensus criteria. We evaluated non-relapse mortality (NRM), relapse and failure-free survival (FFS). FFS was defined as time to a switch in systemic therapy, NRM or relapse. The Kaplan-Meier method was used for FFS. The cumulative incidences of NRM, relapse and the treatment switch (TS) were calculated considering competing risks. Multivariate analysis was performed using the Cox proportional hazard regression model for FFS. Results: With a median follow-up duration of 26 months, the median time from HCT to cGVHD treatment was 183 days (range, 61-828). 102 patients (36.8%) were classified as classical cGVHD and 175 (63.2%) as overlap syndrome. At the start of cGVHD treatment 25 patients (9.0%) had mild cGVHD by the NIH GS, 189 (68.2%) moderate and 63 (22.7%) severe. Median age at allo-HCT was 51 year-old (range, 19-70). 162 patients (58.5%) were males and 65 (23.5%) patients were gender match of female donor to male recipient. 257 patients (92.8%) received peripheral blood stem cells (PBSC).175 grafts (63.2%) were from matched sibling donors (MSD). 180 patients (65%) received myeloablative conditioning. GVHD prophylaxis was calcineurin inhibitor (CNI) and methotrexate (n=82, 29.6%), CNI and mycophenolate mofetil (n=141, 50.9%), CNI and T-cell depletion (n=37, 13.5%) or others (n=17, 6.1%). The median FFS was 255 days (95% CI, 218-321). The severity of cGVHD, NIH GS correlated with FFS: median FFS was 164 days in severe vs 238 days in moderate vs 304 days in mild (p=0.001). The overlap syndrome was associated with a shorter FFS than classical cGVHD (223 vs 329 days, p=0.015). Patients receiving MSD graft showed longer FFS (329 days) than unrelated donor (196 days; p=0.004). The cumulative incidence of TS was 47.7% at 1 year. The NRM was 7.1% and relapse rate was 6.8% at 1 year. The MSD was associated with a lower 1-year NRM than the unrelated donors (4.2% vs 12.3%, p=0.003) while no difference between 2 groups for TS (p=0.731) or relapse at 1 year (p=0.565). Patients with overlap syndrome had higher NRM at 1 year than with classical cGVHD (10.0% vs 2.2%, p=0.009), but no differences in TS or relapse at 1 year (p=0.167 and p=0.138). Chronic GVHD severity by NIH GS showed a significant correlation with TS (28% in mild, 51.9% in moderate, and 43.8% in severe grade at 1 year, p=0.02) and NRM (4% in mild, 3.6% in moderate, and 19.1% in severe grade at 1 year, p<0.001), but with relapse (p=0.784). Multivariate analysis for FFS confirmed that the use of unrelated donor showed a worse FFS (hazard ratio (HR) 1.660, p=0.001). FFS was also associated with the severity of cGVHD, NCC GS (mild vs moderate vs severe; HR 1 vs 2.1 vs 2.9, p=0.002) and the cGVHD subtype (classical vs overlap, HR 1 vs 1.39, p=0.028). We then assigned score 0 for NIH GS mild, 1 for moderate, and 2 for severe; for NIH subtype, score 0 for classical and 1 for overlap; for donor types, score 0 for MSD and 1 for unrelated donors. After summation of the scores, we regrouped them into low (score 0, n=11, 3.9%), intermediate (score 1-2, n=168, 60.6%), and high risk groups (score 3-4, n=98, 35.3%). The risk stratification model correlated nicely with FFS (FFS duration, 1977 days in low vs 341 days in intermediate, and 150 days in high risk group, p<0.001). Conclusion: the use of unrelated donor, overlap subtype of chronic GVHD and severe grade of chronic GVHD at the time of initiation of chronic GVHD treatment affect adversely on failure-free survival. Disclosures Kim: Novartis Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding.

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Development and Analysis of a Weighed Prognostic Model in Newly Diagnosed Multiple Myeloma Patients

Blood ◽

10.1182/blood-2020-140464 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 47-48

Author(s):

Xue-Han Mao ◽

Yan Xu ◽

Yuting Yan ◽

Jiahui Liu ◽

Huishou Fan ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Multivariate Analysis ◽

Prognostic Factors ◽

High Risk ◽

Prognostic Factor ◽

Prognostic Model ◽

Cytogenetic Abnormalities ◽

Total Score Range ◽

Prognosis Model

Background and Objective: Multiple myeloma (MM) is characterized with significant cytogenetic changes and complex tumor microenvironment, thus patient survival is extremely heterogeneous. Various disease-related or patient-related factors affect the prognosis of patients. This study tried to analyze the prognostic indicators of patients with newly-treated MM, especially explored the prognosis of multiple cytogenetic abnormalities and the ratio of lymphocytes to monocytes (LMR). Additionally, we established a comprehensive prognostic model to help determine the patient prognosis. Methods: After screening, 603 patients of untreated MM from January 2008 to June 2017, with complete baseline indicators were enrolled into the study. By univariate and multivariate Cox analysis, risk factors related to the prognosis of patients were evaluated, and a weighted prognosis model was established to compare the survival differences of patients in each risk stratification. Result: Optimal thresholds of ALC, LWR, NLR and LMR were determined by ROC curve and Youdex index: ALC = 1.415, LWR = 0.325, NLR = 1.935, LMR = 2.95. Survival analysis showed that patients with LMR ≤ 2.95, ALC ≥ 1.415 and LWR ≥ 0.325 had significantly better survival compared with their respective control groups. Cox multivariate analysis showed that among the four indicators, only LMR≤2.95 was an independent adverse prognostic factor for overall survival (OS)(Figure 1A). 17p deletion, 1q21 amplification, t (4; 14) / t (14; 16) were define as high-risk cytogenetic abnormalities (HRA). Of the 603 patients, about 60% were associated with at least one high-risk cytogenetic event. Among them, the occurrence of cumulative 0, 1, 2, and 3 HRA were 39.6% (239/603), 42.5% (256/603), 16.6% (100/603), and 1.3% (8/603), respectively. There was no significant difference in survival among patients with same number of HRAs. The median OS of patients with 0, 1 and ≥ 2 HRA were not reached, 62.1 months (95% CI, 49.3-74.9) and 30.4 months (95% CI, 24.5-36.3), respectively (p <0.001)(Figure 1B).Final Cox regression model showed that age 65 ~ 74 (HR=1.77, 95%CI, 1.24-2.51, p=0.001), age ≥75 (HR=2.46, 95%CI, 1.69-3.58, p < 0.001), LDH≥247 U/L (HR =1.65, 95%CI, 1.07-2.51, p=0.023), ISS stage III (HR=1.76, 95%CI, 1.24-2.50, p=0.002), LMR≤2.95 (HR=1.53, 95%CI, 1.08-2.18, p=0.017), 1 HRA (HR=1.87, 95%CI, 1.27-2.75, p=0.002) and ≥2 HRA (HR=3.48, 95%CI, 2.22-5.45, p<0.001) are independent adverse prognostic factors for OS. Then weighted risk factors were summed to establish a comprehensive prognosis model, with a total score range of 0-6 points. Accordingly, the whole cohort was divided into low risk (0-1 points, 45.4%), intermediate risk (2 points, 27.9%), high risk (3 points, 19.2%) and ultra-high risk (4-6 points, 7.5 %) groups. The median OS of the four risk groups were 85.8 months (67.1-104.5), 49.0 months (44.7-53.3), 35.4 months (31.3-39.5), and 23.2 months (18.8-27.6), respectively (p<0.001). The C-statistics of this prognostic model is 0.68 (95% CI, 0.64-0.71), which is significantly better than the D-S stage (C-statistics = 0.52, 95% CI, 0.50-0.55, p <0.001), ISS (C-statistics = 0.60, 95% CI, 0.57-0.64, p <0.001) and R-ISS stage (C-statistics = 0.60, 95% CI, 0.57-0.63, p <0.001). Bootstrap resampling and calibration curve showed that the model has an accurate predictive effect on both short-term and long-term prognosis of patients(Figure 1C). Conclusion: In our analysis, ALC, LWR, LMR were associated with poor prognosis in NDMM patients, while NLR had no significant prognostic significance. Among the four indicators, LMR≤2.95 was the only independent prognostic factor. In NDMM patients, survival of patients with the same number of high-risk cytogenetic abnormalities were comparable with each other, regardless of whichever combination of HRA. Higher number of high-risk cytogenetic abnormalities were associated with worse prognosis. Cox multivariate analysis showed that, old age (65-74 years old, ≥75 years old), increased LDH (≥247 U/L), decreased LMR (≤2.95), ISS III, 1 HRA and ≥ 2 HRA were independent adverse prognostic factors that affect the OS of MM patients. 4. A comprehensive weighted prognostic model was established with the above factors, which was proved to effectively distinguish different prognosis of patients. Figure 1 Disclosures No relevant conflicts of interest to declare.

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The Interaction of Response and FISH-Based Risk Stratification to Better Define Clinical Outcome in Myeloma

Blood ◽

10.1182/blood.v118.21.1823.1823 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1823-1823

Author(s):

Kevin D Boyd ◽

Fiona M Ross ◽

Mark T Drayson ◽

Roger G Owen ◽

Alex J Szubert ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

High Risk ◽

Prognostic Factor ◽

Induction Therapy ◽

Response Rates ◽

Phase Iii ◽

Prognostic Impact ◽

Cell Transplant ◽

Important Prognostic Factor

Abstract Abstract 1823 Background: The achievement of a complete response (CR) is an important prognostic factor in myeloma. The international staging system (ISS) and tumor genetic lesions detected by FISH also impact survival. It is not known whether response rates are adversely affected by these factors, whether achieving CR overcomes the adverse prognosis associated with these factors, or if achievement of CR is more important in a specific biological subgroup. We have examined the importance of CR in the context of these other prognostic factors in the intensive arm of a phase III randomized trial, MRC Myeloma IX, in which all patients were planned to proceed to autologous stem cell transplant (ASCT) after induction. Patients and Methods: Patients were randomized to a conventional or thalidomide-based induction regimen followed by ASCT, with a second randomization to maintenance thalidomide versus no maintenance. Response was assessed after completion of induction therapy and 100 days post-ASCT. iFISH was performed on diagnostic bone marrow samples and genetic lesions associated with adverse progression free survival (PFS) were defined as t(4;14), t(14;16), t(14;20), +1q and 17p-. Results: To confirm that CR was prognostically important in the data set, patients with a CR at 100 days post-ASCT (N=355) were compared to non-CR (N=344) (comprising VGPR, PR and SD). CR was strongly associated with improved PFS (median 30.8 months vs 38.7 months, P<0.001) but was not associated with improved OS at median follow-up of 3.7 years. Response rates were assessed in the context of other prognostic factors. Interestingly, the presence of high risk FISH lesions was not associated with impaired CR rates following induction therapy (P=0.584) or following ASCT (P=0.314). Patients without adverse genetic lesions had a CR rate of 11.1% post-induction which improved to 48.3% post-ASCT. In comparison, patients with adverse FISH lesions had a 13.3% CR rate, rising to 44.9% post ASCT. Similarly, there was no correlation between ISS stage and response. The absence of adverse FISH lesions (hazard ratio (HR) 2.68 (1.94-3.70) P<0.001) and achievement of CR (HR 1.58 (1.15-2.17) P=0.005) were independently associated with improved PFS in multivariate analysis. The prognostic impact of achieving CR was assessed in various prognostic groups. CR was associated with improved PFS in patients with no adverse FISH lesions (N=179)(median PFS 58.4 vs 37.1 months, P=0.031), and in ISS I (N=182)(median PFS 51.2 vs 33.2 months, P=0.008). In patients with adverse FISH lesions, and in ISS II and III, there was a trend towards improved PFS with CR that was not significant. For patients achieving CR as their maximum response (N=398), in a multivariate analysis including the ISS, the presence of high risk FISH lesions was the most significant factor associated with impaired PFS and OS. Patients with more than 1 adverse FISH lesion were associated with an especially high risk of progression or death (PFS HR 6.63 (3.23-13.53) P<0.001; OS HR 5.35 (1.98-14.45) P=0.001). Conclusion: These data show that attainment of CR is an important prognostic factor associated with improved PFS in patients treated with ASCT, and this benefit was most significant in patients with favorable prognostic factors such as lack of adverse FISH lesions and ISS I. The presence of t(4;14), t(14;16), t(14;20), +1q or 17p- was also strongly associated with PFS, and the impaired outcome associated with these adverse genetic lesions was not overcome by achievement of CR, within the context of the therapies used in this trial. The presence of more than 1 adverse FISH lesion identified a patient group with an especially poor prognosis, despite achieving CR. However, CR rates within these high risk patients were similar to patients without adverse genetic features, showing that they were sensitive to chemotherapy, but progressed quickly after therapy was stopped. The implication of these data is that it may be possible to improve the poor outcome of this genetically-defined high risk group with an alternative treatment strategy aimed at maintaining these responses. Disclosures: Gregory: Celgene: Honoraria. Child:Celgene: Honoraria.

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Prognostic Factors in the Blastic and Accelerated Phase of Patients with Chronic Myeloid Leukemia (CML) in the Tyrosine Kinase Inhibitor (TKI) Era

Blood ◽

10.1182/blood.v120.21.3786.3786 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3786-3786

Author(s):

Young Kwang Chae ◽

Hagop M. Kantarjian ◽

Carlos G. Romo ◽

Clay Whitaker ◽

Elias J. Jabbour ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

Ace Inhibitors ◽

Research Funding ◽

Chronic Phase ◽

Initial Diagnosis ◽

Favorable Outcome ◽

Spleen Size ◽

Platelet Counts ◽

Concurrent Use

Abstract Abstract 3786 With the advent of TKIs, significant improvement has been made in the survival outcome of CML patients. Many prognostic factors have in identified in chronic phase CML patients. However, prognostic factors in blastic phase (BP) and accelerated phase (AP) of CML patients have not been previously investigated, especially in the era of TKIs. We have analyzed CML patients either been diagnosed in or progressed into BP or AP from 2000 to 2010 enrolled into the clinical trials with different TKIs such as imatinib, nilotinib, dasatinib, and bosutinib at MD Anderson Cancer Center. All demographic, clinicopathologic variables and medication data including TKIs and other medication were collected at the time of the diagnosis of BP or AP. Primary outcomes; progression free survival (PFS) and overall survival (OS) were defined as time from diagnosis of either BP or AP to treatment failure and death, respectively. Among a total of 260 CML patients, mean age was 51.4 (SD 14.1). Males were 59%. Caucasians were 72%; African-Americans, 12%; and Hispanics, 14%. Only 17% reached complete hematologic remission and 62% eventually died during the follow up (mean 4.1 yrs, SD 4.0 yrs). 26% were in BP and 74% in AP. 38 patients were in BP (n=9) or AP (n=29) at initial diagnosis. Mean time from initial diagnosis in chronic phase to BP or AP was 4.1 yrs (0 to 23 yrs). Among BP, 17% had lymphoid BP and 84% myeloid BP. Cytogenetic analysis at diagnosis demonstrated 38% had only Philadelphia chromosome (Ph) present while 62% had other chromosomal abnormalities besides Ph. 30% had received one or more prior TKI by the time of transformation. 64% started on monotherapy imatinib (no prior TKI), 15% nilotinib (86% prior TKI), 14% dasatinib (93% prior TKI), and 3% bosutinib (100% prior TKI); 3.5% received imatinib combined with other agents (57% prior monotherapy with imatinib). Median PFS was 0.7 yr and median OS, 2.4 yrs. Factors linked with worse PFS were higher bone marrow (BM) blast % (HR=1.01, p<0.001), higher peripheral blood (PB) blast % (HR=1.01, p<0.001), higher PB basophil % (HR=1.01, p=0.02), lower PB polymononuclear cells (HR=0.98, p<0.001), lower hemoglobin (HR=0.91, p=0.02), lower platelet counts (HR=0.99, p=0.045), and higher number of prior TKI treatments (HR=1.52, p<0.001). In AP, compared to other TKIs, imatinib was associated with superior PFS (HR=0.63, p=0.03) while nilotinib was linked with inferior PFS (HR=1.81, p=0.04). Dasatinib (HR=1.17, p=0.57) and bosutinib (HR=1.85, p=0.18) did not show difference in PFS. In BP, there was no difference in OS by TKIs. Concurrent use of ACE inhibitors, ARBs, statins, aspirin, or metformin with TKIs was not associated with change in PFS. In multivariate analysis adjusting for the above variables, only prior TKI use was associated with worse PFS (adjusted HR [AHR]=1.57, p=0.001). Imatinib (AHR=0.70, p=0.36) nor dasatinib (AHR=0.67, p=0.11) were no longer associated with favorable or unfavorable PFS. Factors associated with inferior OS were old age (HR=1.02, p<0.001), bigger spleen size (HR=1.03, p=0.001), higher BM blast % (HR=1.02, p<0.001), higher PB blast % (HR=1.02, p<0.001), lower PB polymononuclear cells (HR=0.98, p<0.001), lower hemoglobin (HR=0.80, p<0.001), lower platelet counts (HR=0.99, p=0.008), higher LDH (HR=1.0002, p<0.001), presence of other cytogenetic abnormality besides Ph (HR=1.45, p=0.03),and higher number of prior TKI treatments (HR=1.64, p<0.001). In AP, imatinib was associated with more favorable OS (HR=0.65, p=0.07) compared to others (nilotinib: HR=1.28, p=0.47; dasatinib: HR=1.70, p=0.077; bosutinib: HR=1.09, p=0.88). In BP, there was no difference in OS by TKIs. Concurrent use of ACE inhibitors, ARBs, statins, aspirin, or metformin with TKIs was not associated with change in OS. In multivariate analysis adjusting for the above variables, only age (AHR=1.01, p=0.002) and BM blast% (AHR=1.02, p=0.005) were associated with worse OS. Imatinib was no longer associated with favorable outcome (AHR=1.27, p=0.57). In conclusion, we identified spleen size, blast counts, and number of prior TKI use as major prognostic factors in CML patients in BC or AP. Imatinib was associated with favorable outcome. This is likely due to the fact that patients treated with imatinib had received no prior TKIs while most patients treated with 2nd generation TKI had. Further studies are required to validate our findings in a larger and prospective cohort. Disclosures: Kantarjian: Novartis: Research Funding; Bristol Myers Squibb: Research Funding; Ariad: Research Funding; Pfizer: Research Funding. Jabbour:Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Cortes:Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

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Prognostic Factors of Severe Infections, and Effect of Primary Anti-Infectious Prophylaxis in MDS Patients Treated with Azacitidine (AZA). A Single Center Study On 144 Patients

Blood ◽

10.1182/blood.v120.21.3812.3812 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3812-3812

Author(s):

Valérie Vidal ◽

Marie Sebert ◽

Sylvain Thepot ◽

Thorsten Braun ◽

Claude Gardin ◽

...

Keyword(s):

Prognostic Factors ◽

Antibiotic Prophylaxis ◽

Research Funding ◽

Primary Prophylaxis ◽

Median Number ◽

Secondary Prophylaxis ◽

Infection Prophylaxis ◽

Fatal Infection ◽

Severe Infections ◽

Incidence Of Hospitalization

Abstract Abstract 3812 Background: Hypomethylating agents, especially AZA, have become the reference treatment of higher risk MDS. Myelosuppression, although less important than with chemotherapy, is however notable especially during the first cycles of AZA, leading to potentially life threatening infections(Santini, Eur J Haematol 2010), and often to delay or discontinuation of treatment. Prognostic factors of severe infections in MDS patients (pts) receiving AZA have however not systematically been evaluated, and whether infection prophylaxis would be useful in this situation is unknown. Methods: Between January 2005 and November 2011, we treated at our institution 155 consecutive MDS pts, including FAB RAEB-T/WHO AML 20–30% blasts with AZA (75 mg/m2/d ×7 d every 4 weeks). Between March 2008 and November 2011 most of them (n=90) received primary prophylaxis (PRO+) with levofloxacin 500 mg/d and Posaconazole 200 mg tid started at onset of the first cycle, and planned for the first 6 cycles. G-CSF was not used. We analyzed the number of hospitalizations for sepsis requiring IV antibiotics during the first 4 cycles of AZA, the severity of those infections (admission in ICU, death) and factors influencing the severity and outcome of those episodes in this PRO+cohort. The PRO+ cohort was compared with MDS treated with AZA between January 2005 and March 2008 at our center, who received no antibiotic prophylaxis(PRO-; n=54). 11 pts who received secondary prophylaxis were excluded from the present analysis. Results: The patient population (PRO+ and PRO-) included 144 pts (68% males). IPSS was high, int 2, int 1 in 36%, 46% and 18% of the pts, respectively. The median number of AZA cycles administered was 6 (range 1–41) and, according to IWG2006 criteria, 26 (18%), 7 (5%), 13 (9%) and 15 (10%) pts achieved CR, PR, mCR and stable disease (SD) with HI, respectively leading to an overall response rate of 42%. With a median follow-up of 28 months, median OS was 18 months. Overall, 49 pts (34%) were hospitalized for sepsis during the first 4 cycles of AZA, including 7 (5%) in ICU, and 21 (14.5%) died from sepsis. The only prognostic factor of fatal infections was baseline ANC (median 0.7 G/L in pts with fatal infection vs 1.9 G/L in other pts, p= 0.0348), while age, sex, IPSS, cytogenetics and bone marrow blast % had no influence. Admission in ICU tended to be more frequent in males (all ICU pts were males, p=0.09), and was more frequent in pts with low baseline ANC (0.2 vs 1.7 G/L,p=0.04) and younger pts (median 67 vs 70, p=0.032), this last parameter being probably a bias related to some age limitation for admission in ICU. Other parameters (IPSS, marrow blasts, karyotype) had no significantly prognostic value for ICU admission. 90 pts received antiprophylaxis with Levofloxacin and Posaconazole (PRO+) and 54 did not (PRO-). Baseline characteristics (including age, sex, marrow blast %,Karyotype according to IPSS or IPSS-R, and IPSS) were similar between PRO+ and PRO- patients, except that baseline ANC<1G/l was more frequent in PRO + pts (47% vs 31% in PRO- pts, p=0.04). The ORR was 49% in PRO+ and 43% in PRO- pts (p=0.32). In spite of lower ANC in pts who died from infection, and lower baseline ANC in PRO+ pts, the proportion of hospitalization for sepsis(29% vs 39%, p= 0.33), deaths due to infection (11.5% v 16.8%, p=0.275) and admission in ICU (9% vs 4%, p= 0.251) were similar in PRO+ and PRO- pts. Moreover, among pts with baseline ANC<1G/L, there was a trend for a lower incidence of deaths due to infection in PRO+ than in PRO- (11% v 30%, p=0.076). PRO+ pts had a higher probability of receiving >= 6 cycles of AZA (76 vs 61% in PRO-pts, p=0.04). Median OS was 22.6 months in PRO+ and 15.7 months in PRO- pts (p=0.17). Conclusion: Baseline ANC was the only factor significantly influencing the incidence of hospitalization in ICU for infection and the risk of fatal infection in MDS treated with AZA. In this comparison, primary anti infectious prophylaxis (PRO+) was not associated with a clear reduction in the incidence of infections requiring hospitalization and of fatal infections. However, the fact that ANC below 1G/L was associated with more infectious deaths, that ANC was lower in PRO+ pts and that patients with ANC <1G/L tended to have fewer infectious deaths when they received PRO may suggest some protective effect of antibiotic prophylaxis. This effect, which may have contributed to the fact that more PRO+ pts could receive>= 6 cycles of AZA, will have to be confirmed in prospective studies. Disclosures: Fenaux: Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

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Post Transplant Lymphoproliferative Disorders (PTLD) after Solid Organ Transplant: Cleveland Clinic Experience

Blood ◽

10.1182/blood.v124.21.3008.3008 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3008-3008 ◽

Cited By ~ 1

Author(s):

Deepa Jagadeesh ◽

Sharjeel Hooda ◽

Kathleen B Fenner ◽

Lisa Rybicki ◽

Robert M Dean ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

Median Time ◽

Research Funding ◽

Lung Transplant ◽

Lymphoproliferative Disorders ◽

Large Cohort ◽

Age At Diagnosis ◽

Solid Organ ◽

Post Transplant

Abstract Background: Post transplant lymphoproliferative disorders (PTLD) are rare pathologically and clinically heterogeneous diseases arising in the setting of immunosuppression following hematopoietic stem cell and solid organ transplants (SOT). Our understanding of PTLD is restricted by its low incidence and heterogeneous treatment approaches, resulting in paucity of data. We sought to further describe characteristics and outcomes in PTLD patients who underwent treatment at our institution. Methods and Patients: We performed a retrospective study to describe our institutional experience in a relatively large cohort of PTLD patients after SOT. Patient and disease characteristics were examined and prognostic factors for survival were determined using univariate and multivariate Cox analysis. Results: Between May 1987 to January 2014, 98 patients with a confirmed diagnosis of PTLD underwent treatment at our institution. Median time from SOT to PTLD diagnosis was 60 months with median follow of 68 months from PTLD diagnosis. Baseline characteristics include male gender 77%, ECOG performance status (PS) 0-1 in 61%, and stage III-IV 69% with a median age at diagnosis of 47 years. Most common transplanted organ included heart 30%, lung 24%, kidney 20% and liver 19% and median time from SOT to PTLD diagnosis was 60 months. Most cases had monomorphic histology (81%) and were EBV+ (82%). Graft involvement and rejection were observed in 32% and 43% respectively. Of the 84% with extranodal (EN) involvement, gastrointestinal tract (37%) and lung (27%) were the common sites, while 3.2% had bone marrow (BM) involvement. Central nervous system (CNS) was involved in 11% of the cases. Only 58% received rituximab as part of the initial therapy, as significant part of our cohort was treated prior to rituximab era. Reduction in immunosuppression (73%), chemotherapy (40%), radiation (11%) and surgery (8%) were utilized either as single modality or in combination for treatment. Of the 66 patients with response data, 59% had complete response (CR) and 14% had progressive disease (PD). Relapse occurred in 23% of cases. Median overall survival (OS) from diagnosis of PTLD was 6 years (Figure 1), but in rituximab treated patients it was 8 years. On univariate analysis, higher age at diagnosis (HR 1.19, 95% CI 1.01-1.40, p=0.033), lung transplant (HR 2.42, 95% CI 1.36-4.33, p=0.003), higher IPI (HR 1.83, 95% CI 1.40-2.39, p=<0.001), decreased PS (HR 2.43, 95% CI 1.70-3.48, p=<0.001), and platelet count <200,000 (HR 2.84, 95% CI 1.27-6.33, p=0.011) were associated with lower OS, whereas liver transplant (HR 0.24, 95% CI 0.09-0.68, p=0.007) and GI involvement (HR 0.47, 95% CI 0.24-0.95, p=0.036) predicted better OS. Rituximab treatment (Figure 2) and achieving CR were associated with better OS. Histology, EN involvement, and EBV status were not significant predictors for survival. On multivariate analysis only lung transplant, IPI, and PS were predictive for OS. Lung transplant patients had a higher risk of mortality compared to other SOT (HR 2.63, 95% CI 1.39-4.95, p=0.003). Both higher IPI (HR 1.66, 95% CI 1.18-2.32, p=0.003) and poor PS (HR 1.94, 95% CI 1.27-2.96, p=0.002) were associated with inferior OS. Conclusions: In this large cohort of PTLD patients after SOT, lung transplants, higher IPI and poor PS were identified as poor prognostic factors for OS on both univariate and multivariate analysis. Rituximab treatment was a favorable prognostic factor for OS that resulted in prolonged survival observed in this cohort. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Hill: Millenium: Research Funding; Novartis: Research Funding.

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Sequential Intensified Conditioning Regimen Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with High-Risk AML in Complete Remission: A Survey from the ALWP of the EBMT

Blood ◽

10.1182/blood.v126.23.3105.3105 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3105-3105

Author(s):

Florent Malard ◽

Myriam Labopin ◽

Gernot Stuhler ◽

Johanna Tischer ◽

Joerg Thomas Bittenbring ◽

...

Keyword(s):

Multivariate Analysis ◽

High Risk ◽

Research Funding ◽

Antithymocyte Globulin ◽

De Novo ◽

Conditioning Regimen ◽

Secondary Aml ◽

Off Label ◽

Advisory Boards ◽

De Novo Aml

Abstract Introduction. Allogeneic hematopoietic cell transplant (HCT) is an established treatment modality that is potentially curative for many patients with acute myeloid leukemia (AML). The development of reduced intensity conditioning (RIC) allows performing HCT in elderly and/or in heavily pretreated patients and in those with comorbidities precluding the use of standard myeloablative conditioning. Post-transplant relapse remains a challenge after RIC, particularly in patients with adverse prognosis factors.The so-called "sequential" transplant approach (e.g. FLAMSA regimen combining both intensive chemotherapy and RIC HCT within the same procedure) initially developed in patients with refractory AML, could be a promising strategy to improve disease control and decrease the risk of relapse in high-risk AML patients in complete remission (CR). Patients and methods. In the current study we analyzed transplantation outcomes in a cohort of 411 adults AML patients in CR at time of transplant, treated between 2002 and 2013. Patients received a "sequential" conditioning regimen based on Fludarabine 30 mg/m2/d, high-dose aracytine 1-2 g/m2/d, amsacrine 100 mg/m2/d for 5 days and after a 3 days rest, total body irradiation (TBI) 4Gy, cyclophosphamide 50-120 mg/kg, and antithymocyte globulin (ATG) for 2 to 3 days (TBI group, n=269 [65%]). In 142 (35%) patients, TBI was substituted by IV Busulfan 3.2 mg/kg/d for 2 days, or orally equivalent dose (Bu group). 323 patients (79%) had de-novo AML and 88 (21%) had a secondary AML (with prior myelodysplastic syndrome). At time of transplant, 300 (73%) patients were in CR1 and 111 (27%) in CR2. Cytogenetic study in de novo AML was favorable in 19 patients (6%), intermediate in 102 (32%) and poor in 41 (13%). Cytogenetic data were missing in 161 (50%). 104 (25%) patients received matched related donors (MRD) and 307 (75%) unrelated donor (URD) HCT. Majority of patients (94%) received mobilized peripheral blood stem cells graft. Results. Median follow-up of surviving patients was 28 months and median age at transplant was 54 years (18-76). ANC>500/μL was achieved at a median of 17 (range, 9-74) days after HCT. Sixteen patients (4%) failed to engraft. Two year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) were 22% (95%CI, 18-26%) and 22% (95%CI, 18-27%), respectively. The Kaplan-Meier estimate of overall (OS) and leukemia-free survival (LFS) at 2 years were 59% (95%CI, 54-65%) and 56% (95%CI, 50-61%), respectively. Acute GVHD (grade II-IV) occurred in 109 (28%) patients. The 2-year cumulative incidence of chronic GVHD was 31% (95%CI, 26-36), extensive in 17% (95%CI, 12-21). Two years RI, NRM, LFS and OS in TBI vs. Bu patients were 21.8% vs 21.7% (p=0.69), 29.4% vs 18.3% (p=0.008), 48.8% vs 59.6% (p=0.045) and 51.2% vs 64.0% (p=0.013), respectively. In multivariate analysis adjusted for variable with different distribution between Bu and TBI groups, the type of conditioning (TBI vs Bu) has no impact on RI, NRM, LFS and OS. Age over 55 at transplant was an independent adverse prognostic factor in multivariate analysis for NRM (hazard ratio (HR: 1.61, 95% CI: 1.00-2.61, p=0.05)), LFS (HR: 1.39, 95% CI: 1.00-1.92, p=0.05) and OS (HR: 1.55, 95% CI: 1.11-2.18, p=0.01). Being treated in an experienced center (defined as having including 10 or more transplants in the study) was associated with a significant lower RI (HR: 0.84, 95% CI: 0.75-0.93, p=0.001) and better LFS (HR: 0.91, 95% CI: 0.84-0.98, p=0.01) and OS (HR: 0.91, 95% CI: 0.84-0.98, p=0.02). Finally, transplantation from an URD was associated with a significant increase in NRM (HR: 2.11, 95% CI: 1.14-3.91, p=0.02). Of note, CR1 vs. CR2 and de novo vs. secondary AML had no impact on patients' outcome. Conclusions. These results in a rather large cohort of patients with AML suggest that a FLAMSA "sequential" regimen provided an efficient disease control in high-risk AML patients including in CR2 and secondary AML. Furthermore Busulfan and TBI based FLAMSA "sequential" regimens provide a similar outcome. These results should be confirmed in a multicenter well design randomized study. Disclosures Off Label Use: off-label drug use: antithymocyte globulin (ATG) for allo-SCT conditioning. Tischer:Sanofi-Aventis: Other: advisory board. Schmid:Neovii: Consultancy; Janssen Cilag: Other: Travel grand. Mayer:Janssen: Research Funding. Hallek:Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Boards; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding.

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