Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) Induction Followed By ASCT with HDM or Bor-HDM Conditioning Regimens: A Single Center Experience

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5492-5492
Author(s):  
Victor H Jimenez-Zepeda ◽  
Peter Duggan ◽  
Paola Neri ◽  
Ahsan Chaudhry ◽  
Joanne Luider ◽  
...  
Keyword(s):  
Research Funding ◽  
Clinical Characteristics ◽  
Plasma Cells ◽  
High Dose ◽  
Single Center Experience ◽  
Bone Marrow Plasma ◽  
Conventional Cytogenetics ◽  
High Dose Melphalan ◽  
The Impact

Abstract Introduction Preclinical and clinical data suggest that bortezomib in combination with high-dose melphalan (Bor-HDM) provides with a synergistic effect able to improve response for MM patients undergoing auto-SCT. In the present study, patients receiving Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) induction followed by ASCT with Bor-HDM and HDM alone were evaluated. Methods All consecutive patients treated with CyBorD induction at our center from 01/2010 to 01/2015 were evaluated. All patients received induction chemotherapy before undergoing auto-SCT. Patients received conditioning with either HDM at 200 mg/m2 (or adjusted as per renal failure) or HDM with Bortezomib (Bor-HDM). Definitions of response and progression were used according to the EBMT modified criteria. MRD negativity was assessed by flow cytometry at day-100 post-ASCT. Results Clinical characteristics are shown in Table 1. Among 66 cases receiving CyBorD induction, 42 were conditioned with Bor-HDM and 24 with HDM. At the time of analysis, 90.5% and 91.7% of patients in the Bor-HDM and HDM group are still alive and 4 and 5 patients have already progressed, respectively. At day-100 post ASCT, ORR of 97%, with CR/VGPR rate of 81% was seen in the Bor-HDM group compared to 91% and 70% in the HDM group (p=0.2). MRD negativity was higher in the Bor-HDM group (29.2%) compared to HDM (9%) (p=0.04). Median OS and PFS was similar for Bor-HDM and HDM (p=0.8) with a median follow-up of 12 months. In conclusion, CyBorD is an efficacious regimen for patients with MM and overall seemed to be well tolerated. Our data is one of the first to show the impact of this regimen on MRD negativity rates after receiving HDM or Bor-HDM conditioning, suggesting that higher rates of MRD negativity are seen with Bor-HDM. Further evaluation on a prospective manner and longer follow-up is required to assess the impact of Bor-HDM on OS and PFS. Table 1. Clinical Characteristics of patients with MM undergoing single auto-ASCT treated with CyBorD induction at our Institution Characteristic HDM (n=24) Bor-HDM (42) Age (median) 55 57 GenderMaleFemale 19 (79.1%)5 (20.9%) 25 (59.5%)17 (40.5%) Hb (g/L) 104 (75-157) 106 (76-139) Calcium (µmol/L) 2.3 (1.92-3.28) 2.3 (1.97-3.12) Creatinine (µmol/L) 86 (60-426) 84 (49-950) B2microglobulin (µmol/L) 2.73 (1.55-14.7) 3.41 (1.47-8.47) Albumin (g/L) 32 (21-43) 31 (16-42) Stage IStage IIStage III 7 (29.1%)14 (58.3%)3 (12.5%) 6 (14.2%)25 (59.5%)11 (26.1%) LDH (IU/L) 172 (71-448) 192 (103-669) BMPC (%) 32% (5-84%) 38% (5-90%) Heavy chain:IgGIgAIgDBiclonalIgMFLC oncly 17(70.8%)4 (16.6%)01 (4.1%)0 (1.5%)2 (8.3%) 22 (52.3%)10 (23.8%)01 (2.3%)1 (2.3%)8 (19%) Light chain:KappaLambdaBiclonal 17 (77.2%)5 (20.8%)1 (2%) 21 (50%)20 (47.6%)1 (2.3%) High risk (t(4;14), t(14;16), p53 del, del 13q by CCStandard risk 9 (37.5%)15 (62.5%) 11 (26.1%)31 (73.9%) BMPC: Bone marrow plasma cells; FLC: Free-light chains only; CC: Conventional cytogenetics Disclosures Jimenez-Zepeda: J&J: Honoraria; Amgen: Honoraria; Celgene: Honoraria. Duggan:Jansen: Honoraria; Celgene: Honoraria. Neri:Celgene: Research Funding. Bahlis:Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Johnson & Johnson: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

High Dose Melphalan with Autologous Stem Cell Transplantation Overcomes Poor Prognosis of Primary Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1350-1350
Author(s):  
Simrit Parmar ◽  
Mubeen Khan ◽  
Gabriela Rondon ◽  
Nina Shah ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Plasma Cells ◽  
High Dose ◽  
Al Amyloidosis ◽  
Hematologic Response ◽  
Bone Marrow Plasma ◽  
Organ Response ◽  
High Dose Melphalan

Abstract Abstract 1350 Background: Systemic Primary AL Amyloidosis is a rare but potentially fatal disease resulting from tissue deposits of amyloid fibrils derived from monoclonal immunoglobulin light chains. High-dose melphalan followed by autologous hematopoietic stem cell transplant (auto HCT) is associated with hematologic and organ responses and improved survival. Methods: In this retrospective analysis we identified 46 patients with primary AL amyloidosis who received auto HCT between 01/1998 to 05/2010 at MDACC. Organ responses were determined using Amyloidosis Consensus Criteria. Results: The median age at auto HSCT was 56 years (34-74) where 61% were males and 35% were older than 60 years of age. 61% had lambda light chain restriction and only 4% had cytogenetic abnormalities. Disease characteristics are summarized in Table 1. The median time from diagnosis to auto HCT was 6.6 months (2.2-29.4 months). 22 pts (47.8%) had one organ, 19 pts (41.3%) had 2 organ and 4 pts (8.7%) had 3 organ involvement. 11 pts (23.9%) had heart and 35 pts (76.1%) had kidney involvement. The median follow up from the time of diagnosis was 22.4 months and from time of auto HCT was 16.7 months. High dose Melphalan dose was 200mg/m2 in 24 pts (52%) and 140mg/m2 in 22 (47.8%). There were 4 early deaths and 4 pts whose follow up was less than 3 months and their response was not assessed. Out of the 38 evaluable patients, the post-transplant organ responses were as follows ≥PR 25(66%), ≥stable disease 35(92%) (Table2). The hematologic responses were: CR=5 (13%), ≥VGPR=10(26%), ≥PR=26 (68%), ≥SD=37(97%). One patient had progressive disease. There was a correlation between organ response and hematologic response (chi square;p<10-3). The day-100 treatment related mortality (TRM) was 8.7% and 1-yr TRM was 13%. The median progression-free (PFS) and overall survival (OS) from auto HCT was 73.8 months and not reached (from transplant). The median PFS and OS from diagnosis were 93 months and 59.8 months respectively. In multivariate analysis, heart involvement (p=0.01), female sex (p=0.011), age ≥60 years (p=0.002), bone marrow plasma cells≥10% (p=0.043) and Beta-2 microglobulin>3.5mg/l (p=0.02) were associated with poor OS. Improved OS correlated with organ response (52.6 vs 11.4 months; p=0.01) and hematologic response (52.6 vs.6.1months; p=0.002). Hemoglobin <10 g/dl (p=0.047), bone marrow plasma cells≥10% (p=0.043) and age≥60 years (p=0.075) were associated with shorter PFS. Hematologc response (p=0.48) and organ response (p=0.12) were not associated with improved PFS. Conclusion: In this analysis the outcome of patients with primary systemic AL amyloidosis was durable with auto HCT with acceptable mortality risk and improved survival. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Bortezomib and High Dose Melphalan (Bor-HDM) Compared to HDM Conditioning for the Treatment of Transplant Eligible Multiple Myeloma: Report from a Single Center

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3189-3189
Author(s):  
Victor H Jimenez-Zepeda ◽  
Peter Duggan ◽  
Paola Neri ◽  
Ahsan Chaudhry ◽  
Marcia Culham ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Overall Survival ◽  
Research Funding ◽  
Clinical Characteristics ◽  
Conditioning Regimen ◽  
Progression Free Survival ◽  
High Dose ◽  
Free Survival ◽  
High Dose Melphalan ◽  
The Impact

Abstract Introduction Preclinical and clinical data suggest that bortezomib in combination with high-dose melphalan (Bor-HDM) provides with a synergistic effect able to improve the quality of response for MM patients undergoing auto-SCT. In the present study, we aimed to assess the impact of Bor-HDM conditioning on ORR, and MRD negativity for MM patients undergoing single auto-SCT at our Institution. Methods All consecutive patients who underwent single auto-SCT at Tom Baker Cancer Center (TBCC) from 01/2004 to 06/2015 using Bor-HDM or HDM as conditioning regimen were evaluated. Definitions of response and progression were used according to the EBMT modified criteria and a category of very good partial response (VGPR) was added. MRD negativity was assessed by multiparameter flow cytometry. All patients received induction chemotherapy before undergoing auto-SCT. Bortezomib was administered intravenously at 1-1.3 mg/m2 on days −5, −2, 1, and 4, while melphalan was given at 200 mg/m2 on day −1. A p value of <0.05 was considered significant. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test. Results Two-hundred and fifty-eight consecutive patients receiving Bor-HDM or HDM alone were evaluated. A total of 85 patients received Bor-HDM conditioning and 173 received HDM. Clinical characteristics and chemotherapy induction regimens are listed in Table 1. At day-100 post auto-SCT a ³VGPR was seen in 83.3% in the Bor-HDM group compared to 67.6% for HDM patients. The CR/nCR rate was higher in the Bor-HDM group (47.6% vs 23.6%) as well as MRD negativity assessed by flow cytometry (30.9% vs 9.7%, p=0.0001). Median OS in the Bor-HDM group was NR compared to 95 months for HDM alone (p=0.572), while median PFS was 39.3 months for Bor-HDM compared to 27 months for HDM (p=0.1). Median OS was shorter in the HR cytogenetic group regardless of the type of conditioning regimen employed (39 months vs NR for SR cytogenetics). In addition, patients who achieved MRD negativity, exhibited a longer OS (NR vs 78 months, p=0.007). Transplant-related mortality (TRM) was similar between both groups (p0.5). In conclusion, Bor-HDM is a safe and efficacious conditioning regimen able to increase the nCR/CR and MRD negativity rates compared to HDM. Further studies are warranted to explore this regimen, especially when other upfront therapies are employed, with special view on the high-risk MM patients where response rates are good but sustainability remains an issue. Table 1. Clinical Characteristics Characteristic Bor/HDM, N=85 HDM alone, N=173 Age (median) 58 59 GenderMaleFemale 51 (60%)34 (40%) 113 (65.3%)60 (34.7%) Hb (g/L) 112 117 Calcium (µmol/L) 2.25 2.29 Creatinine (µmol/L) 85 80 B2microglobulin (µmol/L) 3.3 2.79 Albumin (g/L) 31 35 Stage IStage IIStage III 154723 617333 M-spike (g/L) 34 30 LDH (IU/L) 194 180 BMPC (%) 40 33 Heavy chain:IgGIgAIgDFLC onlyBiclonalIgM 491811511 1142403210 Light chain:KappaLambdaBiclonal 50351 124471 High riskStandard risk 2263 36135 InductionCyBorDVDDexamethasoneRVD 4524016 16544315 Figure 1. Overall Survival for patients with MM undergoing single auto-SCT according to the type of conditioning regimen Figure 1. Overall Survival for patients with MM undergoing single auto-SCT according to the type of conditioning regimen Figure 2. Progression-Free survival for patients with MM undergoing single auto-SCT according to the type of conditioning regimen Figure 2. Progression-Free survival for patients with MM undergoing single auto-SCT according to the type of conditioning regimen Figure 3. Overall Survival for patients with MM undergoing single auto-SCT according to MRD negativity assessed by flow cytometry Figure 3. Overall Survival for patients with MM undergoing single auto-SCT according to MRD negativity assessed by flow cytometry Disclosures Jimenez-Zepeda: Celgene: Honoraria; J&J: Honoraria; Amgen: Honoraria. Duggan:Jansen: Honoraria; Celgene: Honoraria. Neri:Celgene: Research Funding. Bahlis:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Johnson & Johnson: Research Funding.

Alemtuzumab Plus Oral Dexamethasone, Followed by Alemtuzumab Maintenance or Allogeneic Transplantation in Ultra High-Risk CLL: Interim Analysis of a Phase II Study of the GCLLSG and fcgcll/MW

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2854-2854 ◽  
Author(s):  
Stephan Stilgenbauer ◽  
Florence Cymbalista ◽  
Véronique Leblond ◽  
Alain Delmer ◽  
Dirk Winkler ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Response Rates ◽  
Long Term Results ◽  
High Dose ◽  
Significant Difference ◽  
Ultra High Risk ◽  
Grade 3 ◽  
The Impact

Abstract Abstract 2854 Alemtuzumab (A) proved to be efficacious in CLL patients (pts) with very poor prognosis, either due to fludarabine (F) refractoriness or due to unfavorable cytogenetics (17p-). However, rate and duration of remissions still remain unsatisfactory. Therefore, the French and German CLL study groups jointly embarked on this trial, trying to achieve higher overall response rates (ORR) by adding high-dose dexamethasone (D) to A and, simultaneously, investigating the consolidation effect of prolonged A maintenance or allogeneic stem-cell transplantation (allo-SCT), respectively. Induction treatment consisted of subcutaneous A 30 mg weekly × 3 for 28 days, combined with oral D 40 mg on days 1–4 and 15–18, and prophylactic pegfilgrastim 6 mg on days 1 and 15. Depending on the remission status, pts were treated for up to 12 weeks. If CR was documented at 4 or 8 weeks, or at least SD was achieved at 12 weeks, consolidation was scheduled with either allo-SCT or A maintenance with 30 mg every 14 days for up to 2 years (y), at the discretion of pt and physician. Between January 2008 and July 2011, 124 pts were recruited at 26 centers, 120 of whom were eligible. Pts were generally subdivided into three cohorts: 55 pts were refractory (i.e. no response or relapse within 6 months) to regimens containing F or a similar drug (i.e. pentostatin, cladribine, bendamustine). Non-refractory pts all exhibited 17p- and had either untreated (n=39) or relapsed CLL (n = 26) requiring therapy. The median age was high with 66/64/66 y in 17p- 1st line, 17p- relapse, and F-refractory pts, respectively. The three cohorts had 46/54/75% Binet C disease, 41/35/27% B symptoms, 38/42/53% reduced performance status (ECOG 1/2), median thymidine kinase levels of 35/49/24 U/L, median ß2MG levels of 3.8/5.5/4.6 mg/L, and IGHV was unmutated in 89/96/87%. In the F-refractory group, 53% exhibited 17p deletion and 22% had 11q deletion. Pretreated patients had received a median of 3 (F-refractory) or 2 prior lines (17p- relapse). 5 pts had previously undergone autologous and 1 pt allo-SCT. Treatment and efficacy data are currently available for 87 pts who completed induction therapy :17p- 1st-line (n=30), 17p- relapse (n=17), and F-refractory (n=40). Of these, 80/53/55% received the full induction of 12 weeks. ORR (best observed status) was generally high with 97/76/70%. CR was achieved in 20/0/5%. After a median follow-up of 11.8 months (mo), median progression-free survival (PFS) was 16.9/10.4/8.4 mo. Deaths are recorded in 13/27/36% of pts, with median overall survival (OS) not yet reached (>24 mo) in the 17p- 1st line group, and 15/12 mo in 17p- relapse/F-refractory pts. Consolidation treatment was performed as maintenance A (median duration 32 weeks, range 2 – 89) in 34%, and allo-SCT in 30%, with a median age of 66 and 61 y in these subgroups. The main reasons for going off-study without consolidation were death due to infection (14%, n=11, of these 6 without response, and 10 in the F-refractory cohort), CLL progression (12%), and other toxicity (5%). Among the 28 pts not receiving consolidation, there were 19 (68%) deaths, 15 of them in the F-refractory cohort. When comparing A maintenance and allo-SCT for consolidation, there were 9 (35%) and 7 (30%) PD events, respectively and there was so far no significant difference in PFS (median 17 mo in both groups) or OS. During induction, grade 3/4 hematotoxicity consisted of anemia in 28%, neutropenia in 47%, and thrombopenia in 44%. Grade 3/4 non-CMV infection occurred in 29% of 17p- 1st-line, 15% of 17p- relapsed, and 56% of F-refractory pts. CMV reactivation was observed in 54/25/40%, without severe sequelae recorded. During A maintenance, grade 3/4 toxicity consisted of neutropenia in 39% pts and thrombopenia in 4% pts with 6 SAEs (ITP, diarrhea, infection, erythema, tachycardia, and thrombosis). Conclusions: The combination of A and D shows high response rates in ultra high-risk CLL, with promising preliminary findings for PFS and OS, despite the high median age of the pts. The results compare favorably to ORR/CR of 68%/5%, and median PFS of 11.3 mo in the 17p- subgroup of the CLL8 study treated with FCR, consisting of younger pts (median 61 y). In F-refractory CLL however, when compared to the preceding CLL2H study with single agent A, the improved initial response by adding dexamethasone does not seem to translate into improved long-term results. More mature follow-up is needed, especially with respect to the impact of allo-SCT. Disclosures: Stilgenbauer: Amgen: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding. Off Label Use: Alemtuzumab in 1st line CLL treatment. Cymbalista:Roche (d) Mundipharma (e) Genzyme (e): Honoraria, Research Funding. Hinke:WiSP (CRO): Employment.

Bortezomib-High Dose Melphalan Conditioning for the Treatment of MM Patients Undergoing ASCT

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2273-2273
Author(s):  
Victor Jimenez-Zepeda ◽  
Peter Duggan ◽  
Paola Neri ◽  
Ahsan Chaudhry ◽  
Jason Tay ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Overall Survival ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Clinical Characteristics ◽  
Conditioning Regimen ◽  
Progression Free Survival ◽  
High Dose ◽  
Free Survival ◽  
High Dose Melphalan

Abstract Introduction Recent data suggests that bortezomib, a proteasome inhibitor, in combination with high-dose melphalan (Bor-HDM) provides with a synergistic effect able to improve the level of response for MM patients undergoing auto-SCT. In the present study, patients receiving induction followed by ASCT with Bor-HDM and HDM alone were evaluated. Methods All consecutive patients undergoing ASCT from 01/2004 to 03/2016 were evaluated. All patients received induction chemotherapy before undergoing auto-SCT. Patients received conditioning with either HDM at 200 mg/m2 (or adjusted as per renal failure) or HDM with Bortezomib (Bor-HDM). Most of patients received Bortezomib conditioning at 1.3 mg/m2. As per physician discretion, the dose of 1 mg/m2 was also employed in 30% of cases. Definitions of response and progression were used according to the EBMT modified criteria. MRD negativity was assessed by flow cytometry at day-100 post-ASCT. Results Clinical characteristics are shown in Table 1. Among 301 cases, 129 were treated with Bor-HDM while 172 patients went onto receive HDM alone as part of the conditioning regimen. Induction regimens are shown in Table 1. At the time of analysis, 83% and 58% of patients in the Bor-HDM and HDM group are still alive and 34% and 69.1% of patients have already progressed, respectively. At day-100 post ASCT, ORR of 97%, with CR/VGPR rate of 84.2% was seen in the Bor-HDM group compared to 94.2% and 68.6% in the HDM group (p=0.001). MRD negativity was higher in the Bor-HDM group (33.3%) compared to HDM (12.2%) (p=0.001). Median OS was similar for Bor-HDM and HDM (p=0.864) (Fig 1a). In addition, median PFS did not differ among patients receiving HDM or Bor-HDM (37.7months vs 29.3 months, p=0.2) (Fig1b) In conclusion,Bor-HDMis a conditioning regimen able to provide higher rates ofnCR/CR, as well as MRD negativity compared to HDM alone. Further studies are warranted to explore this regimen, especially when other upfront therapies are employed. Overall Survival according to the conditioning regimen employed for patients with MM undergoing ASCT Overall Survival according to the conditioning regimen employed for patients with MM undergoing ASCT Figure 1 Progression-Free Survival according to the conditioning regimen employed for patients with MM undergoing ASCT Figure 1. Progression-Free Survival according to the conditioning regimen employed for patients with MM undergoing ASCT Disclosures Jimenez-Zepeda: Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene, Janssen, Amgen, Onyx: Honoraria. Neri:Celgene and Jannsen: Consultancy, Honoraria. Bahlis:Onyx: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria; BMS: Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau.

scholarly journals Chemoimmunotherapy for Patients with Chronic Lymphocytic Leukemia: MD Anderson Experience Beyond FCR300

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2047-2047 ◽  
Author(s):  
Dai Chihara ◽  
Philip A Thompson ◽  
Hagop M. Kantarjian ◽  
Susan M. O'Brien ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Research Funding ◽  
Risk Model ◽  
Lymphocytic Leukemia ◽  
Cox Proportional Hazards Model ◽  
High Dose ◽  
First Line ◽  
Ighv Gene ◽  
The Impact

Abstract Background: Novel, targeted therapies, such as ibrutinib, have transformed outcomes for patients with relapsed CLL and for older and unfit patients in the first-line setting. However, chemoimmunotherapy (CIT) remains the standard-of-care in fit patients. We reported that a subgroup of patients with IGHV mutated CLL experience prolonged PFS and potential cure after first-line CIT withfludarabine, cyclophosphamide and rituximab (FCR). However, FISH data was not available for this cohort of patients. Accurate knowledge of which patients are likely to experience prolonged PFS after FCR is essential to better select patients who may benefit from CIT in the era of novel therapies. Patients and Methods: We analyzed 492 patients who were treated on six clinical trials of first-line CIT between 2004 and 2015. Treatments were FCR, (n=277) FCR with high dose rituximab (n=65), FCR plusmitoxantrone (n=30), FCR plusalemtuzumab (n=60) and FCR with GM-CSF (n=60). Progression-free survival (PFS) and overall survival (OS) were calculated and pretreatment characteristics were evaluated for association with survival outcomes using a Cox Proportional Hazards model. Cumulative incidence was calculated by competing risk (death without event) regression analysis. Results: The median age of patients was 59 (range 28-84). Sixty-seven percent of the patients were male, 33% of the patients had mutated IGHV gene. Thirty percent of patients had del(13q), 19% had Trisomy12, 21% had del(11q), 8% had del(17p) and 21% were negative by FISH. Fifty-nine percent of patients received six cycles of CIT. With a median follow up duration of 6.2 years, the median PFS and OS were 6.3 years and not reached, respectively. Recently reported risk model by Rossi and colleagues using IGHV mutation status and FISH results (Blood 2015) discriminated PFS very well; 5-year PFS for low risk {mutated without del(11q)}, intermediate risk {unmutated or del(11q)} and high risk group {del(17p)} were 81%, 45% and 22%, respectively. Of note, there was a plateau in PFS after 8 years in patients with mutated IGHV gene, with 10-year PFS of 63% (Figure A). There was a significantly improved OS after relapse by the time. Three-year OS in patients who started salvage chemotherapy in 2004 to 2012 and 2012 to 2016 were 59% and 83%, respectively, suggesting the impact of improved salvage treatment options, particularly B cell signaling pathway inhibitors (Figure B). Five-year cumulative incidence of Richter transformation (RT) and AML/MDS was 4.8% and 4.2%, respectively (Figure C, D). There was a difference in onset for these two complications; 52% of RT occurred within 2 years, while 62% of AML/MDS occurred in 2-4 years after CIT. Overall, 110 patients (22.4%) died during the follow-up; the three major causes of death were CLL progression (4.9%), Richter transformation (3.7%) and AML/MDS (3.3%). Conclusion: Patients with mutated IGHV gene and who do not have del(11q) or del(17p) have favorable outcomes and demonstrate a plateau on the PFS curve, consistent with prior studies. Effective salvage therapy has improved outcomes at relapse, but the development of RT and AML/MDS remain major causes of mortality in CLL patients. Given favorable outcomes for patients with mutated IGHV gene treated with FCR, further studies are warranted to identify predictors of non-response among the mutated patients, risk factors for development of AML/MDS and RT and whether choice of first-line therapy can modulate this risk. Disclosures Thompson: Pharmacyclics: Consultancy, Honoraria. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Jain:Servier: Consultancy, Honoraria; Novimmune: Consultancy, Honoraria; Incyte: Research Funding; Celgene: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Novartis: Consultancy, Honoraria; Abbvie: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Infinity: Research Funding. Wierda:Abbvie: Research Funding; Novartis: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Genentech: Research Funding.

A Phase 2 Study of High-Dose Melphalan Plus Bortezomib (Mel/Vel) Conditioning Followed By Autologous Hematopoietic Cell Transplantation in Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3987-3987
Author(s):  
Taiga Nishihori ◽  
Jose L Ochoa-Bayona ◽  
Rachid Baz ◽  
Kenneth H. Shain ◽  
Christine Simonelli ◽  
...  
Keyword(s):  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
High Dose ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Autologous Hct ◽  
High Dose Melphalan ◽  
Autologous Hematopoietic Cell Transplantation

Abstract Background: High-dose melphalan followed by autologous hematopoietic cell transplantation (HCT) remains the integral component of multiple myeloma (MM) therapy in the era of novel agents. We published our prior study with the use of high-dose melphalan + bortezomib (Mel/Vel) conditioning regimen for tandem transplants in refractory MM patients (Nishihori, et al. Br J Haematol 2012). We designed a phase 2 trial using MelVel conditioning followed by autologous HCT in patients with newly diagnosed chemosensitive MM (NCT 00948922). Methods: Sixty seven newly diagnosed MM patients who achieved ≥ partial response (PR) to induction therapy with ≤grade 1 peripheral neuropathy (PN) were enrolled from 12/2009 to 06/2014. Patients received high-dose melphalan at 100 mg/m2 IV for 2 days, immediately followed by 1 dose of bortezomib at 1.3 mg/m2 (Mel/Vel conditioning). Maintenance therapy was not prescribed by design. The protocol later was modified to include maintenance bortezomib subcutaneously (started at 3 months after HCT) at 1.3 mg/m2 weekly x4, every 8 weeks, for a total of 6 cycles. Progression-free and overall survival (PFS and OS) estimates were calculated using Kaplan-Meier method. Results: A total of 67 patients received autologous HCT. The median age was 58 (25 - 73) years with the following disease characteristics: Durie-Salmon stage, 3A (72%) and 3B (10%); IgG (55%), IgA (21%), IgD (1%), and light chain (22%). High-risk cytogenetics/FISH were seen in 28% of patients. The median beta-2 microglobulin was 3.3 (range, 1.3 – 34.8). Induction regimens were bortezomib-based in 39%, lenalidomide-based in 19% and, both bortezomib and lenalidomide in 42%. Median time from initiation of induction to HCT was 204 days (range, 101 - 664). Responses prior to HCT were stringent CR (sCR) 21%, CR 12%, very good partial response (VGPR) 34%, and PR 33%. Neutrophil engraftment was achieved after a median of 11 days (range, 10 – 14) and platelet engraftment occurred after a median of 15 days (range, 11 – 22). Median CD34 cell dose was 3.8 x 106/kg (range, 2 – 20.08). Responses at 3 months after HCT (in 64 evaluable patients) were sCR 47%, CR 14%, VGPR 20%, PR 16% and progressive disease 3%. Bortezomib maintenance was prescribed to 31 patients (46%). Prevalence of grade 1 PN before (n=67) and at 3 months (n=64) after HCT were 37% and 38%, respectively. Two patients withdrew consent to initiate maintenance and 1 patient was unable to initiate maintenance due to grade 1 PN (baseline PN of 0). At the time of review, a median number of maintenance delivered was 4 (range, 1-6) and only one patient required dose reduction. The 2-year PFS and OS estimates are 62% (95% CI 0.47 – 0.75) and 90% (95% CI 0.80 – 0.97) with a median follow-up of 21 months (range, 2 – 54). The 1-year PFS estimates were 85% (95% CI 0.65 – 0.97) for bortezomib maintenance vs. 81% (95% CI 0.66 – 0.92) for no maintenance (p=0.6). There were no significant differences in PFS or OS stratified by cytogenetic/FISH risk status. There was no transplant related mortality. Conclusions: The combination of bortezomib and high-dose melphalan (Mel/Vel) as conditioning regimen for autologous HCT is well tolerated and appears to improve responses after HCT. Weekly x4 post HCT bortezomib maintenance given every 8 weeks appears to be well tolerated and is a promising strategy for eligible patients. Longer follow up is required to assess the benefit of post HCT maintenance strategy. Disclosures Baz: Millennium: Research Funding. Alsina:Millennium: Consultancy, Research Funding.

scholarly journals Phase I/II Study of Lenalidomide and High Dose Melphalan As Preparative Regimen in Autologous Transplant in Myeloma: Report of Phase II Efficacy and Safety Data

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3193-3193 ◽  
Author(s):  
Attaya Suvannasankha ◽  
Sherif Farag ◽  
Rebecca Silbermann ◽  
Mary Cangany ◽  
Anita Rush-Taylor ◽  
...  
Keyword(s):  
Stem Cell ◽  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
High Dose ◽  
Disease Response ◽  
Preparative Regimen ◽  
Grade 3 ◽  
High Dose Melphalan

Abstract Background: High-dose melphalan and autologous hematopoietic stem cell transplantat (auto-HCT) is a standard consolidation therapy for eligible multiple myeloma (MM) patients due to superior survival outcome as compared to chemotherapy alone. However, patients remain at continuous risk of disease relapse following auto-HCT. Lenalidomide is active in newly diagnosed and relapsed MM and has synergistic activity with melphalan, but has not previously been incorporated into preparative regimen for auto-HCT. While high dose lenalidomide induces myelosuppression, the anti-tumor activity of lenalidomide is dose-dependent. Methods: We conducted a single center, phase I/II study of lenalidomide and melphalan in patients with MM undergoing auto-HCT. The phase I portion included MM patients at all disease stages, including patients undergoing auto-SCT as salvage therapy. The phase II portion enrolled patients undergoing a first auto-SCT after achieving at least stable disease following their induction regimen. Phase I objectives included determination of side effect profile and recommended phase II dose (RP2D). Phase II objectives were disease response at day +100 and toxicity. Treatment: All patients received a standard melphalan dose of 200 mg/m2 (100 mg/m2 IV days -1 and -2). Phase I lenalidomide dose was escalated from 50 mg, 75mg, 100 mg, and 150 mg and administered orally daily from days -7 to +2. Phase I data were previously reported (Blood (ASH Annual Meeting Abstracts), Nov 2012; 120: 3146). Thirteen patients were treated and no MTD was reached. The RP2D lenalidomide dose (150 mg orally daily days -7 to +2) was further explored in the phase II portion of this study. Post-transplant lenalidomide maintenance therapy was started between days +100 and +120 in all responders. We now report the planned interim analysis of the efficacy and safety profile of the phase II study. Results: From 5/1/12 to 7/9/15, forty seven subjects were enrolled to the phase II portion of the study. Study accrual is complete. We report below on the 37 patients with at least 100 days follow-up (median duration of follow-up of 12 months). 36 patients were assessable for response. Responses are as followed: stringent CR 8 (22%), CR 3 (8%), VGPR 20 (54%), PR 3 (8%), progressive disease 2 (5%). Among responders, 34 were able to start maintenance lenalidomide on days +100 to +110 (two withdrew from the study to pursue tandem stem cell transplant). To date, 21 patients remain on the treatment. Of 13 who discontinued the therapy; 4 was due to progression, 4 due to physician/patient preference, 2 due to toxicities and 3 from other reasons. Median progression free survival has not been reached. Toxicities were considered treatment related if they occur after the initiation of study drugs. DLTs are defined as any AEs occurring from days -7 to -2 that cause delay or prevent subjects from proceeding to auto-SCTs, grade 3 or more non-hematologic toxicities that do not resolve to a grade 2 or less by day 30 after auto-SCT, or engraftment failure. No DLTs were observed. The median time for ANC and platelet engraftment was 12 and 15 days and no delayed engraftment was observed. Toxicities and posttransplant hematopoietic recovery rates were similar to historical data observed with single agent high dose melphalan. Lenalidomide related toxicities occurred more commonly during the maintenance phase. Common toxicities occurring in more than 10% of patients were diarrhea (24%), peripheral neuropathy (21%) and fatigue (10%). Grade 3-4 toxicities occurred in 16% percent of patients: fatigue (5%), neutropenia (5%) neuropathy (3%), and thrombocytopenia (3%). Conclusion The use of high dose lenalidomide in combination with high-dose melphalan as a preparative regiment for auto-SCT is well tolerated. High VGPR or better disease response rates, compared to historical control, suggest that the preparative combination regimen may improve the depth of response. Stem cell rescue likely overcome lenalidomide induced myelosuppression. The study is now closed to accrual. Updated data on primary endpoints from all subjects will be reported at the meeting. Disclosures Suvannasankha: Celgene: Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Farag:Bristol Myers: Speakers Bureau; Millennium: Speakers Bureau; Teva: Research Funding; Celgene: Speakers Bureau. Silbermann:Amgen: Consultancy; Celgene: Research Funding. Abonour:Celgene: Research Funding, Speakers Bureau.

scholarly journals Impact on Survival Outcomes of Bone Marrow Plasma Cells Percentage and Morphology Evaluation By Conventional Microscopy in Multiple Myeloma after High Dose Therapy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3396-3396
Author(s):  
Camille Claracq ◽  
Murielle Roussel ◽  
Benjamin Hébraud ◽  
Michel Attal ◽  
Herve Avet Loiseau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cells ◽  
Survival Outcomes ◽  
High Dose ◽  
High Dose Therapy ◽  
Impact On Survival ◽  
Bone Marrow Plasma ◽  
Conventional Microscopy

Abstract Impact on Survival Outcomes of Bone Marrow Plasma Cells Percentage and Morphology Evaluation by Conventional Microscopy in Multiple Myeloma after High Dose Therapy. Background: The achievement of at least CR is a crucial step for a long-lasting response and prolonged survival after autologous stem cell transplantation (ASCT) in patients (pts) with multiple myeloma (MM). The current definition of complete remission (CR) or better in MM requires a negative serum and urine immunofixation (IF) and <5% bone marrow plasma cells (BMPCs). Additional prognostic tools are related to sFLC ratio, immunophenotypic and molecular evaluations, when possible. As BMPCs levels could differ if evaluated by BM biopsy or aspirate (the latter supposed to underestimate BMPCs count), we aim to determine a new threshold for PCs in BM aspirate and to determine whether it could be, in association with PCs morphology by standard microscopic evaluation, an easy and cheap surrogate marker for outcome, in the absence of sFLC assay and/or phenotypical-molecular analysis for MRD. Material and Methods: 191 de novo MM pts treated between 2003-2010 in Toulouse's myeloma and BMT center with adequate clinical and biological data were retrospectively studied. Responses were evaluated at day 100 after ASCT in all pts according to IMWG criteria. BM examination comprised PCs count, BM cellularity, and the presence of PCs dysmorphy. Progression free survival (PFS) was calculated from the start of therapy until progression, death or last follow-up. Overall survival (OS) was calculated from the start of therapy until death or last follow-up. The Kaplan-Meier method was used to estimate the survival distribution. Results: Baseline demographics and initial disease characteristics are summarized in table 1. Median follow-up is 6 years. At the completion of ASCT, 49 pts (26%) achieved CR, 89 (47%) VGPR and 41 (21%) PR; 57 pts (30%) had a negative serum IF (sIF). Overall, 151 pts relapsed and 68 died with median PFS and OS of 36 and 99 months, respectively. At D100, median PCs count was 1% (range 0-23%): 1% (0-3%) in CR pts, 1% (0-23%) in VGPR pts, and 1.5% (0-7%) in PR pts. Only 1 pt with negative sIF had 5% BMPCs and a positive urine IF, and was assessed as VGPR. Overall, 55 negative sIF pts had 2% or less BMPCs. The number of 2% of BMPCs was found to be predictive, irrespective of response. Median PFS was 39 vs 21 months if BMPCs is > 2% (p<.001) and median OS was 99 months vs 66 (ns). We further aimed to evaluate the impact of PCs dystrophy on survival outcomes in 176 evaluable pts. PCs dysmorphy was reported in 29 pts including 3 pts in CR, 9 VGPR and 13 PR, respectively. All except 2 pts relapsed, with a median PFS of 26 mo (vs 39, p=.002). Nineteen died with a median OS of 60 mo (vs 101, p=.003). For pts at least in VGPR, median PFS was 26 mo in case of PCs dysmorphy vs 40 mo (p=.004) and median OS was 59 mo vs not reached (p=.005). (see figures) Conclusion: conventional microscopy of BM aspirate is a useful and rapid tool to evaluate the percentage of PCs and their morphology as a first step to assess the residual tumor mass in patients with MM after ASCT, and it constitutes a good predictor for disease progression and survival outcome. These findings have to be confirmed and the exact threshold of PCs remains to be determinate in a large prospective study. Table Characteristics n=191 Sex: M/F, n 109/82 Median age, y (range) 57 (31–68) Isotype, n (%) IgG, IgA, LC 123 (64), 35 (18), 28 (15) ISS stage, n (%) n= 158 I, II, III 85 (54), 40 (25), 33 (21) Median bone marrow plasma cells, % (range) 23 (1-96) Median b2-microglobulin, mg/L (range) 3.1 (1.3–19.4) Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

scholarly journals Consolidation Followed By Maintenance Therapy Versus Maintenance Alone in Newly Diagnosed, Transplant Eligible Patients with Multiple Myeloma (MM): A Randomized Phase 3 Study of the European Myeloma Network (EMN02/HO95 MM Trial)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 242-242 ◽  
Author(s):  
Pieter Sonneveld ◽  
Meral Beksac ◽  
Bronno van der Holt ◽  
Meletios A. Dimopoulos ◽  
Angelo Michele Carella ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Progression Free Survival ◽  
Advisory Board ◽  
Primary Study ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
High Dose Melphalan

Abstract Background The role of up-front consolidation for newly diagnosed, transplant eligible MM (NDMM) patients (pts) has not yet been prospectively addressed in the novel agents era. Methods The EMN02/HO95 trial was designed to randomly (R) compare (R1) 4 cycles of bortezomib-melphalan-prednisone (VMP) vs high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT), either single or double, as intensification therapy after induction with bortezomib-cyclophosphamide-dexamethasone (VCD) (M Cavo et al, ASCO 2016, abstract #8000). A second randomization to consolidation therapy with 2 cycles of VRD vs no consolidation (R2) was performed after intensification, to be followed by lenalidomide maintenance (lenalidomide 10 mg continuously) until progression or toxicity in both arms. (VRD: bortezomib 1.3 mg/m2 intravenously days 1, 4, 8, 11; lenalidomide 25 mg orally days 1 - 21; dexamethasone 20 mg orally days 1, 2, 4, 5, 8, 9, 11, 12 of a 28 days cycle). Primary study end points were progression-free survival (PFS) from R1 and PFS from R2. A first planned interim analysis for R2 was performed in July 2016 when at least 33% (= 172) of the required events for PFS had been observed. Results From February 2011 to April 2014, 1510 pts aged ≤ 65 years with symptomatic MM were enrolled, of whom 1499 were eligible. Of these, 1211 were randomized (stratification by ISS stage) to VMP (505 pts) or HDM (1 or 2 ASCT) (706 pts). For R2 903 eligible patients were randomized to consolidation (459 pts) or no consolidation (444 pts). Median follow up from R2 was 25 months (maximum 53). Response status at time of R2 was ≥ CR (23%), ≥ VGPR (67%), ≥ PR (93%), and will be updated for status at start of maintenance. At the time of analysis, 258 events for PFS after R2 had been reported. 3-year. PFS from R2 was 62% in all patients, i.e., 60% without consolidation and 65% in patients with consolidation, and median PFS had not yet been reached. PFS from R2 with adjustment for R1 was prolonged in pts randomized to VRD (HR=0.78; 95% CI=0.61-1.00; P=0.045), a benefit retained across predefined subgroups with revised ISS stage III (HR=0.67; P=0.26) and in patients randomized in R1 to VMP (HR=0.76; P=0.19) and to HDM (HR=0.79; P=0.13). The benefit of consolidation was observed in patients with low-risk cytogenetics (HR=0.68; P=0.03), but not in patients with high-risk cytogenetics (del(17p) and/or t(4;14) and/or t(14;16); HR=1.03; P=0.91). At 3 years OS from R2 was 86% and 87%, respectively. Toxicity from VRD was limited with 5% CTCAE grade 4, mainly hematological. Conclusions Consolidation treatment with VRD followed by Lenalidomide maintenance until progression or toxicity shows promising results as compared to maintenance alone for younger NDMM pts, but further study follow-up is needed. This trial was registered at www.trialregister.nl as NTR 2528, EudraCT 2009-017903-28 This trial was supported by unrestricted grants from Celgene and Janssen. Disclosures Sonneveld: Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Carella:Millenium: Speakers Bureau; Genentech: Speakers Bureau. Ludwig:Janssen: Speakers Bureau; BMS: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Driessen:janssen: Consultancy; celgene: Consultancy; Mundipharma-EDO: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gay:Celgene: Honoraria; Mundipharma: Other: Advisory Board; Amgen: Honoraria; BMS: Honoraria; Janssen-Cilag: Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board. Mellqvist:Mundipharma: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Zweegman:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Schjesvold:Janssen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Palumbo:Takeda: Employment, Honoraria; Janssen Cilag: Honoraria. Cavo:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria.

Superior 12-yr Survival (66% vs 30%) with 5-yr Continuous (Rc) vs “Discontinuous” Remission (Rd): Results of Total Therapies 1 & 2 (TT1,2) for Multiple Myeloma (MM).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1153-1153
Author(s):  
Bart Barlogie ◽  
Erik Rasmussen ◽  
Guido Tricot ◽  
Teresa Milner ◽  
Elias Anaissie ◽  
...  
Keyword(s):  
Overall Survival ◽  
Laboratory Data ◽  
High Dose ◽  
Key Factors ◽  
Remission Status ◽  
Bone Marrow Plasma ◽  
Study Characteristics ◽  
Pre Treatment ◽  
High Dose Melphalan

Abstract Background: The extension of overall survival (OS) in MM has been partly linked to increasing CR rates especially with high-dose melphalan. Data bases of TT1 and TT2 were examined to determine whether 5-yr Rc was key to prolonged OS. Patients and Methods: TT1 enrolled 231 and TT2 668 patients (median follow-up, 4 years). Pre-study characteristics of Rc vs Rd patients surviving &gt;= 5yrs were compared. Furthermore, subsequent OS was examined in the context of pre-treatment variables, TT2 vs TT1 and Rc vs Rd. Only those Rd patients who were event-free (CR or PR) at least 1 year prior to the 5-yr landmark were included in this analysis. Results: Among 231 TT1 + TT2 patients surviving &gt;= 5yrs, more TT2 patients were Rc compared to Rd (60% vs 19%, p&lt;0.001) and more older patients were Rc (at least 65: 13% vs 3%, p=0.019). Importantly, baseline LDH, B2M, CRP, albumin, presence of cytogenetic abnormalities (CA) and whether thalidomide was part of TT2 were evenly distributed among Rc and Rd groups. Furthermore, the 5-yr risk profile of Rc patients was lower than that of Rd patients: lower bone marrow plasma cell % (at least 33%: 0% vs 14%, p=0.003), higher albumin (less than 3.5g/dL: 7% vs 16%, p=0.047), higher Hb (less than 10g/dL: 4% vs 16%, p=0.023), less frequent CA13 (1% vs 11%, p=0.007). Rc patients had significantly longer subsequent survival than those with Rd (12-year survival from enrollment and 7 yrs post-landmark: 66% vs 30%, p&lt;0.001) (Figure). In addition to Rc, univariately significant factors for post 5-year OS were data at 5 years on CA, albumin, B2M, CRP and creatinine. Rc and no CA at 5yrs were the key factors favoring long subsequent survival; thus, 12-yr OS rates decreased from 57% in the 94 patients with Rc/noCA to 44% in 44 with noRC/noCA; 8 of 9 noRc/CA patients have died by year eight; 1 of the 8 Rc/CA patients has died. Conclusion: 5-yr Rc appears to be an important prerequisite for prolonged subsequent OS, which could be significantly increased with better therapy (TT2 vs TT1). Post-5-yr favorable survival predictors included several laboratory data at 5yrs, especially absence of CA. Overall Survival from 5 Years Post Enrollment by Remission Status at 5 Years (Interrupted vs Continuous Remisssion) Overall Survival from 5 Years Post Enrollment by Remission Status at 5 Years (Interrupted vs Continuous Remisssion)

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