scholarly journals Comparing the Prognostic Significance of Early Predictors of Survival in Chronic Myeloid Leukemia (CML) Treated with Imatinib - an Analysis of the Randomized CML-Study IV

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 156-156
Author(s):  
Benjamin Hanfstein ◽  
Michael Lauseker ◽  
Rüdiger Hehlmann ◽  
Susanne Saussele ◽  
Philipp Erben ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Myeloid Leukemia ◽  
Treatment Failure ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Treatment Intervention ◽  
High Risk Patients ◽  
Log Reduction ◽  
Risk Patients ◽  
Equity Ownership

Abstract Introduction: Early prediction of outcome using response-related predictive landmarks has become a major paradigm in the clinical management of chronic myeloid leukemia (CML). Several studies have shown the predictive impact of 10% BCR-ABLIS at 3 and 6 months for different tyrosine kinase inhibitors. The question, which landmark should define treatment failure and determine treatment intervention has been discussed vividly. However, an objective analysis of quality criteria for different early prognostic landmarks is lacking up to now. Here we compare sensitivity, specificity and the proportion of later disease progressions predicted by 3-month and 6-month landmarks in imatinib-treated patients of the CML-study IV. Methods: A total of 1,303 newly diagnosed patients were assigned to an imatinib-based treatment arm of CML-Study IV by April 2010. Median follow-up was 7.1 years. The number of molecular assessments was as follows: n=789 (at 6 months), n=692 (at 3 months) and n=301 (at 3 months and at diagnosis, without pretreatment). Gene expression levels were determined by quantitative RT-PCR. At 3 and 6 months, a BCR-ABL ratio was calculated using ABL as reference gene and standardized according to the international scale (BCR-ABLIS). In addition, at 3 months and at diagnosis a BCR-ABL ratio was calculated using beta-glucuronidase (GUS) as reference gene in order to ensure linearity of measurement at diagnosis. The log reduction at 3 months was calculated from the BCR-ABL ratio at 3 months and at diagnosis. Due to the time-dependent nature of censored survival data, the sensitivity and specificity at eight years were calculated using the method by Heagerty et al. (Biometrics 2000). Overall survival (OS) is defined by the absence of death from any reason, progression-free survival (PFS) is defined as survival in the absence of progression to accelerated or blastic phase. Landmark analyses were performed to compare survival outcomes according to Kaplan-Meier. Results:Comparing the 10% BCR-ABLIS landmark at 3 and 6 months, 8-year OS and PFS rates are equal or comparable (table). In contrast, sensitivity and specificity differ substantially with an advantage in favor of sensitivity for the 3-month landmark and in favor of specificity for the 6-month landmark. This difference is paralleled by a smaller proportion of high-risk patients and less progressions identified by the 6-month landmark. From a clinical point of view the 6-month landmark is not only less than half as sensitive, moreover a treatment intervention at 6 months might also prevent less progressions due to the delay of 3 months. The half-log reduction landmark at 3 months is as sensitive as 10% BCR-ABLIS at the same time. However, it shows improved specificity and defines the smallest proportion of high-risk patients. Conclusion: The 10% BCR-ABLIS landmark, which is currently defining treatment failure at 6 months according to European LeukemiaNet (ELN) criteria, fails to detect the majority of patients with later disease progression. Less than a half-log reduction of individual baseline BCR-ABL transcript levels at 3 months on treatment identifies patients with later progressions as sensitive but with higher specificity as compared to 10% BCR-ABLIS. Abstract 156. Table Prognostic landmark 8-year OS (%) 8-year PFS (%) P-value for PFS Sensitivity to predict progression (%) Specificity to predict progression (%) High-risk patients Disease progressions classified as high-risk / total 3 months (n=692) 10% BCR-ABLIS 88 vs. 96 82 vs. 90 0.001 41.1 74.6 191 (28%) 32/74 (43%) 6 months (n=789) 10% BCR-ABLIS 88 vs. 96 84 vs. 95 0.001 18.2 93.8 95 (12%) 17/74 (23%) 1% BCR-ABLIS 90 vs. 97 89 vs. 97 <0.001 39.6 68.6 291 (37%) 46/74 (62%) 3 months (n=301) 0.5-log reduction 81 vs. 95 75 vs. 94 <0.001 42.6 86.9 48 (16%) 10/24 (42%) Disclosures Hanfstein: Novartis: Research Funding; Bristol-Myers Squibb: Honoraria. Hehlmann:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding. Saussele:Novartis: Honoraria, Research Funding, Travel Other; Bristol-Myers Squibb: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria, Travel, Travel Other. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Neubauer:MedUpdate: Honoraria, Speakers Bureau. Kneba:Novartis: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pfirrmann:Novartis: Consultancy; Bristol-Myers Squibb: Honoraria. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; ARIAD: Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. Müller:Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.

Changes in the dynamics of the excess mortality rate in chronic phase-chronic myeloid leukemia over 1990-2007: a population study

Blood ◽  
2011 ◽  
Vol 118 (16) ◽  
pp. 4331-4337 ◽  
Author(s):  
Selim Corm ◽  
Laurent Roche ◽  
Jean-Baptiste Micol ◽  
Valérie Coiteux ◽  
Nadine Bossard ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Myeloid Leukemia ◽  
Mortality Rate ◽  
Myeloid Leukemia ◽  
Excess Mortality ◽  
Chronic Phase ◽  
Relative Survival ◽  
High Risk Patients ◽  
Risk Patients ◽  
Sokal Score

Abstract Imatinib has transformed the prognosis and the management of chronic myeloid leukemia (CML) and has probably changed the patterns of mortality rates. We explored this change at each disease severity level (Sokal score) through a flexible statistical modeling of the effect of the year of diagnosis on the excess mortality rate. The study included 691 chronic-phase patients from Nord-Pas-de-Calais French CML registry diagnosed from 1990 to 2007. Imatinib was given to 93% of the patients diagnosed after 2000. Comparing the 1990-1994, 1995-1999, and 2000-2007 periods of diagnosis, the 5-year relative survival improved from 64% to 66% and 88%. The year of diagnosis was associated with a significant reduction of the excess mortality, but only in patients with intermediate to high Sokal scores. In high-risk patients diagnosed in the early 1990s, a peak of excess mortality was observed during the second year of follow-up. That peak decreased progressively over the years of diagnosis until disappearing in patients diagnosed after 2000. This study showed different effects according to Sokal scores of the use of imatinib on mortality in patients with chronic-phase CML and showed that since 2000 the pattern of mortality of high-risk patients became similar to that of intermediate-risk ones.

Chronic myeloid leukemia and interferon-α: a study of complete cytogenetic responders

Blood ◽  
2001 ◽  
Vol 98 (10) ◽  
pp. 3074-3081 ◽  
Author(s):  
Francesca Bonifazi ◽  
Antonio de Vivo ◽  
Gianantonio Rosti ◽  
François Guilhot ◽  
Joëlle Guilhot ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Collaborative Study ◽  
Chronic Phase ◽  
Low Risk ◽  
Interferon Α ◽  
Term Survival ◽  
High Risk Patients ◽  
Risk Patients

Abstract Achieving a complete cytogenetic response (CCgR) is a major target in the treatment of chronic myeloid leukemia (CML) with interferon-α (IFN-α), but CCgRs are rare. The mean CCgR rate is 13%, in a range of 5% to 33%. A collaborative study of 9 European Union countries has led to the collection of data on 317 patients who were first seen between 1983 and 1997 and achieved CCgRs with IFN-α alone or in combination with hydroxyurea. The median time to first CCgR was 19 months (95% CI, 17-21; range, 3-84 months). At last contact, 212 patients were still alive and in continuous CCgR; 105 patients had lost CCgR, but 53% of them were still alive and in chronic phase. IFN-α treatment was discontinued permanently in 23 cases for response loss, in 36 cases for chronic toxicity (15 are still in unmaintained continuous CCgR), and in 8 cases because it was believed that treatment was no longer necessary (7 of these 8 patients are still in unmaintained continuous CCgR). The 10-year survival rate from first CCgR is 72% (95% CI, 62%-82%) and is related to the risk profile. High-risk patients lost CCgR more frequently and more rapidly and none survived more than 10 years. Low-risk patients survived much longer (10-year survival probability 89% for Sokal low risk and 81% for Euro low risk). These data point out that a substantial long-term survival in CCgRs is restricted mainly to low-risk and possibly intermediate-risk patients and occurs significantly less often in high-risk patients.

The Combination of High Expression of CD68-Positive Tumor-Associated Macrophages and PET2-Positivity Predicts Unfavorable Outcome in Patients with Classical Hodgkin Lymphoma Treated in the Lysa AHL2011 Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1825-1825 ◽  
Author(s):  
Alexandra Traverse-Glehen ◽  
Diane Damotte ◽  
Peggy Dartigues ◽  
Laurent Martin ◽  
Marie Parrens ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
High Risk ◽  
Treatment Failure ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Male Gender ◽  
Tumor Associated Macrophages ◽  
High Risk Patients ◽  
Risk Patients ◽  
Risk Of Treatment

Abstract Although progression free survival and overall survival of patients with Hodgkin lymphoma (HL) has improved with modern treatment in the past 10 years, 10 % of patients will fail to conventional therapy and die of their lymphoma. The search of new prognostic factors for identifying these high risk patients at diagnosis of HL remains challenging in daily practice. The evaluation of the tumor microenvironnement was shown to help identifying a subset of patients treated with ABVD having a high risk of treatment failure (Tan KL et al, Blood 2012). PET positivity after 2 cycles of chemotherapy allows also identifying a subset of patients with poor outcome (Gallamini, JCO 2007) and PET-guided strategy were developed to improve the management of HL patients in order to either intensify treatment for high risk patients or deescalate treatment for sparing the others from toxicities. The aim of this study was therefore to evaluate the impact of baseline tumor microenvironnement in a large cohort of HL patients prospectively treated with upfront escalated BEACOPP in a randomized phase III clinical trial evaluating a PET-driven strategy (AHL 2011, NCT01358747) and to compare its prognostic value with other clinicopathological markers. Material and Methods Tumoral material was collected from May 2011 to May 2014 from HL patients prospectively enrolled in the AHL 2011 study. The AHL 2011 trial was designed to evaluate in 16-60 years old HL patients with Ann Arbor stage III, IV or high risk IIB, a de-escalade PET-driven strategy after 2 cycles of BEACOPPesc randomly compared to a standard treatment not driven by PET and delivering 6 cycles of BEACOPPesc. PET were centrally reviewed and interpreted according to Deauville criteria. As recently reported (Casasnovas, ASH 2015 Abs 577), the 2y-PFS was similar in the PET-driven (88%) and the standard arm (91%; p =0.79). The tumor microenvironnement was analyzed on formalin fixed paraffin embedded lymph node biopsy obtained for the diagnosis before treatment by morphological evaluation on standard staining (% polynuclear eosinophils, % lymphocytes, % plasmocytes, % histiocytes), and immunohistochemistry (IHC) scoring (score 0-1-2-3) for CD20, CD3, CD68-TAMs (tumor-associated macrophages) and CD163 and were centrally reviewed. Percentage of tumoral cells and EBV status were also analysed. In this analysis, the prognosis value of tissue markers expressions were compared to those of clinical and biological patient's characteristics, and PET results after 2 cycles of escalated BEACOPP. Results Six hundred fifty eight patients with available IHC data out of 823 enrolled in AHL2011 study were included in the analysis. With a median follow-up of 16.1 months, 2-year PFS was 89.4% (95% CI [86.2% ; 91.9%]) and 2-year OS 98.7% (95% CI [96.4% ; 99.5%]). In univariate analysis male gender, at least one extra-nodal involvement, B symptoms, Hemoglobin <10.5g/dL, Albumin <40g/L, IPS score≥ 3, positive PET2, immunophenotyping CD20 (2-3vs0-1) and CD163 (2-3 vs 1) were significantly associated with shorter PFS. In multivariate analysis positive PET2 was the only factor retaining an independent prognosis value and associated to a shorter PFS (p=.04, HR=2.5, CI95% (1.03-5.8)). Among baseline patients characteristics, male gender, hemoglobin <10.5g/dL, IPS score ≥3, low % of lymphocytes, immunophenotyping CD3 (score ≥1), high CD20 (score ≥2), CD68 and CD163 expression were significantly associated with a higher risk of PET2 positivity. In multivariate analysis high CD68 expression (score 2-3 vs 1) was the only independent prognostic factor predicting PET2 positivity (p=.03, HR=2.4, CI95% (1.1-5.2)). 79% of PET2 positive patients have high CD68 expression and the combination of high CD68 expression and PET2 positivity identifies a subset of 50 patients (%) with a shorter 2y-PFS (72%) than PET2+/CD68low patients (2y-PFS=100%, p 0.066). In conclusion, CD68 expression was confirmed to be an important prognostic marker in this large prospective cohort of patients treated with upfront escalated BEACOPP in a modern PET-guided strategy. Baseline high CD68 expression is associated to a higher risk of PET2 positivity and the combination of this microenvironment marker and PET2 results allowed identifying a population of patients with high risk of treatment failure. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Brice: Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Bristol Myers-Squibb: Honoraria; Seattle Genetics: Research Funding; Gilead: Honoraria; Roche: Honoraria. Casasnovas:BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; ROCHE: Consultancy, Honoraria, Research Funding.

Complete Molecular Remission (CMR 4.5) of CML Is Induced Faster by Dose – Optimized Imatinib and Predicts Better Survival - Results From the Randomized CML-Study IV

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 67-67 ◽  
Author(s):  
Rüdiger Hehlmann ◽  
Michael Lauseker ◽  
Benjamin Hanfstein ◽  
Martin C. Müller ◽  
Annette Schreiber ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Randomized Study ◽  
Chronic Phase ◽  
Low Risk ◽  
Molecular Remission ◽  
Log Reduction ◽  
Risk Patients ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 67 Dose optimized imatinib (IM) at doses of 400– 800mg has been shown to induce faster and deeper cytogenetic and molecular – responses than standard IM (400mg/day). Since complete molecular remission (CMR 4.5) identifies a subgroup of patients who may stay in remission even after discontinuation of treatment, it was of interest to analyse whether CMR 4.5 is reached faster with dose optimized IM and whether CMR 4.5 correlates with survival. CMR 4 and CMR 4.5 are defined as ≤ 0.01% BCR-ABL IS or ≥ 4. log reduction and ≤ 0.0032% BCR-ABL IS or ≥ 4.5 log reduction, respectively, from IRIS baseline as determined by real-time PCR. CML-Study IV is a five arm randomized study of IM 400 mg vs IM 400 mg + IFN vs. IM 400 mg + Ara C vs. IM after IFN failure vs. IM 800 mg. In the IM 800 arm, a 6 weeks run in period at IM 400 mg was followed by a dose increase to 800 mg and then by a dose reduction according to tolerability. Grade 3 or 4 adverse effects (AE) were to be avoided. From July 2002 to March 2012 a total of 1551 patients with newly diagnosed chronic phase CML were randomized of whom 1525 were evaluable. Median age was 52 years, 88% were EUTOS low risk, 12% high risk, 36% were Euro score low risk, 52% intermediate and 12% high risk, 38% were Sokal low risk, 38% intermediate and 24% high risk. 113 patients were transplanted, 246 received 2nd generation TKI. 152 patients have died, 90 of CML or unknown reasons, 62 of not directly CML-related causes. After a median observation time of 67,5 months 6 years OS was 88.2% and PFS 85.6%. CCR, MMR, CMR 4 and CMR 4,5 were achieved significantly faster with dose optimized IM (400 – 800 mg). No significant differences in remission rates were observed between IM 400 mg and the combination arms IM 400 mg + IFN and IM 400 mg + Ara C, whereas IM after IFN failure thus far yielded significantly slower response rates. After 4 years CCR rates were for IM 400, IM 400 + IFN, IM 400 + Ara C, IM 400 after IFN, and IM 800, 80%, 75%, 73%, 59% and 80%, respectively, MMR rates 84%, 77%, 82%, 61% and 88%, CMR 4 rates 57%, 55%, 55%, 40% and 65%, and CMR 4.5 rates 40%,42%, 42%, 28% and 52%, respectively. CMR 4 was reached after a median of 27 months with IM 800 and 41.5 months with IM 400. CMR 4.5 was reached after a median of 41.5 months with IM 800 and 63 months with IM 400. EUTOS low risk patients reached all remissions faster than EUTOS high risk patients. The differences of CMR 4 rates between IM 800 and IM 400 at 3 years were 13% and at 4 years 8%, and of CMR 4.5 rates at 3 years 10% and at 4 years 13%. Grade 3 and 4 AE were not different between IM 400 and dose optimized IM 800. Independent of treatment approach, CMR 4 and more clearly CMR 4.5 at 3 years predicted better OS and PFS, if compared with patients without CMR 4 or CMR 4.5, respectively. CMR 4 and 4.5 were stable. After a median duration of CMR 4 of 3.7 years only 4 of 792 patients with CMR 4 have progressed. Life expectancy with CMR 4 and 4.5 was identical to that of the age matched population. We conclude that dose optimized IM induces CMR 4.5 faster than IM 400 and that CMR 4 and CMR 4.5 at 3 years are associated with a survival advantage. Dose optimized IM may provide an improved therapeutic basis for unmaintained treatment discontinuation in patients with CML. Disclosures: Hehlmann: Novartis: Research Funding. Müller:Novartis, BMS: Consultancy, Honoraria, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Hochhaus:Novartis, BMS, MSD, Ariad, Pfizer: Consultancy Other, Honoraria, Research Funding.

scholarly journals Open-Labeled, Multicenter Phase II Study of Bortezomib for Maintenance Therapy in Patients with High Risk Diffuse Large B Cell Lymphoma (DLBCL): Borma Trial from Consortium for Improving Survival of Lymphoma (CISL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2884-2884
Author(s):  
Jae-Cheol Jo ◽  
Ho Sup Lee ◽  
Cheolwon Suh ◽  
Hye Jin Kang ◽  
Won Seog Kim ◽  
...  
Keyword(s):  
High Risk ◽  
Maintenance Therapy ◽  
B Cell ◽  
Research Funding ◽  
Maintenance Treatment ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Risk Patients ◽  
Large B Cell Lymphoma ◽  
Risk Patients

Background: High-intermediate or high risk in international prognostic index (IPI) has a long-term chance of cure in the range about 50% in patients with diffuse large B cell lymphoma (DLBCL) treated by R-CHOP. These high risk patients should be considered for additional new treatment to standard R-CHOP or investigational approaches in the context of clinical trials that are designed to ensure that potentially curative therapy. Bortezomib inhibits NF-κB activation through proteasome inhibition, providing rationale for its use in cells that constitutively express NF-κB. Non-germinal center B cell (GCB) DLBCL has a worse survival after upfront chemotherapy and is characterized by constitutive activation of the antiapoptotic NF-κB pathway, which can inhibit chemotherapy. There is no study of bortezomib as maintenance therapy after treated with R-CHOP in high risk patients with DLBCL. So we applied additional bortezomib as maintenance therapy in order to assess improving efficacy and survival rates in high risk patients with non-GCB DLBCL who had been confirmed complete response (CR) after treated with R-CHOP. Methods: Patients with newly diagnosed stage II(bulky)-IV DLBCL with high or high intermediate IPI score of 3 to 5, and patients achieving a CR at the end of 6 or 8 cycles of R-CHOP21 were eligible for enrollment. Non-GCB DLBCL according to Hans criteria confirmed by central review was need before enrollment. Bortezomib maintenance treatment was consisted of bortezomib 1.3mg/m2 subcutaneously administration day 1 and day 15 per 28-day cycle with a total of 12 cycles. The primary endpoint was 3-year progression-free survival (PFS). Secondary endpoints were 3-year overall survival (OS), and toxicites. Toxicity was graded according to the Common Terminology Criteria for Adverse Events v4.0. Results: Fifty-nine patients were enrolled between May 2014 and Oct 2018. The type of Non-GCB DLBCL in all patients was confirmed by the central pathology review. The median age was 65 years (range: 27-86 years), and 60% were > 61 years. The baseline clinical features were as follows: female sex, 45.8%; ECOG >1, 10.2%; stage II bulky (>10cm), 6.8%; stage III/IV, 93.2%. At the time of analysis, 29 patients completed 12-cycles of bortezomib maintenance, and 3 patients is ongoing. Seven patients did not finished maintenance therapy due to toxicities (fatigue, atrial flutter, neuropathy, pleural effusion, thrombocytopenia), and withdrawal of informed consent (n=4). Sixteen patients experienced disease progression during bortezomib maintenance treatment. With a median follow-up of 25.1 months, 3-year PFS rate was 56.9% and 3-year OS rate was 86.4% (Figure 1). Toxicity was assessed in 489 cycles of bortezomib maintenance in all 59 patients. There was no treatment-related death and febrile neutropenia. Conclusion: Bortezomib maintenance showed 3-year PFS rate of 56.9% with acceptable toxicities in patients with high risk DLBCL achieving a CR at the end of 6 or 8 cycles of R-CHOP21. Figure 1 Disclosures Kim: Celltrion: Research Funding; Novartis: Research Funding; J + J: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding.

ABVD Versus Escalated Beacopp in Advanced Stage Hodgkin's Lymphoma: Results from a Retrospective, Multicenter European Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1565-1565 ◽  
Author(s):  
Patrizia Mondello ◽  
Irene Dogliotti ◽  
Jan-Paul Bohn ◽  
Federica Cavallo ◽  
Simone Ferrero ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advanced Stage ◽  
Advisory Committees ◽  
Free Survival ◽  
High Risk Patients ◽  
Risk Patients

Purpose: Hodgkin's lymphoma (HL) is a highly curable disease even in advanced-stage, with &gt;90% of long-term survivors. Currently, the standard of care is ABVD (doxorubicin, etoposide, vinblastine and dacarbazine), as it is less toxic and as effective as other more intensive chemotherapy regimens. Alternatively, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) has been proposed as front-line intensified regimen with a better initial disease control and prolonged time to relapse when compared to ABVD. However, this advantage is associated with higher rates of severe hematologic toxicity, treatment-related deaths, secondary neoplasms and infertility. To date, the debate regarding which regimen should be preferred as first line for advanced-stage HL is still ongoing. To shed some light on this open question we compared efficacy and safety of both regimens in clinical practice. Patients and Methods: From October 2009 to October 2018, patients with HL stage III-IV treated with either ABVD or BEACOPP escalated (BEACOPPesc) were retrospectively assessed in 7 European cancer centers. Results: A total of 372 consecutive patients were included in the study. One-hundred and ten patients were treated with BEACOPPesc and 262 with ABVD. The baseline characteristics of the two groups did not differ significantly, except for a higher rate of high-risk patients in the BEACOPPesc group in contrast to the ABVD one (47% vs 18%; p= 0.003). Complete response rate (CR) assessed by PET imaging at the end of the second cycle was 67% and 78% for the ABVD and BEACOPPesc group (p= 0.003), respectively. Thirteen patients of the ABVD group achieved stable disease (SD) and 6 had a progression disease (PD). On the other hand, 4 of the patients in the BEACOPPesc group progressed, another 2 interrupted therapy because life-threatening toxicity. At the end of the therapy, CR was 76% in the ABVD group and 85% in the BEACOPPesc group (p= 0.01). A total of 20% patients in the ABVD group and 14% patients in the BEACOPPesc group received consolidation radiotherapy on the mediastinal mass at the dose of 30Gy. After radiotherapy, the number of patients with CR increased to 79% and 87% in the two groups (p= 0.041), respectively. Thirty-nine patients (35%) in the BEACOPPesc group required dose reduction of chemotherapy due to toxicity compared to 12 patients (5%; p= &lt;0.001) in the ABVD group. Overall, the rate of severe toxicities was higher in the BEACOPPesc group in comparison with the ABVD cohort. In particular, there was a significant increased frequency of acute grade 3-4 hematologic adverse events (neutropenia 61% vs 24%; anemia 29% vs 4%; thrombocytopenia 29% vs 3%), febrile neutropenia (29% vs 3%), severe infections (18% vs 3%). Myeloid growth factors were administered to 85% and 59% of patients in the BEACOPPesc group compared to the ABVD group. Blood transfusions were required in 51% and 6% of patients in the BEACOPPesc group compared to the ABVD cohort. Progression during or shortly after treatment occurred in 5 patients in the BEACOPPesc group (4%) and in 16 patients in the ABVD group (6%; p= 0.62). Among the 96 patients who achieved a CR after BEACOPPesc and radiotherapy, 8 relapsed (8%), compared to 29 of 208 patients in the ABVD group (14%; p= 0.04). At a median follow-up period of 5 years, no statistical difference in progression free survival (PFS; p=0.11) and event-free survival (EFS; p=0.22) was observed between the BEACOPPesc and ABVD cohorts. Similarly, overall survival (OS) did not differ between the two groups (p=0.14). The baseline international prognostic score (IPS &lt;3 vs ≥ 3) significantly influenced the EFS with an advantage for the high-risk group treated with BEACOPPesc (Figure 1A; p=0.03), but not the PFS (Figure 1B; p=0.06) and OS (Figure 1C; p=0.14). During the follow-up period, in the BEACOPPesc group one patient developed myelodysplasia and one acute leukemia. Second solid tumors developed in one patient in the ABVD group (lung cancer) and one in BEACOPPesc group (breast cancer). Conclusion: We confirm that the ABVD regimen is an effective and less toxic therapeutic option for advanced-stage HL. Although BEACOPP results in better initial tumor control especially in high-risk patients, the long-term outcome remains similar between the two regimens. Disclosures Ferrero: EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau. Martinelli:BMS: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy; Roche: Consultancy; Novartis: Consultancy. Willenbacher:European Commission: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujimoto: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Abbvie: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Intensified Conditioning for Children Undergoing BMT for First Bone Marrow Relapse of Acute Lymphoblastic Leukaemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5169-5169
Author(s):  
John Moppett ◽  
Jerry Hancock ◽  
Christopher J.C. Knechtli ◽  
Anthony Oakhill ◽  
Nicholas J. Goulden
Keyword(s):  
High Risk ◽  
Treatment Failure ◽  
Risk Group ◽  
Control Group ◽  
Childhood All ◽  
High Risk Patients ◽  
Significant Difference ◽  
Risk Patients ◽  
High Level ◽  
Risk Of Treatment

Abstract BMT remains the treatment of choice for early BM relapse of childhood ALL. We reasoned that further intensification of cytoreductive therapy pre-BMT may further improve survival amongst those with the highest risk of treatment failure, early BM relapse (BFM groups S3/4) and high level MRD pre-BMT. A cohort of 32 patients transplanted at a single institution (1996–1999) provided an historical control. 8 high risk patients transplanted 1999–2000 received additional fludarabine cytoreduction therapy at the time of transplant (FLA group). MRD analysis and time to relapse were used in a subsequent cohort of 22 patients (BMT 2000–2002) to allocate those at highest risk of treatment failure to receive a further cytoreductive block, FLX, pre-BMT. Method. All patients were conditioned with cyclophosphamide (60mg/m2 x2) and TBI (14.4 Gy). UD and haplo-BMT were T-cell depleted with Campth-1M in vitro and Campath-1G day -9 to -5 (Control and FLA group), and by Miltenyi CD34+ cell depletion (FLX group). GvHD prophylaxis - CSA + MTX for matched related, CSA for Campath treated grafts and none for Miltenyi grafts. The FLA group received fludarabine 25mg/m2 from d −12 to d −10. Patients with on treatment relapse (S4) or high level MRD pre-BMT (MRD++) in the FLX group received DaunoXome 100mg/m2, fludarabine 30mg/m2 x 5d and cytosine 2g/m2 x 5d 3 weeks prior to BMT. Patients and donors. Control group: 28 precursor-B ALL 4 T-ALL; donors - 7 matched related, 13 matched unrelated (MUD) and 12 mismatched unrelated (MMUD); 14 S2, 18 S3/4. FLA group: 5 presursor-B ALL and 3 T-ALL; donors - 2 SIB, 4 MUD, 1 MMUD and 2 haplo; all S4. FLX group: 21 precursor-B and 1 T-ALL; donors - 6 SIB, 7 MUD, 5 MMUD and 4 haplo;13 S2, 9 S4. 7 patients received FLX intensified conditioning (6 S4, 5 high level MRD ++). 3 high risk patients violated protocol and did not receive FLX (1 age &lt;1yr on treatment relapse, 2 S2 MRD ++). Results. Considering those in the high-risk S3/4 group, there was no significant difference in OS between the 3 groups. Survival by study and risk group Study S2 S3/4 Overall Control 10/14 (71%) 3/18 (17%) 13/32 (41%) FLA 2/8 (25%) 2/8 (25%) FLX 11/13 (85%) 3/9 (33%) 14/22 (64%) No excess cardiac events were seen. The TRM is higher in the FLX group than in the control. Outcome data Study TRM Relapse Alive Total Control 3 16 13 32 S2 2 2 10 14 S3/4 1 14 3 18 FLA 3 3 6 12 S2 - - - - S3/4 3 3 3 9 FLX 6 2 14 22 S2 2 0 11 13 S3/4 4 2 3 9 Total 12 21 33 66 2 of 7 patients treated with FLX are in CCR, 2 relapsed and 3 died of TRM. The 3 high risk patients in the FLX study, but who did not receive FLX, are also in CCR. Survival in those in the S2 group (late BM relapse) has been good throughout the study period. Conclusion. In this study the addition of intensive pre-BMT conditioning has not improved survival amongst high risk (S3/4 or MRD ++ pre-BMT) relapses. The number of post-BMT relapses has fallen but this is not clearly related to the use of FLX. The use of more haploidentical donors, more immunosupressive BMT regimes and additional cytoreductive chemotherapy may have contributed to the increased TRM seen. Time and site of relapse remain the clearest predictor of outcome. Further novel strategies are required to improve survival for the S4 risk group. The good OS for children receiving BMT in the S2 group should be noted.

Aggressive Chemotherapy (CHOEP-14) and Rituximab or High-Dose Therapy (MegaCHOEP) and Rituximab for Young, High-Risk Patients with Aggressive B-Cell Lymphoma: Results of the MegaCHOEP Trial of the German High — Grade Non-Hodgkin Lymphoma Study Group (DSHNHL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 404-404 ◽  
Author(s):  
Norbert Schmitz ◽  
Maike Nickelsen ◽  
Marita Ziepert ◽  
Matthias Haenel ◽  
Peter Borchmann ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Phase Iii ◽  
Conventional Chemotherapy ◽  
High Risk Patients ◽  
Risk Patients ◽  
Aggressive B Cell Lymphoma

Abstract Abstract 404 Comparison of conventional chemotherapy with high-dose therapy followed by autologous stem cell transplantation (HDT/ASCT) administered to young, high-risk patients with aggressive B-cell lymphoma as part of first-line therapy gave conflicting results; none of the randomized studies used rituximab (R) in combination with conventional or HDT. In March 2003 we started a randomized phase III study for young (18-60 years), high-risk (age-adjusted IPI 2 or 3) patients with aggressive lymphoma. For patients with B-cell lymphomas this study compared 8 cycles of CHOEP-14 (CHOP + etoposide 300 mg/m2 given every 2 weeks) with MegaCHOEP. The MegaCHOEP program used cyclophoshamide (1500 mg/m2 in cycle 1; 4500 mg/m2 in cycles 2 and 3; 6000 mg/m2 in cycle 4), doxorubicin (70 mg/m2 in all cycles), vincristine (2 mg, all cycles), etoposide (600 mg/m2 , cycle 1; 960 mg/m2 , cycles 2 and 3; 1480 mg/m2, cycle 4), and prednisone (500 mg, all cycles) to be administered every 21 days. Hematopoietic stem cells were harvested after cycles 1 and 2 and reinfused after HDT cycles 2, 3, and 4. Feasibility, safety, and efficacy of MegaCHOEP + / - R have been described (Glass et al. Blood 2006 and BMT 2006). The phase III study originally had four arms (8 × CHOEP – 14, 8 × CHOEP – 14 and 6 × R, MegaCHOEP, and MegaCHOEP and 6 × R). Treatment arms without R were closed in June 2004 because other studies (e.g the MInT study) had shown major improvement in outcome parameters when R was added to chemotherapy. The study continued comparing 8 × CHOEP – 14 and 6 × R (375 mg/m2) with MegaCHOEP and 6 × R (375 mg/m2). At the time of this analysis 346 patients (pts) had been recruited; 216 pts. (median age 48 years, LDH > N 97 %, stage III or IV 96%, ECOG > 1 35%) had been randomized until 07 / 07 and were availabel for this planned interim analysis ( 8 × CHOEP – 14 + 6 × R, n = 91; MegaCHOEP + 6 × R, n = 94; 8 × CHOEP – 14, n = 15; MegaCHOEP, n = 16). Major toxicities included mucositis, diarrhea, and infections all of which were significantly more frequent in the MegaCHOEP arm of the study. Treatment – related deaths occurred in 5 / 94 pts. ( 5.3%) in the MegaCHOEP arm and in 1 / 91 pts. (1.1 %) in the R – CHOEP arm (p = 0.211). Surprisingly, the 3 – year event – free survival ( EFS : time from randomization to either disease progression, no CR / CRu at the end of treatment, initiation of salvage therapy, relapse or death from any cause) was better after conventional than after HDT / ASCT: 71.0% after 8 × CHOEP-14 + 6 × R vs. 56.7 % after MegaCHOEP + 6 × R (p = 0.050). After a median observation time of 29 months the estimated 3-year overall survival was 83.8 % after 8 × CHOEP – 14 + 6 × R and 75.3 % after MegaCHOEP + 6 × R (p = 0.142). Progression – free survival was 76.0 % after 8 × CHOEP – 14 + 6 × R and 64.6 % after MegaCHOEP + 6 × R (p = 0.119). A comparison of the rituximab-containing treatment arms (8 × CHOEP 14 + 6 × R and Mega CHOEP + 6 × R) with the chemotherapy – only arms (8 × CHOEP -14 and MegaCHOEP) revealed a 27.1 % difference in the 3-year EFS-rate ( p = 0.003 ) pointing to the unexpectedly high efficacy of R particularly in untreated, young, high-risk patients with aggressive B-NHL. These data were presented to the members of the study group and the data safety and monitoring committee who decided to stop the MegaCHOEP arm of the study. In conclusion, 8 × CHOEP -14 + 6 × R gave excellent results in young, high-risk patients with untreated aggressive B cell lymphoma. The 3-year EFS and OS are the best ever reported for this group of patients. MegaCHOEP + 6 × R was no better than aggressive conventional chemotherapy regarding any of the study endpoints; EFS (primary endpoint of the study) was significantly worse. Because of higher toxicity and inferior survival the MegaCHOEP arm was discontinued. HDT / ASCT has no role to play as part of first-line therapy for patients with high-risk aggressive B cell lymphoma if rituximab is combined with aggressive conventional chemotherapy. Disclosures: Schmitz: Roche: Honoraria, Research Funding. Nickelsen:Roche: Honoraria. Trümper:Roche: Honoraria, Research Funding. Pfreundschuh:Roche: Consultancy, Honoraria, Research Funding. Glass:Roche: Honoraria, Research Funding.

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