Phase III Study of Response Adapted Therapy for the Treatment of Children with Newly Diagnosed Very High Risk Hodgkin Lymphoma (Stages IIIB/IVB) (AHOD0831): A Report from the Children's Oncology Group

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3927-3927 ◽  
Author(s):  
Kara M. Kelly ◽  
Peter D. Cole ◽  
Lu Chen ◽  
Kenneth B Roberts ◽  
David C. Hodgson ◽  
...  
Keyword(s):  
High Risk ◽  
Hodgkin Lymphoma ◽  
Fdg Pet ◽  
Pediatric Patients ◽  
Conflicts Of Interest ◽  
Bone Marrow Involvement ◽  
Stage Iiib ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Very High

Abstract PURPOSE: The AHOD0831 study tested a response-based treatment approach for pediatric patients with very high risk Hodgkin lymphoma (HL). Central response review following 2 cycles of dose intensive chemotherapy by FDG-PET was utilized to assign consolidation chemotherapy and risk-adapted radiotherapy. The primary outcome was second event-free survival (2nd EFS), defined as freedom from second relapse or malignancy. Because many patients with relapsed HL can be successfully cured with retrieval therapy, 2nd EFS more accurately reflects long-term overall survival (OS). AHOD0831 was designed to test whether this treatment protocol will maintain 4-year 2nd EFS ≥95%. PATIENTS AND METHODS : Patients aged ≤ 21 with stage IIIB or IVB HL were nonrandomly assigned to receive two 21-day courses of ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide). Rapid Early Response (RER) was defined by FDG-PET negativity (i.e. no activity above background), irrespective of size of residual masses. Patients with RER were consolidated with 2 additional cycles of ABVE-PC. Slow early responders (SER) received 2 cycles of ifosfamide/vinorelbine (IFOS/VINO) followed by 2 more cycles of ABVE-PC. Radiotherapy (RT), 21 Gy in 14 fractions, was administered to sites of initial bulky involvement (large mediastinal mass, nodal aggregate >6cm, splenic macronodular involvement) and regions of SER. For the primary aim of 2nd EFS, second events were defined as any relapse/progression of HL or SMN, new SMN or death after a first event which can be relapse/progression, SMN, persistent bone marrow involvement at completion of chemotherapy, or biopsy proven HL for SER at completion of chemotherapy. RESULTS: Among 165 eligible patients, median age was 15.8 yrs (5.2-21.4), 61% were male, 71 (43%) were stage IIIB, and 94 (57%) IVB. 50% were RER (stage IIIB: 58%; IVB: 45%). At time of current analysis the median follow-up was 42 months. 2nd EFS at 4 years is 89.8% (95% CI:80.8%-94.8%), below the projected baseline with 4-yr rate of 95% (P=0.01). Subgroup analyses showed that 4 yr 2nd EFS for RER (n=77) is 91.9% (76.3%-97.4%), SER (n=68) is 87.8% (75.8%-94.1%) and stage IVB 89.6% (76.3%-95.7%). 20 patients were excluded from 2nd EFS analysis secondary to premature termination or deviation of protocol therapy. 31 patients had reported at least one event for EFS (first event: 29 relapse/progressions, 1 SMN, and 1 death secondary to disseminated fungal infection during RT). Standard 1st EFS rates at 4 yrs are: 80.2% (73%-85.6%). 4 yr OS 95.9% (90%-98.4%). 12 SER patients had persistent PET positive lesions at end of chemotherapy. Eight of these 12 had clinical evidence of active disease (3 biopsy-proven HL, 2 with progressive disease by clinical or radiographic criteria, and 3 later relapses). In retrospective analysis, no specific Deauville score could be identified to predict which patients were at highest risk for progression. CONCLUSIONS: Among pediatric patients with very high risk HL (IIIB, IVB), a response directed approach utilizing limited chemotherapy (4 cycles for RER; 6 cycles for SER) and risk directed RT did not reach the ambitiously high pre-specified target for 2nd EFS. However, 4 year EFS and OS rates are comparable with results of recent trials for this population (POG 9425: IIIB/IVB, n=88: 4 yr EFS 81.7% (71.8%-88.3%); 4 yr OS 92.9% (84.9%-96.8%)). Our study achieved these similar outcomes, despite the reduction in RT volumes from historical involved fields (which did not account for relapse risk). Persistent PET at end of chemotherapy identifies a cohort at an especially high risk for relapse/early progression. Novel approaches incorporating enhanced risk stratification beyond stage and B symptoms, identification of better predictive factors beyond PET response, and incorporation of novel agents are still needed for this highest risk group of patients with newly diagnosed pediatric HL. Disclosures No relevant conflicts of interest to declare.

scholarly journals Efficacy of Upfront Daratumumab Combination Regimen in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3158-3158 ◽  
Author(s):  
Kyaw Zin Thein ◽  
Thura Win Htut ◽  
Myint Aung Win ◽  
Sriman Swarup ◽  
Anita Sultan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Novel Agents ◽  
Combination Regimen ◽  
Newly Diagnosed ◽  
Standard Risk

Introduction: Management of newly diagnosed multiple myeloma (NDMM), which accounts for 1% of all cancers, is an area in dire need of therapeutic innovation. In recent years, the introduction of novel agents is one of the major advances in the management of patients with NDMM, in both transplant- eligible and transplant- ineligible candidates. Studies have combined daratumumab, a human IgGκ monoclonal antibody that targets CD38 which is highly expressed on myeloma cells, with proteasome inhibitors and immunomodulatory agents-based regimens in the first-line treatment of NDMM. The purpose of our study is to explore and consolidate the efficacy of upfront daratumumab combination regimen in patients with NDMM. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing daratumumab in patients with newly diagnosed/ untreated multiple myeloma were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) with 95% confidence interval (CI). Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) for overall response rate (ORR), including stringent complete response (sCR), CR and very good partial response (VGPR). Heterogeneity was assessed with Cochran's Q -statistic. Random effects model was applied. Results: Three phase III RCTs with a total of 2,528 patients with NDMMwere included.Studies compared daratumumab (D) + bortezomib (V) + melphan (M) + prednisone (P) vs VMP, D + lenalidomide (R) + dexamethasone (d) vs Rd, and DVd + thalidomide (T) vs VTd. The randomization ratio was 1:1 in all studies. The I2statistic for heterogeneity was 0, suggesting homogeneity among RCT. The pooled HR for PFS was statistically significant at 0.52 (95% CI: 0.44-0.61; P < 0.0001). The PFS benefit was observed in all ISS categories, types of immunoglobulin (Ig) and standard risk cytogenetic; ISS I cohort (HR, 0.55; 95% CI: 0.37- 0.82; P = 0.003), ISS II cohort (HR, 0.43; 95% CI: 0.33- 0.55; P < 0.0001), ISS III cohort (HR, 0.63; 95% CI: 0.48- 0.82; P = 0.0006), IgG cohort (HR, 0.56; 95% CI: 0.40- 0.77; P = 0.0003), non-IgG cohort (HR, 0.52; 95% CI: 0.28- 0.97; P = 0.04), and standard risk cytogenetic cohort (HR, 0.43; 95% CI: 0.35- 0.53; P < 0.0001). The pooled HR for PFS in high risk cytogenetic cohort was not statistically significant at 0.76 (95% CI: 0.53- 1.10; P = 0.15). The pooled RR for ORR was 1.13 (95% CI: 1.01-1.26; P = 0.03), sCR was 2.02 (95% CI: 1.33-3.08; P = 0.001), CR was 1.46 (95% CI: 1.20-1.79; P = 0.0002),and VGPR was 1.01 (95% CI: 0.82-1.25; P = 0.93). The pooled RR for negative minimal residual disease (MRD) was 2.54 (95% CI: 1.24-5.20; P = 0.01). Conclusions: Upfront combination regimen with daratumumab significantly improved PFS, ORR, sCR and CR along with negative MRD, compared to control arm in patients with NDMM. The improvement in PFS was noted across all subgroups except in high-risk cytogenetic group. More randomized studies are required to explore further novel agents and to formulate optimal combination regimen to improve survival in this high-risk cytogenetic subset. Disclosures No relevant conflicts of interest to declare.

Excellent Outcome for Pediatric Patients with High Risk Hodgkin Lymphoma with Brentuximab Vedotin and Risk Adapted Residual Node Radiation

2020 ◽  
Author(s):  
Monika Metzger ◽  
Michael P. Link ◽  
Amy L. Billett ◽  
Jamie Flerlage ◽  
John T. Lucas Jr. ◽  
...  
Keyword(s):  
High Risk ◽  
Hodgkin Lymphoma ◽  
Pediatric Patients ◽  
Brentuximab Vedotin ◽  
Excellent Outcome

scholarly journals FDG PET/CT to detect bone marrow involvement in the initial staging of patients with aggressive non-Hodgkin lymphoma: results from the prospective, multicenter PETAL and OPTIMAL>60 trials

2021 ◽  
Author(s):  
Dominic Kaddu-Mulindwa ◽  
Bettina Altmann ◽  
Gerhard Held ◽  
Stephanie Angel ◽  
Stephan Stilgenbauer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Predictive Value ◽  
Fdg Pet ◽  
Bone Marrow Involvement ◽  
Non Hodgkin Lymphoma ◽  
Pet Ct ◽  
Fdg Pet Ct ◽  
Initial Staging

Abstract Purpose Fluorine-18 fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG PET/CT) is the standard for staging aggressive non-Hodgkin lymphoma (NHL). Limited data from prospective studies is available to determine whether initial staging by FDG PET/CT provides treatment-relevant information of bone marrow (BM) involvement (BMI) and thus could spare BM biopsy (BMB). Methods Patients from PETAL (NCT00554164) and OPTIMAL>60 (NCT01478542) with aggressive B-cell NHL initially staged by FDG PET/CT and BMB were included in this pooled analysis. The reference standard to confirm BMI included a positive BMB and/or FDG PET/CT confirmed by targeted biopsy, complementary imaging (CT or magnetic resonance imaging), or concurrent disappearance of focal FDG-avid BM lesions with other lymphoma manifestations during immunochemotherapy. Results Among 930 patients, BMI was detected by BMB in 85 (prevalence 9%) and by FDG PET/CT in 185 (20%) cases, for a total of 221 cases (24%). All 185 PET-positive cases were true positive, and 709 of 745 PET-negative cases were true negative. For BMB and FDG PET/CT, sensitivity was 38% (95% confidence interval [CI]: 32–45%) and 84% (CI: 78–88%), specificity 100% (CI: 99–100%) and 100% (CI: 99–100%), positive predictive value 100% (CI: 96–100%) and 100% (CI: 98–100%), and negative predictive value 84% (CI: 81–86%) and 95% (CI: 93–97%), respectively. In all of the 36 PET-negative cases with confirmed BMI patients had other adverse factors according to IPI that precluded a change of standard treatment. Thus, the BMB would not have influenced the patient management. Conclusion In patients with aggressive B-cell NHL, routine BMB provides no critical staging information compared to FDG PET/CT and could therefore be omitted. Trial registration NCT00554164 and NCT01478542

scholarly journals A Prognostic Model Incorporating Tumor Lesion Morphology and Texture Features Identifies High-Risk Patient Subpopulations in De Novo DLBCL and FL

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 28-28
Author(s):  
Xiao Li ◽  
Skander Jemaa ◽  
Richard AD Carano ◽  
Thomas Bengtsson ◽  
Joseph N Paulson ◽  
...  
Keyword(s):  
High Risk ◽  
Fdg Pet ◽  
De Novo ◽  
Risk Group ◽  
Low Risk ◽  
Phase Iii ◽  
Publicly Traded ◽  
Prognostic Performance ◽  
Pet Scans ◽  
Worse Prognosis

Background: Despite effective first-line (1L) treatment options for patients with NHL almost 40% of patients with diffuse large B cell lymphoma (DLBCL) will have a poor response or disease progression after 1L treatment. In follicular lymphoma (FL) 15-20% of patients experience early relapse, and almost 8% may develop transformation to more aggressive forms of the disease (such as DLBCL) after 1L treatment. More accurate identification of patients at high-risk for a poor prognosis with the standard of care could lead to improved outcomes. Although the International Prognostic Index (IPI) and its FL extension (FLIPI) are often used to stratify patients by prognosis, they have relatively modest sensitivity and specificity for predicting individualized risk. Radiomics is a promising approach to improve upon existing prognostic models because it provides a comprehensive quantification of tumor lesion morphology and texture derived from FDG-PET scans and may provide new and important information about disease biology and progression risk on an individual level. Methods: A collection of 107 radiomics features [pyradiomics v2.20] that describe shape, size or volume and texture of tumor lesions, including complex features that are believed to reflect the underlying biological tumor phenotype and microenvironment, were derived for n=1093 de novo DLBCL patients with available baseline FDG-PET scans from the Phase III GOYA study (NCT01287741) evaluating obinutuzumab plus CHOP chemotherapy (G-CHOP) versus rituximab plus CHOP chemotherapy (R-CHOP) (Vitolo, et al. J Clin Oncol 2017). The same set of features were also extracted from n=451 de novo FL patients with available baseline FDG-PET scans from the Phase III GALLIUM study (NCT01332968) comparing obinutuzumab plus chemotherapy with rituximab plus chemotherapy [Marcus, et al. N Engl J Med 2017]. To investigate the association between the derived radiomics features along with baseline clinical variables and progression-free survival (PFS), a Cox proportional hazard model with L1 regularization was trained and internally validated using the GOYA study. We used a nested Monte Carlo Cross Validation (nMCCV) strategy to train our model and provide high- and low-risk group predictions on held-out samples of data. This modeling strategy allows us to make a group prediction on all GOYA patients while reducing overfitting. To evaluate prognostic performance, we ported the final model trained using the GOYA study (called the Li prognostic model) to the fully independent GALLIUM study. Results: Using our nMCCV approach we identified 11 factors, with an inclusion probability of &gt;50%, that are associated with PFS of DLBCL patients (Figure A). Included within the top features are several image-derived morphometric (i.e. metabolic tumor volume, surface area) and radiomics features (i.e. tumor elongation, NGTDM contrast, GLCM inverse variance). When stratifying patients on the predicted (via majority vote) low-risk vs high-risk groupings we found that our high-risk group had significantly worse prognosis vs the low-risk group (Figure B). In comparison, the high-risk group from the IPI model (defined as IPI &gt; 2) had significantly worse prognosis vs the low-risk group, but the performance was slightly worse than our model (Figure C). PFS probability estimates at 2 and 5 years for predicted high-risk patients was 72.7% [70.0-76.6] and 59.8% [54.8-65.2] (vs 74% [70.0-78.2] and 60.4% [55.1-66.2] for the IPI model). After training and testing in the DLBCL population, we evaluated the prognostic performance of our model in an independent set of FL patients. We found that high-risk FL patients had a significantly worse prognosis than the low-risk group (Figure D). PFS probability estimates at 2 and 5 years for predicted high-risk patients was 77.4% [69.8-85.8] and 48.9% [39.5-60.5] (vs. 80% [0.748-0.856] and 58.3% [51.6-65.9] in the full group). Conclusions: Radiomics features are prognostic in DLBCL and provide a modest improvement in prognostic performance when combined with traditional IPI scores, clinical features, and lab values (vs IPI alone). Our prognostic signature, developed in DLBCL, has significant prognostic performance in an independent dataset of patients with FL. While these results are promising, our FL validation dataset was relatively small and further evidence is required to confirm our findings. Disclosures Li: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Jemaa:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Carano:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Bengtsson:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Paulson:F. Hoffmann-La Roche: Current equity holder in private company, Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Jansen:F. Hoffmann-La Roche: Current Employment; Molecular Health GmbH: Ended employment in the past 24 months; F. Hoffmann-La Roche, Abbvie, Alphabet, other (non-healthcare), indexed funds and ETFs: Current equity holder in publicly-traded company. Nielsen:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Hibar:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company.

scholarly journals Remission in Patients with Acute Promyelocytic Leukemia Treated with Arsenic Trioxide (varitrinox) As the First Line in Colombia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-3
Author(s):  
Gustavo Milone ◽  
Samuel Sarmiento Doncel ◽  
Carol Agudelo Rico ◽  
Fabiola Vizcarra Reyes ◽  
Gina Alejandra Diaz Mosquera ◽  
...  
Keyword(s):  
High Risk ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Conflicts Of Interest ◽  
Promyelocytic Leukemia ◽  
Remission Induction ◽  
Intermediate Risk ◽  
Newly Diagnosed ◽  
First Line ◽  
Risk Patients

Acute promyelocytic leukemia (APL) is a subtype of Acute Myeloid Leukemia (AML) in which a chromosomal translocation t (15; 17) (q22; q12) is generated by fusing produces a hybrid PML / RARα gene, generating an altered signal . The combination of transretinoic acid (ATRA) plus arsenic trioxide (ATO) has been shown to be superior to ATRA plus chemotherapy in the treatment of newly diagnosed standard risk patients with acute promyelocytic leukemia (APL) in several countries. The objective of the present study is to describe the frequency of remission in patients with acute promyelocytic leukemia who were administered as a first line Arsenic Trioxide (varitrinox) during the period from November 2017 to June 2020 in Colombian patients. Methods: Retrospective observational and descriptive study of 12 patients diagnosed with acute promyelocytic leukemia treated with ATO Arsenic trioxide (Varitrinox) as first line, the source of information was provided by the treating hematologists (medical records) by filling out the technical concept format. Active pharmacovigilance scientist in Colombia, this format keeps the identification information of the patient anonymized and the confidentiality of the data is guaranteed as well as compliance with the rules of good clinical practice. Results: Twelve patients with age range between 22 and 69 years with a median age of 34.0 were analyzed. It was found in the analysis that 100% had induction hematologic remission with a median of 45 days. 75% of patients received ATO + ATRA and were at low and intermediate risk, the remaining 25% received ATRA + ATO + Chemotherapy and were at high risk, and intermediate risk. 91.7% of molecular remission in consolidation was obtained and it was measured in cycle 3 by means of PCR (undetectable), 8.3% (n = 1) was positive 3% and is finishing consolidation. Regarding the most frequent adverse events, intravascular coagulation (n = 9), neutropenia (n = 6) and thrombocytopenia (n = 6) were observed. 75% of patients are disease-free, 16.7% are on maintenance (they received ATO + ATRA + Induction chemotherapy) and 8.3% are on consolidation. So far, none of the patients under study have died. Conclusions: Our results support the use of ATO (Varitrinox) in newly diagnosed APL patients (as first line), as a care strategy for low, intermediate and high risk patients. The role of ATRA-ATO is guaranteed in other studies where they manage patients of different risks. Key words: Arsenic trioxide, leukemia promyelocytic acute, leukemia myeloid acute, remission induction, tretinoin. Disclosures No relevant conflicts of interest to declare.

High-Dose Interferon Alfa-2b Does Not Diminish Antibody Response to GM2 Vaccination in Patients With Resected Melanoma: Results of the Multicenter Eastern Cooperative Oncology Group Phase II Trial E2696

2001 ◽  
Vol 19 (5) ◽  
pp. 1430-1436 ◽  
Author(s):  
John M. Kirkwood ◽  
Joseph Ibrahim ◽  
David H. Lawson ◽  
Michael B. Atkins ◽  
Sanjiv S. Agarwala ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Ii ◽  
Interferon Alfa ◽  
Immunoglobulin M ◽  
Phase Iii ◽  
High Dose ◽  
High Risk Melanoma ◽  
Risk Melanoma ◽  
High Dose Interferon ◽  
Very High

PURPOSE: High-dose interferon alfa-2b (IFNα2b) is the only established adjuvant therapy of resectable high-risk melanoma. GM2-KLH/QS-21 (GMK) is a chemically defined vaccine that is one of the best developed of a range of vaccine candidates for melanoma. A single-institution phase III trial conducted at Memorial Hospital served as the impetus for an intergroup adjuvant E1694/S9512/C509801 trial, which recently completed enrollment of 880 patients. To build on the apparent benefit of IFNα2b in resectable high-risk American Joint Committee on Cancer (AJCC) stage IIB or III melanoma, this phase II study was designed to evaluate the combination of GMK and IFNα2b. The E2696 trial was undertaken to evaluate the toxicity and other effects of the established adjuvant high-dose IFNα2b regimen in relation to immune responses to GMK and to evaluate the potential clinical and immunologic effects of the combined therapies. PATIENTS AND METHODS: This trial enrolled 107 patients with resectable high- or very high–risk melanoma (AJCC stages IIB, III, and IV). RESULTS: The results demonstrate that IFNα2b does not significantly inhibit immunoglobulin M or G serologic responses to the vaccine and that the combination of high-dose IFNα2b and GMK is well tolerated in this patient population. CONCLUSION: Cox analysis of the results of the combination with IFNα2b show improvement in the relapse-free survival of patients with very high–risk melanoma (including those with resectable M1 disease).

scholarly journals PET-adapted approaches to primary therapy for advanced Hodgkin lymphoma

2020 ◽  
Vol 11 ◽  
pp. 204062072091449 ◽  
Author(s):  
Noemie Lang ◽  
Michael Crump
Keyword(s):  
Hodgkin Lymphoma ◽  
Fdg Pet ◽  
Chemotherapy Regimen ◽  
Treatment Decisions ◽  
Phase Iii ◽  
Response Criteria ◽  
Primary Therapy ◽  
Advanced Stage ◽  
Phase Iii Studies

Recent results of randomized phase III studies of FDG-PET-adapted therapy for advanced Hodgkin lymphoma (HL) have clearly demonstrated benefit to alteration of treatment according to interim response, in particular regarding reducing toxicity while maintaining efficacy. However, these studies have differences in design including initial chemotherapy regimen, PET response criteria, patient populations enrolled, and inclusion of radiation, and report different results regarding efficacy and toxicities, which makes cross-trial comparisons difficult. Practitioners are presented with deciding which of these approaches will provide the optimum outcome, balancing toxicity and efficacy, and for which patient with advanced-stage HL. This review summarizes the observations reported from these trials and provides context to help guide physicians and patients in treatment decisions for advanced HL.

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