Clinical outcomes and prognostic factors to predict treatment response in high risk neuroblastoma patients receiving topotecan and cyclophosphamide containing induction regimen: a prospective multicenter study

Abstract Background Neuroblastoma is the most common extra-cranial solid tumor among children. Despite intensive treatment, patients with advanced disease mostly experience dismal outcomes. Here, we proposed the use of topotecan and cyclophosphamide containing induction regimen as an upfront therapy to high risk neuroblastoma patients. Methods Patients with high risk neuroblastoma undergoing ThaiPOG high risk neuroblastoma protocol from 2016 to 2017 were studied. All patients received 6 cycles of induction regimen consisting of 2 cycles topotecan (1.2 mg/m2/day) and cyclophosphamide (400 mg/m2/day) for 5 days followed by cisplatin (50 mg/m2/day) for 4 days combined with etoposide (200 mg/m2/day) for 3 days on the third and fifth cycles and cyclophosphamide (2100 mg/m2/day) for 2 days combined with doxorubicin (25 mg/m2/day) and vincristine (0.67 mg/m2/day) for 3 days on the fourth and sixth cycles. Treatment response after the 5th cycle before surgery and treatment-related toxicities after each topotecan containing induction cycle were evaluated. Relevant prognostic factors were analyzed to measure the treatment response among those patients. Results In all, 107 high risk neuroblastoma patients were enrolled in the study. After the 5th cycle of induction regimen, the patients achieved complete response (N = 2), very good partial response (N = 40), partial response (N = 46) and mixed response (N = 19). None of the patients experienced stable disease or disease progression. The most significant prognostic factor was type of healthcare system. The most common adverse effect was febrile neutropenia followed by mucositis, diarrhea and elevated renal function. Conclusion The topotecan and cyclophosphamide containing induction regimen effectively provides favorable treatment response. The regimen is well tolerated with minimal toxicity among patients with high risk neuroblastoma in Thailand.

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Phase II Study of Temozolomide in Relapsed or Refractory High-Risk Neuroblastoma: A Joint Société Française des Cancers de l’Enfant and United Kingdom Children Cancer Study Group–New Agents Group Study

Journal of Clinical Oncology ◽

10.1200/jco.2006.06.1572 ◽

2006 ◽

Vol 24 (33) ◽

pp. 5259-5264 ◽

Cited By ~ 44

Author(s):

Hervé Rubie ◽

Julia Chisholm ◽

Anne Sophie Defachelles ◽

Bruce Morland ◽

Caroline Munzer ◽

...

Keyword(s):

High Risk ◽

Partial Response ◽

Phase Ii ◽

Response Assessment ◽

Complete Response ◽

Lesion Size ◽

Mixed Response ◽

Duration Of Response ◽

Heavily Pretreated ◽

Grade 3

Purpose To determine the response rate (RR) of neuroblastoma (NB) in children to temozolomide (TMZ), and evaluate the duration of response and tolerance of the drug in this patient population. Patients and Methods A multicenter, phase II evaluation of an oral, daily schedule of TMZ (200 mg/m2/d × 5 days every 28 days) was undertaken in children with refractory or relapsed high-risk NB (metastatic or localized with Myc-N amplification). Response assessment was based on imaging with two-dimentional measurement of disease and meta-iodobenzylguanidine (MIBG) score. Activity was defined by a reduction in lesion size or isotope uptake at anytime. Methodology included a two-step design using Fleming’s method with a first step of 15 patients and a second of 10 additional patients if two to four responses had been observed in the first cohort. All data was centrally reviewed by a panel. Results Twenty-five assessable patients were recruited over a 14-month period in 14 centers and received 94 cycles of chemotherapy. Twenty-three patients had metastatic NB either refractory (n = 9) or in relapse (n = 14). Grade 3 or 4 thrombocytopenia was the most frequent toxicity (16% of cycles). Myelosuppression resulted in treatment delays and dose reductions (24% and 21% of cycles, respectively). Response (complete response, very good partial response, or partial response) was observed in five patients (RR = 20% ± 8%) with a median duration of 6 months and an objective or mixed response in five additional patients. Conclusion Temozolomide shows activity in heavily pretreated patients with NB, and deserves further evaluation in combination with another drug.

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Prognostic Significance of Serum S100B Protein in High-Risk Surgically Resected Melanoma Patients Participating in Intergroup Trial ECOG 1694

Journal of Clinical Oncology ◽

10.1200/jco.2008.17.1777 ◽

2009 ◽

Vol 27 (1) ◽

pp. 38-44 ◽

Cited By ~ 73

Author(s):

Ahmad A. Tarhini ◽

Joseph Stuckert ◽

Sandra Lee ◽

Cindy Sander ◽

John M. Kirkwood

Keyword(s):

Prognostic Factors ◽

High Risk ◽

Univariate Analysis ◽

Prognostic Significance ◽

S100b Protein ◽

Lymph Node Status ◽

Significant Prognostic Factor ◽

Serum S100b ◽

Time Points

PurposeWe evaluated adjuvant trial E1694 to more precisely define the prognostic significance of serum S100B in patients with high-risk resected melanoma.Patients and MethodsSera from 670 E1694 patients banked at baseline and three additional time points were tested for S100B protein using chemiluminescence.ResultsS100B testing results showed that the higher the S100B level is, the higher the risk of relapse and death, regardless of the cutoff value. Univariate analysis showed that baseline S100B ≥ 0.15 μg/L is significantly correlated with overall survival (OS; P = .01). Multivariate analysis was performed adjusting for significant prognostic factors (ulceration and lymph node status) and treatment. Baseline S100B was a significant prognostic factor for survival (hazard ratio = 1.39; 95% CI, 1.01 to 1.92; P = .043). S100B values measured at later time points over 1 year were also demonstrated to be significant prognostic factors for relapse-free survival (RFS) and OS. Lower S100B values at baseline and during follow-up were associated with longer survival. A changing S100B from low at baseline to high on follow-up seemed to be associated with the worst RFS and OS.ConclusionFor patients with high-risk surgically resected melanoma, a high baseline or increasing serum S100B is an independent prognostic marker of risk for mortality that may allow us to refine the application of adjuvant therapy in the future.

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Frontline Therapy with Low Risk Chemotherapy (R-CVP/R-CHOP) in Follicular B-Cell Lymphoma Recently Diagnosed. Clinical Experience in Two Centers of Bogotá, Colombia

Blood ◽

10.1182/blood.v120.21.4893.4893 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4893-4893

Author(s):

Carlos Daniel Bermudez ◽

Martha Leticia Suarez ◽

Sergio Andres Cancelado ◽

Carlos Alberto Ramirez

Keyword(s):

High Risk ◽

Partial Response ◽

Follicular Lymphoma ◽

B Cell Lymphoma ◽

Complete Response ◽

Low Risk ◽

Long Term Results ◽

Severe Toxicity ◽

Primary Therapy ◽

Overall Response

Abstract Abstract 4893 Background: The follicular lymphoma (FL) it is a subset of non-Hodgkin lymphomas, accounting for between 15% and 30% of new diagnoses of lymphoma. It has raised many combinations of treatments, but the long-term results remain unchanged. At present there is no consensus on the first line therapy for the management of follicular lymphoma. Since the advent of rituximab use, this change, achieving better response rates and survival, the paradigm is the use of R-CHEMO, but there are many active combinations, including the use CVP, CHOP, FCM, and others, which have shown benefit, but with consequences given for severe toxicity, and treatment-related deaths. In Colombia, the situation it is not different, the use of chemotherapy is left for consideration by the treating physician. This study aimed to assess treatment preferences for patients with new diagnosis of follicular lymphoma in Colombia, evaluate the responses of the combination R-CHEMOTHERAPY in our population, considering the specific ethnic characteristics and limitations of a developing country. Patients and Methods: The study included patients diagnosed with follicular lymphoma confirmed by hematopathologist with experience by performing at least 10 immunohistochemical tumor markers. This study is a descriptive study. During the study took into account the principles of autonomy, beneficence and justice written in the Belmont report. Informed consent was obtained from patients for participation in this study. It also welcomes the resolution expressed law Colombian Ministry of Health No. 008 430 1993 (4 October 1993) Article 11 investigation classified as safe. We analyzed cases diagnosed from January 2007 to July 2011 in two private institutions in the city of Bogotá, Colombia, we obtained 20 cases meeting the inclusion criteria. All the patients were scheduled to undergo primary therapy with 6 cycles of full-dose R-CVP or R-CHOP. Results: in this group, there were 5 men and 15 women (75% of all patients), and the median age at diagnosis was 56 years, the initial stage was 10% for stage II, 40% for stage III and the remaining 50% for stage IV, the bone marrow compromise reached by 45% (9 cases). The initial functional status classified by the ECOG scale was 0: 45%, 1: 50% and 3: 5%. the B symptoms were present in 95% of the patients analyzed. In accordance with the International Prognostic Index (FLIPI), we find the following: low risk: 25% (5 cases), intermediate risk: 35% (7 cases) and high risk: 40% (8 patients). the pathological grading was grade 1: 55% (11 patients), grade 2 for 35% (4 patients) and 3 for 10% (2 patients). When we reviewed found that the preferred treatment, for 80% of the population uses the R-CVP and the remaining 20% use of R-CHOP scheme, one patient in the R-CHOP group was complicated with high-risk febrile neutropenia requiring hospitalization. There were no treatment-related deaths. We found that 80% of patients achieved a complete hematologic remission and 20% partial response for an overall response of 100%. If we analyze separately patients treated with R-CVP scheme was 75% complete response and 25% partial response, with an overall response of 100%. Conclusion: This study shows the preference of treatment in 2 institutions in Bogotá, Colombia, which are in accordance with international guidelines, the results show a population with similar general characteristics with the others studies, in which a 100% overall hematologic response was achieved, 75% complete response for the R-CVP and 100% for the R-CHOP, however the latter with 25% of severe infectious complications. We consider a good treatment strategy for the implementation in our population is the R-CVP scheme, which is well tolerated, showing benefit in our patients and remission rates even higher than the studies previously published. Disclosures: No relevant conflicts of interest to declare.

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Real-World Clinical Outcomes By Cytogenetic Risk Category in Relapsed or Refractory Multiple Myeloma: Evidence from a Cohort Review in France

Blood ◽

10.1182/blood.v128.22.4784.4784 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4784-4784

Author(s):

Huamao Mark Lin ◽

Keith L Davis ◽

James A. Kaye ◽

Katarina Luptakova ◽

Lu Gao ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Partial Response ◽

Research Funding ◽

Complete Response ◽

Line Treatment ◽

Second Line ◽

High Risk Patients ◽

Risk Patients ◽

Standard Risk

Abstract INTRODUCTION: Multiple Myeloma (MM) is an incurable hematologic cancer characterized by multiple recurrences. With each recurrence, patients have a lower probability of response and duration of response is shorter. Therefore, there is an unmet need to improve outcomes in relapsed/refractory multiple myeloma (RRMM). There is a shortage of data describing clinical features and outcomes in these patients in real-world practice, particularly with regard to differences in outcomes by baseline cytogenetic risk. To help address this information gap, this study analyzed data from a cohort of RRMM patients in France. METHODS: A retrospective observational review of medical records was conducted in a cohort of 200 patients with RRMM in France. Patients were selected (based on randomly generated first letter of last name) from the caseloads of 40 hematology/oncology providers across France practicing mainly in academic hospitals. Inclusion criteria were: ≥18 years of age at initial MM diagnosis; first determined to have RRMM between January 1, 2009 and December 31, 2011, where RRMM was defined by (1) first-line (induction) regimen of chemotherapy with or without stem cell transplant (SCT) and with or without other post-induction/SCT therapy and (2) disease progression while on or at any time after completion of first-line therapy. Patients could be alive or deceased at the time of record abstraction. Baseline cytogenetic risk was defined as follows: high-risk: cytogenetic abnormalities del(17p), t(4:14), or t(14;16); unknown/unassessed risk: patients for whom cytogenetics were unavailable; or standard-risk: all patients with known cytogenetics not classified as high-risk. Patients were assessed for treatment response, overall survival (OS) and progression-free survival (PFS) from date of first relapse (study index date). All analyses were descriptive. Survival was assessed using the Kaplan-Meier (K-M) method. RESULTS: Demographic and clinical characteristics of the study sample are presented in Table 1. A total of 55 high-risk and 113 standard-risk patients were identified; risk category was unknown or unassessed for 32 patients. Among all patients, mean (SD) age at RRMM diagnosis was 66.3 (8.9) years and 62% of the sample was male. Lenalidomide + dexamethasone was the most common second-line systemic regimen initiated (50% of high-risk patients, 59.5% of standard-risk patients receiving second-line treatment). A total of 114 patients (57%) initiated a third-line treatment. Despite clinical response in second-line treatment occurring sooner in high-risk patients (median: 106 days) than in standard-risk patients (median: 237 days), physician-assessed overall response rate (ORR) was lower in high-risk patients (63%: 17% complete response, 46% partial response) than standard-risk patients (91%: 26% complete response, 65% partial response) across all second-line treatments combined (Table 2).. For third-line treatment, ORR was lower in high-risk patients (54%: 12% complete response, 42% partial response) than standard-risk patients (74%: 9% complete response, 65% partial response). Among patients who initiated a second-line treatment (n = 192), 47.4% were deceased at the time of data collection. From second-line initiation, K-M estimates of 1- to 5-year OS and PFS were substantially lower for high-risk patients versus standard-risk. Specifically, the proportions of patients still alive 1, 3, and 5 years after second-line treatment initiation were 73%, 51%, and 36%, respectively, for high-risk patients and 94%, 73%, and 61% for standard-risk patients. The proportions of patients without disease progression at 1, 3, and 5 years after second-line initiation were 48%, 13.5%, and 5% for high-risk patients and 82%, 42%, and 14% for standard-risk patients. CONCLUSIONS: The importance of cytogenetic risk classification as a prognostic factor in RRMM was apparent in this retrospective review, in which patients with high-risk cytogenetics had less favorable outcomes in terms of ORR, OS, and PFS than standard-risk patients. Decreased response rate and lower PFS and OS was documented among patients with high-risk cytogenetics, which is in contrast to shorter time needed to achieve best clinical response in this subgroup. Results from this real-world study provide further confirmation of the unmet medical need presented by RRMM, especially for patients with high-risk cytogenetics. Disclosures Lin: Takeda: Employment. Davis:Takeda: Research Funding. Kaye:Takeda: Research Funding. Luptakova:Takeda Oncology: Employment. Gao:Takeda: Employment. Nagar:Takeda: Research Funding. Seal:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership.

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Children's Oncology Group (COG) AALL0434: Successful Disease Control without Cranial Radiation in Newly Diagnosed T Lymphoblastic Lymphoma (T-LL)

Blood ◽

10.1182/blood-2018-99-113481 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1000-1000 ◽

Cited By ~ 1

Author(s):

Robert James Hayashi ◽

Stuart S. Winter ◽

Kimberly P. Dunsmore ◽

Meenakshi Devidas ◽

Brent Wood ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Partial Response ◽

Board Of Directors ◽

Complete Response ◽

Newly Diagnosed ◽

Advisory Committees ◽

Risk Patients ◽

To Receive ◽

Standard Risk

Abstract Background: COG AALL0434 evaluated the safety and efficacy of a multi agent chemotherapy backbone containing Capizzi based methotrexate/pegaspargase in newly diagnosed T-LL patients. High-risk patients were randomized to receive the COG augmented BFM (ABFM) regimen with or without Nelarabine. This was part of a larger trial including T-Lymphoblastic Leukemia (T-ALL) patients featuring a 2 x 2 pseudo-factorial randomization at the end of induction using the COG ABFM regimen with a randomization of Capizzi MTX/pegaspargase (C-MTX) verses high dose MTX and a randomization with or without Nelarabine (Nel). Methods: AALL0434 enrolled 277 patients with T-LL (2010-2014). Patients were assigned to two risk categories based upon the degree of bone marrow involvement at diagnosis: (≥1%, High Risk, <1% Standard Risk), and the ability to achieve at least a partial response at the end of induction. Patients with prior steroid treatment were assigned to the high risk group. Both groups were treated using the ABFM C-MTX regimen. High-risk patients were randomized to receive or not receive six, 5-day courses of Nel 650 mg/m2/day. No patients received prophylactic cranial radiation and CNS3 patients were ineligible. Response criteria included, Complete Response (CR): disappearance, Complete Response unconfirmed (CRu): >75% reduction, Partial Response (PR): >50% reduction, of all measurable disease, all without new lesions. Results: At the end of induction, 98.9% of the evaluable patients achieved at least a partial response (30.7% CR, 34.7% CRu, 33.5% PR). For all T-LL patients, the 4-year event free survival (EFS) and overall survival (OS) were 87.0 +/- 2.1% and 90.0+/-1.8%. The 4-year Disease Free Survival (DFS) from end of induction was 90.0+/- 2.1%. There was no difference in DFS observed between the high risk and standard risk groups, (p=0.25) or by treatment regimen (p=0.31). Nel did not show an advantage for high-risk T-LL patients, with 4-year DFS 85.0 +/- 5.6% with Nel (N=60) vs 89.0 +/- 4.7% without Nel (N=58) (p=0.28). Neither stage nor tumor response at the end of four weeks of induction therapy resulted in differences in EFS (p= 0.34 and p= 0.22, respectively). Minimal detectable disease (MDD) of the bone marrow at diagnosis (<0.1%, 0.1-0.99%, >1.0%), used to establish the risk assignment for this trial, failed to demonstrate thresholds at diagnosis that resulted in differences in EFS (p=0.27). Relapse involving the CNS only occurred in 4 patients (1.4%). Overall toxicity and neurotoxicity was acceptable and not significantly different than that experienced from the ALL cohort. There was one observed second malignancy and 5 deaths not from progressive disease. Conclusion: COG AALL0434 produced excellent outcomes in one of the largest trials ever conducted for patients with newly diagnosed T-LL. The COG ABFM regimen with C-MTX provides excellent disease control regardless of stage, or the degree of disease involvement of the bone marrow at diagnosis. Nelarabine did not show an improvement in the outcome, although the trial was underpowered to address this specific question. Disclosures Teachey: Amgen: Consultancy; La Roche: Consultancy. Bollard:Torque: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Neximmune: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Beneficial Effect of Lenalidomide-Dexamethason Treatment in Relapsed/Refractory Multiple Myeloma Patients: Results of Real-Life Data From 11 Hungarian Centers

Pathology & Oncology Research ◽

10.3389/pore.2021.613264 ◽

2021 ◽

Vol 27 ◽

Author(s):

Gergely Varga ◽

András Dávid Tóth ◽

Virág Réka Szita ◽

Zoltán Csukly ◽

Apor Hardi ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Partial Response ◽

Real World ◽

Randomized Clinical Trials ◽

Treatment Options ◽

Real Life ◽

Progression Free Survival ◽

Staging System ◽

Complete Response

In Hungary, the cost of lenalidomide-based therapy is covered only for relapsed multiple myeloma (MM) patients, therefore lenalidomide is typically used in the second-line either as part of a triplet with proteasome inhibitors or as a doublet. Lenalidomide-dexamethasone is a standard treatment approach for relapsed/refractory MM, and according to recent large randomized clinical trials (RCT, the standard arm of POLLUX, ASPIRE, TOURMALINE), the progression-free survival (PFS) is expected to be approximately 18 months. We surveyed ten Hungarian centers treating MM and collected data of 278 patients treated predominantly after 2016. The median age was 65 years, and patients were distributed roughly equally over the 3 international staging system groups, but patients with high risk cytogenetics were underrepresented. 15.8% of the patients reached complete response, 21.6% very good partial response, 40.6% partial response, 10.8% stable disease, and 2.5% progressed on treatment. The median PFS was unexpectedly long, 24 months, however only 9 months in those with high risk cytogenetics. We found interesting differences between centers regarding corticosteroid type (prednisolone, methylprednisolone or dexamethasone) and dosing, and also regarding the choice of anticoagulation, but the outcome of the various centers were not different. Although the higher equivalent steroid dose resulted in more complete responses, the median PFS of those having lower corticosteroid dose and methylprednisolone were not inferior compared to the ones with higher dose dexamethasone. On multivariate analysis high risk cytogenetics and the number of prior lines remained significant independent prognostic factors regarding PFS (p < 0.001 and p = 0.005). Our results show that in well-selected patients Lenalidomide-dexamethasone can be a very effective treatment with real-world results that may even outperform those reported in the recent RCTs. This real world information may be more valuable than outdated RCT data when treatment options are discussed with patients.

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Efficacy and toxicity of weekly paclitaxel, carboplatin, and cetuximab as induction chemotherapy or in cases of metastases or relapse for head and neck cancer in elderly or frail patients.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.6042 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 6042-6042

Author(s):

Rebecca Forman ◽

Aarti K. Bhatia ◽

Barbara Burtness

Keyword(s):

Adverse Effect ◽

Partial Response ◽

Head And Neck ◽

Induction Chemotherapy ◽

Locally Advanced ◽

Gastrointestinal Symptoms ◽

Common Adverse Effect ◽

Complete Response ◽

Definitive Treatment ◽

Frail Patients

6042 Background: Standard of care treatments for locally advanced and metastatic head and neck squamous cell carcinoma (HNSCC) are not well tolerated, particularly in elderly or frail patients. One combination that has been studied in recent years is paclitaxel, carboplatin and cetuximab (PCC). Studies have shown this regimen yields promising results when used as an induction chemotherapy for locally advanced disease. PCC has also been studied in patients with metastatic or recurrent incurable disease, and has shown good response with tolerable toxicity rates, but there is a relative dearth of evidence surrounding its use. Methods: This retrospective observational study utilized EMR data analysis software to generate the cohort of adult patients that received PCC for HNSCC in 2014-2019 as well as demographic data. Chart review was used to gather details about the patients’ tumors and clinical course. Modified RECIST response rates (MRRR), progression free survival (PFS) and overall survival (OS) were the primary end points calculated for the metastatic/recurrent group, and percentage of successful inductions (e.g., patients went on to definitive treatment, avoided surgery) and MRRR were used for the induction group. Results: There were 80 patients in the cohort. The average age was 65 (range 33-84) and the patients were 81% male. The most common tumor site was the tongue (25 patients), followed by tonsil (15), oropharynx (9), and larynx (7). 13 patients had p16 positive disease. Most patients had Stage IVA (36 patients), followed by IVB (20), and IVC (15); the remainder had stage III or below or unknown stage. The most common reasons patients did not receive cisplatin were performance status (13 patients), hearing loss (11), concern for nephrotoxicity (6) and age (5). 97.5% of patients experienced at least one adverse effect. The most common adverse effect was dermatologic (69%), followed by hematologic (51%), fatigue (41%) and gastrointestinal symptoms (41%). 53 patients (66%) experienced at least one dose interruption due to adverse effects. 11 patients (14%) stopped treatment due to toxicities. 58 patients received PCC for metastatic or recurrent disease. They had received a median of 1 line of systemic treatment prior; 72% had prior radiation, and 26% had prior salvage surgery. The MRRR was 22% (5 patients with complete response, 8 partial response, 15 stable, 27 progression). There was a 7.0 month mean PFS, and 17.3 month mean OS. Of the 22 patients who received PCC as induction, 86% (19) successfully reached their induction endpoint. The MRRR was 64% (8 patients with complete response, 6 partial response). Conclusions: PCC is a relatively well-tolerated combination with a very good induction success rate. More research is needed around alternate options for frail and elderly patients with HNSCC.

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Superior Rate of Complete Response with up-Front Velcade-Thalidomide-Dexamethasone Versus Thalidomide-Dexamethasone in Newly Diagnosed Multiple Myeloma Is Not Affected by Adverse Prognostic Factors, Including High-Risk Cytogenetic Abnormalities.

Blood ◽

10.1182/blood.v112.11.1662.1662 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1662-1662

Author(s):

Michele Cavo ◽

Nicoletta Testoni ◽

Carolina Terragna ◽

Giulia Marzocchi ◽

Sandra Durante ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Multivariate Analysis ◽

Prognostic Factors ◽

High Risk ◽

Light Chain ◽

Complete Response ◽

Phase Iii ◽

Newly Diagnosed ◽

Cox Regression Analysis

Abstract Complete response (CR) is an important objective of autologous stem-cell transplantation (ASCT) in multiple myeloma (MM). In comparison with conventional induction treatments, newer combinations of novel agents may effect increased rates of CR and near CR (nCR), a benefit potentially translating into even higher frequencies of CR/nCR after ASCT and improved clinical outcome. We designed a phase III study to detect an increase in CR+nCR rates from 10–15% with conventional Thalidomide-Dexamethasone (TD) to 20–30% with Velcade added to TD (VTD) in newly diagnosed MM. Both TD and VTD were given as three 21-day cycles in preparation for double ASCT. In the present analysis, CR+nCR rates by the two induction treatments were examined in relationship to baseline prognostic variables in 399 evaluable pts aged ≤65 years, of whom 199 randomized to VTD and 200 to TD. All analyses were intent to treat. In comparison with TD, VTD effected higher rates of CR+nCR (12% vs 33%, P<0.001) and of ≥very good partial response (VGPR) (30% vs 61%, P<0.001). By univariate analysis, superiority of VTD to TD was maintained across all sub-group analyses according to standard prognostic factors, including β2-m, albumin, stage (ISS), Hb, PLTs, bone marrow PC, M protein isotype, LDH, CRP. In particular, the rates of CR+nCR with VTD vs TD in pts with standard poor prognostic factors were as follows: ISS stage 3 (23.5% vs 6%, P=0.03), Hb<10 g/dL (24% vs 4%, P=0.002), PLTs<150.000/μL (35% vs 4%, P=0.009), bone marrow PC ≥50% (31% vs 13%, P<0.001), IgA isotype (63% vs 15%, P<0.001), LDH >190 U/L (33% vs 9%, P<0.001), CRP ≥8 mg/L (29% vs 10%, P=0.004). We next examined CR+nCRs by treatment arms in relationship to cytogenetics (FISH data available in 93% to 99% of all pts). Superior CR+nCR rates were effected by VTD vs TD in the presence of high-risk cytogenetics, including del(13) (39% vs 10%, P<0.001), t(4;14) (39.5% vs 10%, P=0.002), combined t(4;14) and del(13) (32% vs 0%, P=0.001), and del(17p) (28.5% vs 0%, P=0.03). Remarkably, when examined in the context of the VTD arm, high-quality response rates were significantly higher for pts carrying del(13) and t(4;14) vs those who lacked these abnormalities [del(13): CR+nCR:39% vs 24%, P=0.03; ≥VGPR: 71% vs 48%, P=0.001] [t(4;14): ≥VGPR:79% vs 55%, P=0.007)]. An opposite trend was noted for pts in the TD arm, whose probability to attain ≥VGPR was adversely affected by the presence of del(13) (P=0.07) and del(17p) (P=0.03). Variables associated with achievement of CR+nCR in the two arms that retained statistical significance when assessed by multivariate Cox regression analysis included randomization to VTD (P<0.001), light chain only subtype (P<0.001), IgA isotype (P<0.001) and Hb>10 g/dL (P=0.01). In the VTD arm, a positive correlation was observed with del(13) (P=0.006) and t(4;14) (P=0.02). Response to first ASCT with melphalan 200 mg/m2 could be evaluated in 297 pts, of whom 145 randomized to VTD and 152 to TD. Randomization to VTD was closely associated with increased CR+nCR rates (54% vs 29% with TD, P<0.001) and remained statistically significant (P<0.001) also in the multivariate analysis. Additional factors predicting for superior post-ASCT CR+nCR rates in the multivariate setting included light chain only subtype (P<0.001) and IgA isotype (P=0.005). We conclude that randomization to up-front VTD was the strongest and independent factor associated with increased rates of CR+nCR before ASCT. Superiority of VTD to TD pertained in both low-risk and high-risk sub-groups, including the traditionally unfavorable sub-groups carrying del(13), t(4,14) and del(17p). Remarkably, in the VTD arm improved postinduction CR+nCR rates were significantly associated with the presence of del(13) and t(4;14) in the multivariate analysis. Benefit from VTD vs TD as primary induction therapy translated into significantly improved CR+nCR rates after the first ASCT and remained statistically significant when assessed by multivariate analysis.

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Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study

Blood ◽

10.1182/blood-2012-02-408922 ◽

2012 ◽

Vol 120 (8) ◽

pp. 1589-1596 ◽

Cited By ~ 304

Author(s):

Laura Rosiñol ◽

Albert Oriol ◽

Ana Isabel Teruel ◽

Dolores Hernández ◽

Javier López-Jiménez ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Progression Free Survival ◽

Complete Response ◽

Phase 3 ◽

Free Survival ◽

Treatment Groups ◽

Intention To Treat ◽

Induction Regimen ◽

Treat Analysis

Abstract The Spanish Myeloma Group conducted a trial to compare bortezomib/thalidomide/dexamethasone (VTD) versus thalidomide/dexamethasone (TD) versus vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, doxorubicin, dexamethasone/bortezomib (VBMCP/VBAD/B) in patients aged 65 years or younger with multiple myeloma. The primary endpoint was complete response (CR) rate postinduction and post–autologous stem cell transplantation (ASCT). Three hundred eighty-six patients were allocated to VTD (130), TD (127), or VBMCP/VBAD/B (129). The CR rate was significantly higher with VTD than with TD (35% vs 14%, P = .001) or with VBMCP/VBAD/B (35% vs 21%, P = .01). The median progression-free survival (PFS) was significantly longer with VTD (56.2 vs 28.2 vs 35.5 months, P = .01). In an intention-to-treat analysis, the post-ASCT CR rate was higher with VTD than with TD (46% vs 24%, P = .004) or with VBMCP/VBAD/B (46% vs 38%, P = .1). Patients with high-risk cytogenetics had a shorter PFS and overall survival in the overall series and in all treatment groups. In conclusion, VTD resulted in a higher pre- and posttransplantation CR rate and in a significantly longer PFS although it was not able to overcome the poor prognosis of high-risk cytogenetics. Our results support the use of VTD as a highly effective induction regimen prior to ASCT. The study was registered with http://www.clinicaltrials.gov (NCT00461747) and Eudra CT (no. 2005-001110-41).

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Select High-Risk Genetic Features Predict Earlier Progression Following Chemoimmunotherapy With Fludarabine and Rituximab in Chronic Lymphocytic Leukemia: Justification for Risk-Adapted Therapy

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.1021 ◽

2006 ◽

Vol 24 (3) ◽

pp. 437-443 ◽

Cited By ~ 184

Author(s):

John C. Byrd ◽

John G. Gribben ◽

Bercedis L. Peterson ◽

Michael R. Grever ◽

Gerard Lozanski ◽

...

Keyword(s):

Treatment Outcome ◽

Prognostic Factors ◽

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Progression Free Survival ◽

Complete Response ◽

Lymphocytic Leukemia ◽

Interphase Cytogenetics ◽

Mutational Status ◽

The Impact

Purpose Several new prognostic factors predicting rapid disease progression in chronic lymphocytic leukemia (CLL) have been identified, including unmutated Ig VH mutational status, del(11)(q23), del(17)(p13.1), and p53 mutations. To date, the impact of these same prognostic factors have not been examined relative to treatment outcome with chemoimmunotherapy. Methods We examined the impact of these new prognostic factors on predicting treatment outcome in symptomatic, untreated CLL patients who received chemoimmunotherapy with fludarabine and rituximab as part of a completed, randomized phase II study, Cancer and Leukemia Group B (CALGB) 9712. Results Eighty-eight patients treated as part of CALGB 9712 had detailed prognostic factor assessment performed. Using Ig VH mutational status to classify risk, there was no association between complete response rate with either unmutated Ig VH mutational status or high-risk interphase cytogenetics. However, the median progression-free survival (PFS; P = .048) and overall survival (OS; P = .01) were shorter among the Ig VH unmutated patients as compared with the Ig VH mutated patients. Using the hierarchical classification of Döhner, PFS (P = .005) and OS (P = .004) were significantly longer as the classification moved from high risk [del (11)(q22.3) or del (17)(p13.1)] to low risk. Conclusion These data demonstrate that high-risk CLL patients characterized by Ig VH unmutated (≥ 98%) or high-risk interphase cytogenetics, including either del(17p) or del(11q), appear to have a shorter PFS and OS with chemoimmunotherapy. Larger prospective studies will be required to determine the independent influence of Ig VH mutational status and interphase cytogenetics on treatment outcome.

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