17p Deletion Predicts for Inferior Overall Survival after Fludarabine - Based First Line Therapy in Chronic Lymphocytic Leukemia: First Analysis of Genetics in the CLL4 Trial of the GCLLSG.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 715-715 ◽  
Author(s):  
Stephan Stilgenbauer ◽  
Alexander Kröber ◽  
Raymonde Busch ◽  
Barabara Eichhorst ◽  
Dirk Kienle ◽  
...  
Keyword(s):  
Overall Survival ◽  
Overall Response Rate ◽  
Response Rate ◽  
Lymphocytic Leukemia ◽  
First Line ◽  
Mutation Status ◽  
Overall Response ◽  
First Line Therapy ◽  
Line Therapy ◽  
Genomic Aberrations

Abstract The CLL4 trial evaluated first line treatment with fludarabine (F) or F + cyclophosphamide (FC) among 375 CLL patients up to 65 years enrolled between 1999 and 2003. FC resulted in a higher overall response rate (94% vs. 83%; P=0.001), longer median progression free survival (PFS) (48 vs. 20 months (m); P=0.001), but no difference in overall survival (OS) (Eichhorst et al., ASH 2003 and submitted). At enrollment, genomic aberrations and the VH mutation status have been analyzed for 307 and 280 cases thus far. The most frequent genomic aberrations were 13q-: 50.3%, 13q- single: 34.1%, 11q-: 20.3%, +12q: 13.7%, 6q-: 8.7%, 14q-: 6.1%, and 17p-: 4.9%. VH was mutated in 33.9% and unmutated in 66.1% of cases. The aberrations 13q- and 13q- single were more frequently observed in the VH mutated subgroup (45.4% vs. 32.7% and 35.5% vs. 18.8%, respectively), while 11q- (26.9% vs. 12.2%) and 6q- (14.2 vs. 1.7%) were more common in the VH unmutated subgroup. Clinical outcome was evaluated in subgroups defined by genomic aberrations and VH status for both treatment arms combined. In univariate analyses, significant associations were found for the following parameters: the overall response rate was significantly lower in the subgroup with 17p- (53.8% vs. 89.6%, P=0.001), the median PFS was significantly shorter in the subgroups with 11q- (17.4 vs. 26.8 m, P=0.044), 14q- (14.5 vs. 24.5 m, P=0.018), and 17p- (11.0 vs. 24.1 m, P=0.002), and the median OS was significantly shorter in the subgroup with 17p- (15.9 m vs. not reached, 75% survival at 43.8 m, P<0.001, Figure 1). Multivariate analysis was performed including the treatment arms, specific genomic aberrations, and the VH mutation status as possible prognostic factors: the parameters with significant adverse impact were F monotherapy (HR 1.70, 95%CI 1.12-2.58, P=0.013) and 17p- (HR 3.67, 95%CI 1.66-8.14, P=0.001) regarding PFS, but only 17p- (HR 7.32, 95%CI 2.44-21.90, P<0.001) regarding OS. In conclusion, this first analysis of the prospective CLL4 trial shows that 17p- CLL is characterized by a short OS after F-based first line therapy. In future trials, alternative primary treatment strategies of proven efficacy in 17p- CLL such as alemtuzumab should be considered for these patients. Figure Figure

Is First Line Single Agent Rituximab the Best Treatment for Indolent Non-Hodgkin’s Lymphoma? Update of a Multicentric Study Comparing Rituximab vs CNOP vs Rituximab Plus CNOP.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2431-2431 ◽  
Author(s):  
Silvia Rivas-Vera ◽  
Enrique Baez ◽  
Pedro Sobrevilla-Calvo ◽  
Severiano Baltazar ◽  
Francisco Tripp ◽  
...  
Keyword(s):  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Disease Free Survival ◽  
First Line ◽  
Free Survival ◽  
Overall Response ◽  
First Line Therapy ◽  
Line Therapy ◽  
Disease Free

Abstract Purpose: To evaluate efficacy, safety, Disease-Free Survival (DFS) and Overall Survival (OS) in patients with indolent non-Hodgkin’s lymphoma (NHL) treated with chemotherapy vs. immunotherapy vs immunochemotherapy as first-line therapy, an up-date report. Methods: Patients with indolent NHL were randomized to receive: (A) Rituximab x 6/w, (B) CNOP (cyclophosphamide, mitoxantrone, vincristine and prednisone) x 6 or (C) R-CNOP x 6, at standard doses. Results: 195 patients were included, 183 are evaluable for OS and toxicity (A:62, B:55 and C:66), 144 are evaluable for overall response rate (ORR) and DFS (A:53, B:41 and C:50). Clinical characteristics: 89 male (45.6%), mean age 59±14 (±SD), 148 (75.9%) in stage (III/IV), without significant differences between groups. Overall Response Rate (CR+PR) was: A: 84.9%, B:83.4% and C:90% (P=0.545). Neutropenia grade 3/4 was more frequent in the chemotherapy groups: A: 4.8%, B: 23.6% and C:18.2% (P=0.001) as it was the infectious toxicity (grade 2/4): A:4.8%, B:5.5% and C:15.2% (P=0.07). DFS at 24 months was: A 68%, B:65% and C:70%, (P=0.93) and the OS was A:87%, B:84% and C:78%. P=0.89. Conclusions: We did not find any important differences, between groups, regarding the Overall Response Rate, Disease Free Survival and Overall Survival at 24 months. However, single agent rituximab was better tolerated, with less toxicity in comparison with the chemotherapy containing groups. Based on these findings, it maybe reasonable to use immunotherapy only, as first-line therapy for patients with indolent NHL.

Fludarabine Monophosphate as First Line Therapy for Chronic Lymphocytic Leukemia (CLL) - 11 Years Clinical Experience.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4970-4970
Author(s):  
J.E. Novoa ◽  
A.L. Rojo ◽  
B. Beñaran ◽  
R. Draper ◽  
H. Calvo ◽  
...  
Keyword(s):  
Overall Survival ◽  
Monoclonal Antibodies ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Response Rate ◽  
Lymphocytic Leukemia ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Intravenous Formulation

Abstract Background: fludarabine (F) has become the standard first line therapy for chronic lymphocytic leukemia (CLL) in younger patients. Treatment of early stage patients with chlorambucil without risk stratification has not been shown to prolong survival. In recent years effective and potentially curative approaches such as nucleosides analogues, stem cell transplantation or monoclonal antibodies have been developed. The attraction of monoclonal antibodies is based on selective targeting of tumor - relevant surface markers and a distinct mechanism of action (antibody-dependent cellular cytotoxicity). Aims: to assess the efficacy, safety and quality of life of F in previously untreated B-cell CLL patients in a group of medical institutions in Uruguay during 11 years (1995–2006). Methods: 168 patients between the period 1995 – 2006 were evaluated.120 of them received F intravenous formulation (1995–2006) and 48 the oral one (2002–2006). Age: 48 – 85 years old, media 67 years old. Gender: male 90, female 78. Inclusion criteria for B-cell CLL was Binet stages B, C and A progressive (Ap), 18 to 85 years old, non multiorganic failure, performance status 0 – 2 (WHO), written informed consent. First condition was non previous treatment. Staging: Binet A 12/168, B 116/168 & C 40/168. Treatment: as first line therapy all the patients received (minimum): 6 cycles of i.v. Fludarabine (Fludara®, Schering) 25 mg/m2/daily (5 days) e/30 days or Oral Fludarabine, 40 mg/m2/daily (5 days), 6 cycles. Results: on this B-cell CLL cohort the overall response rate (ORR) was 78% (CR+PR), 80% of them have immunophenotypic response. Safety: on the 1100 cycles in 168 patients, the toxicity was: 1 AIHA, 2 pancytopenia, 3 plaquetopenia. Grade 3–4 infection rate was 1,3%. No alopecia was observed in any patient. Kaposi sarcoma (0,7%). Mortality rate: 1,7% (3/168 patients). Other adverse factors to overall survival were, age over 65 (p=0,0001) and hepatic impairment (p=0,0001). Toxicity: (WHO>2): granulocytopenia 28%, thrombocytopenia 8%, infection 2%. Although fludarabine-treated patients experienced more significant myelosuppression, no difference in the treatment group was demonstrated. Causes of death: Richter 12%, sepsis 5%, associated disease 34%, second malignancy 17% and others 30%. Comparing oral with intravenous formulation in overall survival the results were: CLL 34% vs 36% (p= NS). Conclusions: fludarabine monofosfate (Fludara®) looks like an effective and safe treatment for B-cell CLL. The oral and intravenous formulations have a similar response rate in elderly and young patients. The challenge remains to integrate new information to apply novel therapies in a disease-specific and risk-adapted maner. A longer follow up and a larger trial, might be needed to confirm these results.

scholarly journals Phase II Study of WEE1 Inhibitor AZD1775 Plus Carboplatin in Patients With TP53-Mutated Ovarian Cancer Refractory or Resistant to First-Line Therapy Within 3 Months

2016 ◽  
Vol 34 (36) ◽  
pp. 4354-4361 ◽  
Author(s):  
Suzanne Leijen ◽  
Robin M.J.M. van Geel ◽  
Gabe S. Sonke ◽  
Daphne de Jong ◽  
Efraim H. Rosenberg ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Adverse Events ◽  
Phase Ii ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase Ii Study ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy

Purpose AZD1775 is a first-in-class, potent, and selective inhibitor of WEE1 with proof of chemopotentiation in p53-deficient tumors in preclinical models. In a phase I study, the maximum tolerated dose of AZD1775 in combination with carboplatin demonstrated target engagement. We conducted a proof-of-principle phase II study in patients with p53 tumor suppressor gene ( TP53)–mutated ovarian cancer refractory or resistant (< 3 months) to first-line platinum-based therapy to determine overall response rate, progression-free and overall survival, pharmacokinetics, and modulation of phosphorylated cyclin-dependent kinase (CDK1) in skin biopsies. Patients and Methods Patients were treated with carboplatin (area under the curve, 5 mg/mL⋅min) combined with AZD1775 225 mg orally twice daily over 2.5 days every 21-day cycle until disease progression. Results AZD1775 plus carboplatin demonstrated manageable toxicity; fatigue (87%), nausea (78%), thrombocytopenia (70%), diarrhea (70%), and vomiting (48%) were the most common adverse events. The most frequent grade 3 or 4 adverse events were thrombocytopenia (48%) and neutropenia (37%). Of 24 patients enrolled, 21 patients were evaluable for efficacy end points. The overall response rate was 43% (95% CI, 22% to 66%), including one patient (5%) with a prolonged complete response. Median progression-free and overall survival times were 5.3 months (95% CI, 2.3 to 9.0 months) and 12.6 months (95% CI, 4.9 to 19.7), respectively, with two patients with ongoing response for more than 31 and 42 months at data cutoff. Conclusion To our knowledge, this is the first report providing clinical proof that AZD1775 enhances carboplatin efficacy in TP53-mutated tumors. The encouraging antitumor activity observed in patients with TP53-mutated ovarian cancer who were refractory or resistant (< 3 months) to first-line therapy warrants further development.

Evaluation of Therapy in Symptomatic Patients with Lymphoproliferative Disorders of Large Granular Lymphocytes in Italy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4607-4607
Author(s):  
Laura Pavan ◽  
Roberta Zanotti ◽  
Elena De March ◽  
Cinzia Sissa ◽  
Monica Cavraro ◽  
...  
Keyword(s):  
Immunosuppressive Therapy ◽  
Lymphoproliferative Disorder ◽  
Overall Response Rate ◽  
Response Rate ◽  
First Line ◽  
Overall Response ◽  
First Line Therapy ◽  
Line Therapy ◽  
Short Period ◽  
Duration Of Response

Abstract Abstract 4607 Background. Chronic proliferations of large granular lymphocyte (LGL) are characterized by the expansion of cytotoxic T or NK cells. Relevant clinical features include neutropenia and anemia, either symptomatic or asymptomatic. The immunological and biological features of patients’LGL and the frequent association with autoimmune conditions represent the rationale for the immunosuppressive therapy frequently used in these conditions. However, no common criteria for starting therapy have been defined nor standard therapy has been established. We herein present data on 30 symptomatic patients treated in different Italian Centers, in the context of a collaborative study sponsored by the GIMEMA group. Methods. Diagnosis of lymphoproliferative disorder of LGL was made according to published criteria (Blood 1997, 1:89) and WHO classification 2008. Twentyseven patients were diagnosed as LGL leukemia and 3 as NK chronic lymphoproliferative disorder (NK-CLPD). Patients required treatment for symptomatic neutropenia, more frequently represented by recurrent bacterial infections (23/30), transfusion dependent anemia (4/30), other reasons (5/30; n: 2 pulmonary hypertension, n:2 aggressive disease and n:1 neurologic involvement). Treatments. First line therapy consisted of methotrexate (MTX) at 7,5 mg/m2/week in 13/30 patients; cyclosporin A (CyA, (2-3 mg/Kg/die) in 10/30 patients; cyclophosphamide (CY, 50–100mg/die) in 5/30 patients; (immuno)-chemotherapy (Campath-fludarabine, CVP, CHOP-like regimens) in 2 patients characterized by aggressive clinical presentation of disease with B symptoms. Steroid was generally given for short period (1 mg/kg p.o. prednisone) and then tapered off in all but 2 patients. Growth factors (G-CSF and EPO) were also used for short period of times. Before considering failure, each treatment was continued for at least 4 months. Response criteria were defined according to Lamy and Loughran (Blood 2011, 10:117). Second line therapy with MTX, CyA and CY was used in 2, 4 and 3 patients, respectively. Results. Time to response to MTX therapy ranged from 1 to 12 months. The overall response rate were 60% (9/15), with 3 CR and 6 PR. The duration of response ranged from 5 to 48 months. The 5 patients failing MTX as first line therapy were treated with CY (n:2, 1 CR, 1 PD), with CyA (n:2, 2 PR) and 1 rapidly progressed and died. Time to response to CyA ranged from 2 to 12 months. The overall response rate were 50% (7/14) with 2 CR and 5 PR. The duration of response ranged from 1 year to 10 year. The 5 patients failing first line CyA therapy were treated with MTX (n:1, with PR), with CY (n:2, with failure, but one case was rescued using the combination of CyA/CY), 1 patient with chemotherapy with failure; for 1 patient the follow up is too short. Time to response to CY ranged from 3 to 9 months. The overall response rate were 37.5% (3/8):2 CR, 1 PR. The duration of response ranged from 5 months to 5 years. The 3 patients failing CY at first line were treated with bendamustine (n:1), with alemtuzumab (n:1), with MTX (n:1) with failure in each cases Two patients with very aggressive presentation were treated with chemotherapy: 1 case rapidly progressed and died; 1 case, who failed CT, was treated first with CyA and then with MTX with failure. This patient underwent allotransplant. Conclusions. Immunosuppressive therapy with MTX or CyA or CY represents the common initial approach to patients with symptomatic LGL proliferation. Patient failing one therapy can be efficiently rescued by one of the other immunosuppressive drugs. Although any conclusive evaluation is difficult due to the low number of patients, our data are likely to indicate that the duration of response after treatment with CY and CyA is longer than the response obtained with MTX. The aggressive initial presentation of disease correlates with a very dismal prognosis. A prospective randomized clinical trial comparing these three different clinical approaches is going to start in Italy. Disclosures: No relevant conflicts of interest to declare.

A phase II study of combination of bortezomib, liposomal doxorubin, and dexamethasone (VDD) as first line therapy for multiple myeloma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17504-17504 ◽  
Author(s):  
A. J. Jakubowiak ◽  
J. Friedman ◽  
T. Kendall ◽  
A. Al-Zoubi ◽  
M. S. Kaminski
Keyword(s):  
Peripheral Neuropathy ◽  
Partial Response ◽  
Phase Ii ◽  
Response Rate ◽  
Cell Transplant ◽  
First Line ◽  
Overall Response ◽  
First Line Therapy ◽  
Line Therapy ◽  
Grade 3

17504 Background: We have recently reported that a combination of bortezomib (Velcade), liposomal doxorubicin (Doxil), and dexamethasone (VDD) is very active and well tolerated in relapsed/refractory myeloma (MM) producing 83% overall response rate and 33% of complete (CR) or near complete (nCR) response rate. In the current study, we evaluated the activity of VDD as first line therapy in newly diagnosed patients with MM. The primary objective of this study was to determine the efficacy of this regimen. Methods: This is a phase II, single institution trial which opened in July 2005 with target accrual of 30 patients. EBMT criteria were used for evaluation of responses. The regimen was given as follows: Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at 30 mg/m2 on day 4, and Dexamethasone for a total of 160 mg per cycle, initially at 40 mg on days 1–4 and then 20 mg on days of Velcade and the day after. VDD was repeated every 3 weeks for a total of 6 cycles. Results: To date, 19 pts have been enrolled, 18 of whom are presently evaluable for response after receiving a mean of 4.7 cycles (range 1–6). The characteristics of the evaluable patients included the following: median age 58 (range 39–83), chromosome 13 deletion in 4 patients, beta2-microglobulin 4.4 (61% > 4.0). CR + nCR have been observed in 2 patients (11%), very good partial response (VGPR) in 5 patients (28%), partial response (PR) in 9 patients (50%) and minor response (MR) in 1 patients (5%) for an overall response (≥ MR) of 94%, ≥ PR of 89% and ≥ VGPR of 39%. All patients who proceeded to stem cell transplant collected without any problems. The regimen was very well tolerated. Most surprisingly, only 1 patient developed peripheral neuropathy grade 1. One patient developed pneumonia and PE and one patient grade 3 diarrhea, which was found to be secondary to cryptosporidium. Grade 3 or 4 neutropenia was observed in 6 patients and grade 3 thrombocytopenia in 1 patient. The most common grade 1 and 2 toxicities were thrombocytopenia and fatigue, both significantly less common than in relapsed patients treated with the same regimen. One patient developed grade 2 DVT and 1 grade 2 PPE. Conclusions: VDD combination shows high overall activity of 94% and ≥ 90% disease reduction of 39%. The regimen is very well tolerated and has a surprisingly low incidence of peripheral neuropathy. [Table: see text]

Prognostic value of incidental betablockers use in metastatic colorectal cancer patients receiving first-line treatment.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14610-e14610
Author(s):  
Michela Del Prete ◽  
Riccardo Giampieri ◽  
Mario Scartozzi ◽  
Elena Maccaroni ◽  
Luca Faloppi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Cancer Patients ◽  
Response Rate ◽  
Progression Free Survival ◽  
First Line ◽  
Free Survival ◽  
First Line Therapy ◽  
Line Therapy ◽  
Colorectal Cancer Patients

e14610 Background: Preclinical and retrospective studies suggested antitumor activity for the incidental use of betablockers in various tumour types. Data regarding colorectal cancer are lacking. We assessed the correlation between the incidental use of betablockers and clinical outcome in colorectal cancer patients receiving first-line therapy. Methods: 235 patients treated with first-line chemotherapy alone (128 patients) and with Bevacizumab (107 patients) were analysed. Patients were stratified for betablockers use, age, sex, site of metastases, previous adjuvant chemotherapy and ECOG performance status. Results: 29 patients (12%) were on treatment with betablockers at the time of first-line therapy: 20 (16%) in the chemotherapy alone group and 9 in the bevacizumab group (8%). In both groups patients receiving or not betablockers were similar for all main clinical characteristics. In the chemotherapy alone group, patients receiving betablockers showed an improved response rate (60% vs. 33%, p=0.044) and overall survival (mOS 41.3 vs 25.7 months, p=0.03, HR:2.26, 95% CI: 1.05-3.24). Only a trend for improved progression free survival was noticed. In the 107 patients receiving chemotherapy with bevacizumab a trend towards a worse overall survival was seen for patients receiving betablockers, although this was not statistically significant (mOS 16 vs 23.7 months, p=0.26, HR:0.64, 95% CI: 0.22-1.49). No significant differences were seen in regards of progression free survival or different response rate patterns between the two groups. Conclusions: Our analysis confirms a potential prognostic role for the use of betablockers in colorectal cancer patients treated with chemotherapy. Our findings are in line with preclinical studies suggesting that beta-adrenergic signalling may regulate cancerogenesis and tumor invasiveness. Our analysis suggests a potential worse outcome for patients on betablockers receiving Bevacizumab-based treatment, although the small number of patients precludes any definitive conclusion. We suggest that in future prospective trials the incidental use of betablockers will be considered a stratification factor for clinical outcome.

scholarly journals Prognostic factors and effectiveness of the first-line therapy for chronic lymphocytic leukemia: results of 10-year follow-up

2021 ◽  
Vol 27 (3) ◽  
pp. 80-96
Author(s):  
О. B. Kalashnikova ◽  
M. O. Ivanova ◽  
N. P. Volkov ◽  
E. V. Kondakova ◽  
E. A. Izmailova ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Complex Karyotype ◽  
First Line ◽  
New Agents ◽  
Mutation Status ◽  
First Line Therapy ◽  
Line Therapy ◽  
Initial Stage

Introduction.The biological heterogeneity of chronic lymphocytic leukemia (CLL) is reflected in the rate of progression, the need for therapy, and the response to treatment. Analysis of prognostic factors contributes to improving the quality of treatment and rational distribution of healthcare resources.Materials and methods. Among 890 patients with documented stage of CLL, 405 (45.5 %) received treatment. As the first-line of treatment, 173 patients received intensive regimens (FCR or BR), 6 – new agents, and 226 – all other regimens. The initial stage of the disease, mutation status of IGHV, del17p with or without complex karyotype were analyzed as prognostic markers.Results. Immunochemotherapeutic regimens were shown to be highly effective in case planned amount of treatment was completed. The combination of such prognostic parameters as the initial stage of the disease, the mutation status of IGHV, and the presence of del17p and/or complex karyotype allows us to clearly identify a group of patients with an unfavorable prognosis, for which it is advisable to use either intensive programs or new agents in the first-line therapy.

Risk Factors for Response after Initial Therapy for Acute Graft-Versus-Host-Disease (aGVHD).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5015-5015
Author(s):  
Jason R. Westin ◽  
Rima M. Saliba ◽  
Marcos de Lima ◽  
Amin Alousi ◽  
Chitra Hosing ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Response Rate ◽  
Initial Therapy ◽  
Independent Effect ◽  
P Value ◽  
First Line ◽  
Overall Response ◽  
First Line Therapy ◽  
Line Therapy ◽  
Grade Iii

Abstract Introduction: Acute GVHD remains the most important early complication and limitation to allogeneic hematopoietic stem cell transplantation (HSCT). Although far from optimal, corticosteroids remain initial standard therapy with an overall response rate of 50%. Steroid resistant patients have a dismal prognosis, with mortality rates reaching 90%. Objective: To identify the subgroup of patients that would not benefit from initial therapy with corticosteroids. Thus, accrual of these patients into clinical studies would be mandatory. Methods: Retrospective evaluation of all (N= 287) patients who developed biopsy proven aGVHD after allogeneic HSCT at the University of Texas M. D. Anderson Cancer Center from 1998 through 2002. All patients received initial therapy for aGVHD with methylprednisolone. Prognostic factors for response (CR/PR) to initial therapy with corticosteroids were evaluated using logistic regression analysis including age, gender, donor/patient sex mismatch (F/M), donor type, cell type, intensity of conditioning regimen, diagnosis, disease status at transplant, number of prior chemotherapy regimens, number of prior autologous HSCT, CD34+ cell dose infused, time of onset of aGVHD and grade at initiation of first line therapy. Results: At the time of first line therapy, 89/287 patients (31%) had grade I aGVHD, 141 (49%) had grade II, and 57 (20%) had grade III–IV. Overall response to first line therapy was 56% and was comparable between patients with grade I and II aGVHD. Grade III–IV aGVHD (CR/PR 39% vs. 60%, p=0.003) and hyperacute GVHD (occurring by day +14) (CR/PR 42% vs. 61%, p=0.007) were the most significant prognostic factors for failure. Sex mismatch was associated with significantly lower response rate in patients with grade III–IV (CR/PR 12% vs. 49%, p=0.02) but not in patients with grade I–II (CR/PR 61% vs. 60%, p=0.9). Failure to respond to first line therapy was the most significant predictor of non-relapse mortality at one and two years after initiation of first line therapy (p<0.001) for all GVHD grades. Conclusions: Hyperacute GVHD and sex mismatch are significant predictors of response to first line therapy. Response to first line therapy has a strong and independent effect on survival. These factors should be integrated in prognostic scoring systems of aGVHD, which would allow identification of patients who would not benefit from standard therapeutic approaches. Response To First Line Therapy Overall (N=287) n %CR/PR p value CR: complete remission, PR: partial remission Grade at First Line I 89 65% Reference II 141 57% 0.2 III/IV 57 39% 0.003 Grade I/II (N=230) Grade III/IV(N=57) n, %CR/PR p value n, %CR/PR p value Hyperacute GVHD Yes 73 42% 60, 48% 13, 15% No 214 61% 0.007 170, 65% 0.03 44, 45% 0.05 Donor/Patient sex mismatch Yes 73 51% 57, 61% 16, 12% No 214 58% 0.3 173, 60% 0.9 41, 49% 0.02

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