CKS1B Over-Expression Significantly Predicts for a Lower Rate of Response to Primary Therapy with Thalidomide-Dexamethasone (Thali-Dex) for Newly Diagnosed Multiple Myeloma (MM) Patients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 371-371
Author(s):  
Matteo Renzulli ◽  
C. Terragna ◽  
N. Testoni ◽  
E. Montanari ◽  
P. Tosi ◽  
...  
Keyword(s):  
Response To Therapy ◽  
Remission Induction ◽  
Lower Probability ◽  
High Dose ◽  
Fish Analysis ◽  
Primary Therapy ◽  
Newly Diagnosed ◽  
Rt Pcr ◽  
Over Expression ◽  
The Relationship

Abstract In MM tandem duplication and jumping translocations of the q21 band of chromosome (chr.) 1 are acquired during progression of the disease and can lead to chr.1q amplification. In several studies, chr. 1 amplification has been linked to poor prognosis after both conventional and high-dose chemotherapy. Recently, a subset of genes mapping on 1q21 band has been identified, whose increased expression may be due to increased DNA copy number. Among these genes, CKS1B has been one of the most significantly upregulated. CKS1B regulates SCF skp2 mediated ubiquitination and proteolysis of the cyclin dependent kinase inhibitor p27Kip1, whose low expression has been reported to be an independent adverse prognostic factor in MM patients. Aim of the present study was to investigate the relationship between CKS1B expression and response to primary therapy with thali-dex in a large series of patients with newly diagnosed MM. Secondary endpoint was to explore the relationship between CKS1B expression and del(13), as assessed by FISH analysis, and t(4;14), as evaluated by an RT-PCR assay designed to detect the presence of IgH/MMSET fusion gene. A total of 132 patients were analyzed. The presence of t(4;14) and CKS1B expression were investigated in all patients, while del(13) was studied in 129/132 patients. CKS1B expression was evaluated by Real-time RT-PCR. CKS1B values were separated in four different quartiles, with expression levels increasing progressively from quartile 1 to 4. Response to therapy was evaluated according to the criteria proposed by Bladè et al. The Fisher test and the Mann-Whitney test were applied for statistical analysis. On an intent-to-treat basis, the overall probability to respond (≥ partial response, PR) to up-front thali-dex therapy was 71%, while 38 patients (29%) either did not respond (NR) or progressed. Median CKS1B expression value was significantly higher in NR in comparison with patients who attained at least a PR: 1.42 (range 0.15–52.35) vs. 0.89 (range 0–11.88), respectively (p=0.01). In particular, the proportion of NR patients in the CKS1B expression quartile 4 was significantly higher as opposed to the frequency of NR in the CKS1B expression quartiles 1 to 3 (45.5% vs. 23.2%, respectively; p= 0.02). CKS1B over expression did not correlate with the presence of t(4;14) or del(13). Only 6 patients harbouring t(4;14) fell into the CKS1B expression quartile 4, as opposed to 32 patients included into the CKS1B expression quartiles 1–3 (18.2% vs. 32.3%; p, not significant). Similarly, the frequency of del(13) was comparable in the CKS1B expression quartile 4 and in the CKS1B expression quartiles 1–3 (34.4% vs. 44.3%; p, not significant). Likewise, only 2 patients carrying both t(4;14) and del(13) fell into the CKS1B expression quartile 4, as opposed to 15 patients who fell into the CKS1B expression quartiles 1–3 (6.5% vs. 15.3%; p, not significant). In conclusion, in patients with newly diagnosed MM, CKS1B over expression at baseline predicts for a significantly lower probability of response to primary remission induction therapy with thali-dex. Poor response to thali-dex conferred by CKS1B over expression is independent from the presence of t(4;14) and/or del(13). Supported by Università di Bologna, Progetti di Ricerca ex-60% (M.C.); Ministero dell’Università e Ricerca Scientifica (MIUR), progetto FIRB, RBAU012E9A_001 (M.C.); and Fondazione Carisbo.

Total Therapy With Tandem Transplants for Newly Diagnosed Multiple Myeloma

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 55-65 ◽  
Author(s):  
B. Barlogie ◽  
S. Jagannath ◽  
K.R. Desikan ◽  
S. Mattox ◽  
D. Vesole ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Remission Induction ◽  
Comprehensive Treatment ◽  
High Dose ◽  
Newly Diagnosed ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
Total Therapy ◽  
Macrophage Colony ◽  
Intent To Treat

Abstract Between August 1990 and August 1995, 231 patients (median age 51, 53% Durie-Salmon stage III, median serum β-2-microglobulin 3.1 g/L, median C-reactive protein 4 g/L) with symptomatic multiple myeloma were enrolled in a program that used a series of induction regimens and two cycles of high-dose therapy (“Total Therapy”). Remission induction utilized non–cross-resistant regimens (vincristine-doxorubicin-dexamethasone [VAD], high-dose cyclophosphamide and granulocyte-macrophage colony-stimulating factor with peripheral blood stem cell collection, and etoposide-dexamethasone-cytarabine-cisplatin). The first high-dose treatment comprised melphalan 200 mg/m2 and was repeated if complete (CR) or partial (PR) remission was maintained after the first transplant; in case of less than PR, total body irradiation or cyclophosphamide was added. Interferon--2b maintenance was used after the second autotransplant. Fourteen patients with HLA-compatible donors underwent an allograft as their second high-dose therapy cycle. Eighty-eight percent completed induction therapy whereas first and second transplants were performed in 84% and 71% (the majority within 8 and 15 months, respectively). Eight patients (3%) died of toxicity during induction, and 2 (1%) and 6 (4%) during the two transplants. True CR and at least a PR (PR plus CR) were obtained in 5% (34%) after VAD, 15% (65%) at the end of induction, and 26% (75%) after the first and 41% (83%) after the second transplants (intent-to-treat). Median overall (OS) and event-free (EFS) survival durations were 68 and 43 months, respectively. Actuarial 5-year OS and EFS rates were 58% and 42%, respectively. The median time to disease progression or relapse was 52 months. Among the 94 patients achieving CR, the median CR duration was 50 months. On multivariate analysis, superior EFS and OS were observed in the absence of unfavorable karyotypes (11q breakpoint abnormalities, -13 or 13-q) and with low β-2-microglobulin at diagnosis. CR duration was significantly longer with early onset of CR and favorable karyotypes. Time-dependent covariate analysis suggested that timely application of a second transplant extended both EFS and OS significantly, independent of cytogenetics and β-2-microglobulin. Total Therapy represents a comprehensive treatment approach for newly diagnosed myeloma patients, using multi-regimen induction and tandem transplantation followed by interferon maintenance. As a result, the proportion of patients attaining CR increased progressively with continuing therapy. This observation is particularly important because CR is a sine qua non for long-term disease control and, eventually, cure.

Treatment of ANCA-associated vasculitis

2013 ◽  
Author(s):  
David Jayne
Keyword(s):  
Tissue Damage ◽  
Drug Toxicity ◽  
Granulomatosis With Polyangiitis ◽  
Late Complication ◽  
Response To Therapy ◽  
Remission Induction ◽  
High Dose ◽  
Eosinophilic Granulomatosis With Polyangiitis ◽  
Endstage Renal Disease ◽  
Steroid Dependent

The goals of treatment in anti-neutrophil cytoplasm antibody (ANCA) vasculitis are to stop vasculitic activity, to prevent vasculitis returning, and to address longer-term comorbidities caused by tissue damage, drug toxicity, and increased cardiovascular and malignancy risk. Cyclophosphamide and high-dose glucocorticoids remain the standard induction therapy with alternative immunosuppressives, such as methotrexate or azathioprine, to prevent relapse. Refractory disease resulting from a failure of induction or remission maintenance therapy requires alternative agents and rituximab has been particularly effective. Replacement of cyclophosphamide by rituximab for remission induction is supported by recent evidence. Additional therapy with intravenous methylprednisolone and plasma exchange is employed in severe presentations with failing vital organ function. Drug toxicity contributes to comorbidity and mortality and has led to newer regimens with reduced cyclophosphamide exposure. Glucocorticoid toxicity remains a major problem, with controversy over the rapidity with which glucocorticoids can be reduced or withdrawn. Disease relapse occurs in 50% and requires early detection at a stage when it will not adversely affect outcomes. Rates of cardiovascular disease and malignancy are higher than in control populations but strategies to reduce their risk, apart from cyclophosphamide-sparing regimens, have not been developed. Thromboembolic events occur in 10% and may be linked to the recently identified autoantibodies to plasminogen and tissue plasminogen activator. Outcomes of vasculitis depend heavily on the level of tissue damage at diagnosis, especially renal dysfunction, but are also influenced by patient age, ANCA subtype, disease extent, and response to therapy. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)is treated along similar principles to granulomatosis with polyangiitis (GPA) and microscopic polyangiitis but the persistence of steroid-dependent asthma in over one-third and differences in pathogenesis has suggested alternative treatment approaches. Chronic morbidity results from tissue damage and is especially common in the upper and lower respiratory tract and kidneys. Tracheobronchial disease is a severe late complication of GPA, while deafness, nasal obstruction, and chronic sinusitis are sequelae of nasal and ear vasculitis. Chronic infection of damaged epithelial surfaces acts as a drive for vasculitic activity and adequate infection control is necessary for stable remission. Chronic kidney disease can stabilize for many years but the risks of endstage renal disease (ESRD) are increased by acute kidney injury at presentation or renal relapse. Renal transplantation is successful, with similar outcomes to other causes of ESRD.

Up-Front Thalidomide-Dexamethasone (THAL) and Double Autologous Transplantation (Double TX) for Multiple Myeloma: Comparison with Double TX without Added Thalidomide and Prognostic Implications of Chromosome 13 Deletion and Translocation t(4;14).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3081-3081 ◽  
Author(s):  
Michele Cavo ◽  
Nicoletta Testoni ◽  
Carolina Terragna ◽  
Elena Zamagni ◽  
Paola Tacchetti ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Autologous Transplantation ◽  
Lower Probability ◽  
Fish Analysis ◽  
Primary Therapy ◽  
Cytogenetic Abnormalities ◽  
Chromosome 13 ◽  
Prognostic Implications ◽  
Intent To Treat

Abstract Aim of the present sudy was to evaluate the benefit of novel agents combined with conventional therapies in multiple myeloma (MM), with particular emphasis on patients (pts) carrying adverse cytogenetic abnormalities. For this purpose, we analyzed a series of 142 pts who received thalidomide-dexamethasone (thal-dex) and double autologous transplantation (double Tx). By study design, thal-dex was administered from the outset until the second autologous Tx. On an intent-to-treat basis, stringently defined (immumofixation negative) complete remission (CR) rate following double Tx and thal-dex was 54%. This value was significantly higher (P=0.0009) compared to the 33% observed in a comparable series of 129 pts who received double Tx without thal-dex. In comparison with these latter patients, addition of thal-dex to double Tx significantly prolonged PFS (median: 31 vs 42 months; P=0.04) and did not adversely affect survival after post-transplant relapse (P=0.7). All 142 pts included in the study were investigated at baseline for the presence of chromosome 13 deletion [del(13)] by FISH analysis and of t(4;14) using a RT-PCR assay. An analysis on an intent-to-treat basis performed according to the presence or absence of these cytogenetic abnormalities revealed that the probability to respond (more than 90% reduction in M protein concentration) to primary therapy with thal-dex for 94 pts who carried both del(13) and t(4;14) was significantly lower compared to that of 69 pts with del(13) alone (12% vs 41%, respectively; P=0.012) and of 18 pts with t(4;14) alone (12% vs 50%, respectively; P=0.006). The lower probability of response to first-line thal-dex therapy conferred by the presence of both del(13) and t(4;14) was completely offset by subsequent application of double Tx and thal-dex. Indeed, on an intent-to-treat basis, the probability to attain a very good partial response or CR for pts with both del(13) and t(4;14) positivity was 68% compared to 80% for pts with both del(13) and t(4;14) negativity (P=0.1). With a median follow-up of 24 months, the 3-year projected probabilities of OS and PFS were 80% and 59%, respectively (intent-to-treat). The presence or absence of t(4;14) had no significant impact on the 3-year projected probability of OS (80.12% vs 80.42%, respectively; P=0.3). Furthermore, an analysis of pts who actually received thal-dex and double Tx showed that curves of OS and EFS were almost superimposable among pts who carried or lacked both del(13) and t(4;14). Indeed, the 3-year projected probability of OS for pts with both these cytogenetic abnormalities was 92% compared to 88% for pts who were negative for both del(13) and t(4;14); (P=0.7); the corresponding figures for EFS were 70% vs 77%, respectively (P=0.9). These results suggest that thal-dex combined with double Tx may overcome the unfavourable prognosis conferred by del(13) and t(4;14). A longer follow-up is required before definite conclusions can be drawn.

Phase I Study of Bortezomib, (BTZ) Followed by High-Dose Melphalan, (HD Mel) and BTZ as Conditioning Regimen for Tandem Peripheral Blood Stem Cell Transplants (TanPSCT) in Patients with Primary Refractory Multiple Myeloma (MM) and Plasma Cell Leukemia (PCL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5131-5131 ◽  
Author(s):  
Todd Alekshun ◽  
Christine Mcisaac-Simonelli ◽  
Mohamed Kharfan-Dabaja ◽  
William Dalton ◽  
Benjamin Djulbegovic ◽  
...  
Keyword(s):  
Median Time ◽  
Risk Group ◽  
Single Agent ◽  
Conditioning Regimen ◽  
High Dose ◽  
Fish Analysis ◽  
Newly Diagnosed ◽  
Poor Risk ◽  
Early Results ◽  
Pathway Gene

Abstract Background: Approximately 25% of patients with newly diagnosed (MM) fail to respond and progress while receiving conventional induction. As a result, these patients have primary refractory disease. Even though these patients still benefit from HD chemotherapy, their PFS ranges from 4–8 months, while OS is approximately 12 months. PCL accounts for approx. 2% of newly diagnosed MM patients and represents the most aggressive form of disase. These patients often do not respond to standard systemic cytotoxic therapies and their median survival is less than 12 months. Therefore, novel treatment approaches are paramount for patients with primary refractory MM and PCL. The proteasome inhibitor BTZ has been shown to sensitize myeloma cells to melphalan both in vitro and in vivo, but the mechanism is not well understood. In this study we examine the effects of BTZ, followed by BTZ and HDMel as conditioning regimen for TanPSCT in this poor-risk group. Methods: Patients with primary refractory MM or PCL received 2 cycles of BTZ at 1.3 mg/m2. followed by HD Mel (200 mg/m2) and one dose of BTZ at 0.7 mg/m2, 1.0 mg/m2 or 1.3 mg/m2, as a conditioning regimen prior to TanPSCT. The dose of BTZ was given immediately after the last dose of HD Mel. Bone marrow(BM) samples were collected at baseline, on day 4 and after 2 cycles of BTZ, and at 3 months after TanPSCT, for GEP and Fanconi anemia(FA) pathway genes assessment. Results: To date, 17 patients have been enrolled and treated, and 11 patients are evaluable for response. Median age is 59 years (46–70) with the following myeloma distribution: 55% IgA and 45% IgG. FISH analysis showed the following: del 13q (44%), t (4; 14) (11%), t (11; 14) (11%), trisomy 11 (11%), and polyploid (11%); standard karyotype was normal in 88% of patients and complex karyotype in 12%. Median time to WBC engraftment (days) was 13 and 12 after the first and second transplant, respectively. Median time to plt engraftment (days) was 20 and 17, after the first and second transplant, respectively. There were no dose limiting toxicities. Observed grade 3 toxicities were related to the conditioning regimen and similar to those observed with HDMel alone. One patient developed diffuse alveolar hemorrhage after the first cycle of BTZ, which resolved, but was removed from study. After 2 cycles of BTZ, 45% of patients achieved PR, and 55% had stable disease. Overall response rate at 3 months from the second transplant increased to 90%(CR=36%,VGPR=27% andPR=27%). Only 1 patient developed progressive disease after the first transplant. Evaluations of BM samples by GEP and FA pathway gene expression are underway. Conclusions: Single agent BTZ induced responses in 45% and the combination of HD Mel and BTZ as conditioning regimen for TanPSCT was well tolerated and improved response rates to 90%. These early results suggest that this regimen is very active in this poor-risk group. Evaluation of collected BM samples for GEP and FA pathway genes may provide important insight into the mechanisms associated with the observed synergy between BTZ and HD Mel. A Phase II study is underway.

Lenalidomide Plus Dexamethasone Versus Lenalidomide Plus Melphalan and Prednisone: A Case-Control Study in Newly Diagnosed Elderly Myeloma Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2877-2877
Author(s):  
Francesca Gay ◽  
S. Vincent Rajkumar ◽  
Patrizia Falco ◽  
Shaji Kumar ◽  
Angela Dispenzieri ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Case Control Study ◽  
Case Control ◽  
High Dose ◽  
Primary Therapy ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Control Study

Abstract Abstract 2877 Poster Board II-853 Background and Objective: In newly diagnosed multiple myeloma (MM) patients, treatment with lenalidomide plus high-dose dexamethasone (RD) was superior to high-dose dexamethasone in terms of both response rates and 1-year progression-free survival (PFS) (Zonder JA et al, Blood 2007;110:77). Preliminary results suggest that the combination lenalidomide plus low-dose dexamethasone (Rd) compared to the RD regimen yields significantly better 2-year overall survival (OS) (Rajkumar SV et al, J Clin Oncol 2008;26:8504). The combination of melphalan, prednisone, and lenalidomide (MPR) has been investigated in a phase I/II study showing promising results (Palumbo A et al, J Clin Oncol 2007; 25:4459-4465). The goal of this case –control study was to compare the efficacy and the toxicity of the lenalidomide/dexamethasone (len/dex) combination vs MPR as primary therapy for newly diagnosed elderly MM patients, to determine the additive value of melphalan compared to a regimen of lenalidomide plus corticosteroid. Patients and methods: Data from 51 newly diagnosed MM patients enrolled in Italy in a phase I/II dose-escalating trial, from January to October 2005, with MPR, were analyzed. For comparison of their outcome, 37 patients were identified among newly diagnosed patients seen at the Mayo Clinic from March 2005 to December 2008 who received len/dex as primary therapy and were enrolled in phase II or III trials. Patients treated with MPR received 9 monthly cycles of oral melphalan (doses ranging from 0.18 to 0.25 mg/kg on days 1-4), prednisone (2 mg/kg on days 1-4) and lenalidomide (doses ranging from 5 to 10 mg/day on days 1-21). After 9 cycles, patients started maintenance with lenalidomide alone (10 mg, days 1-21) until relapse or progression. Patients treated with len/dex received oral lenalidomide (25 mg/day, days 1-21) plus dexamethasone, either at low-dose (n=17) (40 mg orally days 1, 8, 15, 22) or at high-dose (n=21) (40 mg orally on days 1-4, 9-12, and 17-20). Treatment was continued until progression, relapse or unacceptable toxicity, or could be stopped at the physician's discretion. Patients (n=13) were allowed to receive transplant if they wished and were deemed eligible. Outcome was analyzed on an intention-to-treat basis. The Chi-square or the rank sum tests were used to compare variables. Time-to-event analysis was performed using the Kaplan-Meier method and comparisons were determined by the log-rank test and the Cox proportional hazards model. Results: On intention-to-treat analysis, 15.7% versus 23.7% patients, respectively in the MPR and in the len/dex group, (p=0.342) achieved a complete response, and 43.2% vs 47.4%, (p=0.691) achieved at least a very good partial response. Time-to-progression (TTP) (median: 24.7 vs 27.5 in MPR and len/dex groups, respectively; HR 1.04; 95% CI 0.55-1.98; p=0.903), PFS (median: 24.7 vs 27.5 in MPR and len/dex groups, respectively; HR 1.03; 95% CI 0.55-1.92; p=0.926) and OS (2-year OS: 86.2% in MPR group vs 89.1% in len/dex, HR 0.86; 95% CI 0.38-1.98; p=0.730) were not significantly different between the 2 groups. No significant differences in TTP, PFS and OS were reported when MPR patients were compared with the subgroup of patients treated with low-dose dexamethasone plus lenalidomide. Similar results were found when the analysis was restricted to MPR patients and len/dex pair mates receiving lenalidomide plus low/dose dexamethasone, matched according to age and sex, and who did not received transplant. The toxicity profile was different in the two groups. Hematologic grade 3-4 toxicities were more common with MPR compared with len/dex, in particular neutropenia (66.7% vs 21.1%, p < 0.001) and thrombocytopenia (31.4% vs 2.6%, p < 0.001), respectively. Grade 3-4 gastrointestinal events (13.2% vs 2.0%, p= 0.080), thrombotic events (13.2 vs 5.9, p= 0.279) and fatigue (10.5% vs 3.9%, p= 0.395) were more common with len/dex compared with MPR. Conclusion: Results of this case-control study show that both MPR and Rd are efficacious regimens for elderly MM patients. Data need however to be carefully evaluated and randomized control trials are needed to confirm these results. Disclosures: Off Label Use: research drug in combination to standard of care. Kumar:celgene: Research Funding; millenium: Research Funding; bayer: Research Funding; novartis: Research Funding; genzyme: Research Funding. Dispenzieri:celgene: Research Funding. Gertz:celgene: Honoraria; genzyme: Honoraria; millenium: Honoraria; amgen: Honoraria. Lacy:celgene: Research Funding. Musto:celgene: Honoraria. Fonseca:medtronic: Consultancy; genzyme: Consultancy; celgene: Consultancy; amgen: Consultancy; BMS: Consultancy; otsuka: Consultancy. Petrucci:celgene: Honoraria; Janssen Cilag: Honoraria. Greipp:celgene: Research Funding. Boccadoro:jansen Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; pharmion: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Palumbo:Janssen-Cilag: Honoraria; Celgene: Honoraria.

scholarly journals Effects of Plasma Exchange (PE) Therapy in a Severe Fever with Thrombocytopenia Syndrome (SFTS) Patient with High Virus Quantities

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4900-4900
Author(s):  
Kazuhito Tsutsumi ◽  
Toshiro Takafuta ◽  
Michiko Kida ◽  
Tatsuji Mino ◽  
Miki Kido ◽  
...  
Keyword(s):  
Mortality Rate ◽  
Organ Damage ◽  
High Dose ◽  
Newly Diagnosed ◽  
Rt Pcr ◽  
Virus Level ◽  
First Case ◽  
One Step ◽  
High Virus ◽  
Severe Fever

Abstract Background: Severe fever with thrombocytopenia syndrome (SFTS) is an infectious disease caused by the SFTS bunyavirus, which is carried by ticks, and presents various symptoms such as fever, fatigue, digestive symptoms, and hemophagocytic lymphhistiocytosis (HLH). Since the first case was reported from China in 2011, there has been a rapid increase of newly diagnosed patients in Japan. Because the mortality rate has remained high (10-30%), there is an urgent need to establish a management strategy for SFTS. Method: We retrospectively reviewed two newly-diagnosed cases of severe SFTS in our hospital from April 2015 to July 2015. Diagnosis of SFTS was confirmed rapidly using a conventional one-step RT-PCR (cvPCR) method, and the quantity of SFTS virus in each serum was determined with a quantitative one-step RT-PCR (qPCR) method described by Yoshikawa et al. (JCM2014, 52, 3325-33). Virus titer is indicated in units of log10 copies/ml. Results: Case 1 was an 87-year-old female and Case 2 was an 81-year-old male. They showed similar severe clinical symptoms including disturbance of consciousness and a variety of abnormal laboratory findings. Both cases were quickly confirmed as SFTS using cvPCR on the next day after blood sampling. Bone marrow (BM) aspiration was performed at diagnosis, and confirmed HLH in both cases. [Case 1] Although methylprednisolone (mPSL) 250 mg was administrated to control HLH on day 3, the data indicated that HLH had become worse on day 4. To control HLH, mPSL pulse therapy (1000 mg/day) was administrated from day four to day six. However, multiple organ failure proceeded rapidly, and she expired on day eight. Serum virus quantities increased markedly from 6.99 (day 3) to 9.05 (day 6). In this case, the virus level at diagnosis was extremely high compared to previously reported cases and it was possible that the high-dose mPSL therapy suppressed anti-virus immunity. [Case 2] Although mPSL 500 mg was administrated from day two, organ damage progressed on day three. In this case, instead of increasing the dosage of mPSL, plasma exchange (PE) was performed from day four to day six, and organ damage was relieved and the patient recovered in good condition. The serum virus quantities decreased slowly from 6.62 (day 4) to 6.48 (day 7) after PE. Discussion: Yoshikawa et al. reported that virus level at diagnosis correlated to the outcomes of SFTS patients and that in most fatal cases virus quantities at diagnosis were over 5.0. In our cases, the patients had higher virus quantities at diagnosis and presented with severe symptoms. In the first case of fatality, the virus quantities remarkably increased shortly after mPSL therapy. As most SFTS patients are over the age of 50 and the mortality rate is higher in the elderly, lowered immunity in elderly patients might be the cause of SFTS progression. Moreover, immunosuppression therapy, including high dose mPSL therapy for HLH, might enhance the accelerated proliferation of SFTS virus. Although mPSL therapy is effective in some cases, immunosuppressive therapy for a SFTS patient is still controversial. In the second case, after PE therapy the virus level didn't increase and symptoms were improved. PE therapy does not suppress humoral and cellular immunity, which is different from mPSL therapy. As such, PE therapy might be effective in serious cases of SFTS with high virus quantities. In these cases, treatment plans were developed without information on virus quantities, and we obtained qPCR results afterwards. In the future, if qPCR can be performed as quickly as cvPCR, then data on the virus level at diagnosis may be the most important information for planning treatment. Disclosures No relevant conflicts of interest to declare.

Superiority of First-Line Thalidomide-Dexamethasone over Vincristine-Doxorubicin-Dexamethasone in Preparation for Autologous Stem Cell Transplantation for Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1489-1489 ◽  
Author(s):  
Michele Cavo ◽  
Paola Tacchetti ◽  
Elena Zamagni ◽  
Patrizia Tosi ◽  
Delia Cangini ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Clinical Stage ◽  
Autologous Transplantation ◽  
Cell Mass ◽  
Response To Therapy ◽  
High Dose ◽  
Control Analysis ◽  
Primary Therapy ◽  
Matching Criteria

Abstract The aim of the present study was to compare thalidomide-dexamethasone (THAL-DEX) and vincristine-doxorubicin-dexamethasone (VAD) as primary therapy for newly diagnosed multiple myeloma (MM). For this purpose, we performed a retrospective matched case-control analysis of 200 patients who were treated with THAL-DEX (n=100) or VAD (n=100) on two consecutive studies from 1996 to 2003. Thalidomide was given orally at the daily dose of 200 mg, while VAD was administered by continuous infusion. Pulsed dexamethasone combined with thalidomide or vincristine-doxorubicin was given at the monthly dose of 40 mg/d for 4 days (1 to 4), with courses repeated on days 9 to 12 and 17 to 20 on odd cycles. By design of both studies, THAL-DEX and VAD were planned to be given for 4 months in an attempt to reduce tumor cell mass before collection of peripheral blood stem cells (PBSC) and subsequent autologous transplantation. Matching criteria were age (within 2 years), clinical stage and serum β2-microglobulin (within 1 mg/l). In addition to the above mentioned criteria, all other relevant baseline patient characteristics were comparable between the two groups. Response to therapy was evaluated using an intent-to-treat approach and stringently defined criteria (EBMT). In comparison with VAD, THAL-DEX resulted in a significantly higher ≥ partial response rate (76% versus 52%, respectively; P=0.0004) and effected more profound reduction in serum IgG (P=0.002) and IgA (P=0.01) M protein levels. Nine patients treated with THAL-DEX and 9 patients who received VAD did not proceeded to PBSC mobilization, mainly because of death while on study treatment (THAL-DEX=5 patients; VAD=6 patients) or nonfatal toxicity (THAL-DEX=3 patients; VAD=2 patients). The median number of CD34+ cells collected following high dose cyclophosphamide 7 g/m2 was 7.85 x 106/kg in the THAL-DEX group and 10.5 x 106/kg in the VAD group. Considering 4 x 106 CD 34+/kg as the minimum number of stem cells required to safely perform double autologous transplantation, adequate cell yields were obtained in 83% of patients with prior exposure to THAL-DEX and in 88% of patients treated with VAD (P=0.3). In conclusion, results of the present study (to the best of our knowledge, the first comparing THAL-DEX with VAD as initial cytoreductive therapy in preparation for autologous transplantation) extend and confirm prior observations by our group and others showing that THAL-DEX is an effective and relatively well tolerated induction regimen for previously untreated patients with MM. In comparison with VAD, THAL-DEX significantly augmented tumor cytoreduction without increasing the toxicity or interfering with subsequent collection of PBSC. Based on these data, thalidomide-dexamethasone may be considered an oral, and easy to administer, alternative to the more complex, and cumbersome to administer, combination of vincristine-doxorubicin-dexamethasone as front-line therapy for MM patients who are candidates to subsequent autologous transplantation.

Combination of Intensive Chemotherapy and Imatinib (IDEAMOP Regimen) for the Treatment of Newly Diagnosed BCR-ABL Positive Acute Lymphoblastic Leukemia; Excellent Efficacy without Increasing Toxicity.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2736-2736
Author(s):  
Masamitsu Yanada ◽  
Nobuhiko Emi ◽  
Noriko Usui ◽  
Jin Takeuchi ◽  
Isamu Sugiura ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Median Time ◽  
Lymphoblastic Leukemia ◽  
Remission Induction ◽  
High Dose ◽  
Intensive Chemotherapy ◽  
Consolidation Therapy ◽  
Newly Diagnosed ◽  
Allogeneic Hsct ◽  
Pulmonary Bleeding

Abstract The Philadelphia chromosome, which constitutes BCR-ABL fusion gene, is the most frequent cytogenetic abnormality in adult acute lymphoblastic leukemia (ALL). Although complete remission (CR) is achieved in 50–80% of patients, most of them suffer a relapse, resulting in overall survival (OS) of approximately 10% by standard chemotherapy. Recently, the Japan Adult Leukemia Study Group (JALSG) has started a phase 2 trial for newly diagnosed BCR-ABL positive ALL patients, and 60 patients have been enrolled at this time. We present here the results for the first 41 patients. After screening for BCR-ABL at presentation, those with positive BCR-ABL were treated with IDEAMOP regimen. For remission induction therapy, intensive chemotherapy comprising daunorubicin, cyclophosphamide, vincristine (VCR) and predonisolone (PSL) was combined with imatinib at a dose of 600 mg/day administered from day 8 to day 63. Consolidation therapy consisted of the odd courses with high-dose methotrexate and high-dose cytarabine and the even courses with 600 mg/day of imatinib alone for 28 days, which were repeated alternatively for 4 cycles. Thereafter, patients received maintenance therapy with VCR, PSL and imatinib until 2 years from the date they had attained CR. If an HLA-identical sibling donor was available, allogeneic hematopoietic stem cell transplantation (HSCT) was recommended. HSCT from an alternative donor was used at the discretion of the institution. Between September 2002 and March 2004, a total of 41 patients with newly diagnosed BCR-ABL positive ALL were treated with IDEAMOP. All patients except two cases of early death (95%) attained CR. PCR negativity in bone marrow was achieved in 25% of the patients on day 28, in 57% on day 63, and in up to 73% during the follow-up period. Toxicity of the remission induction therapy was almost similar to that observed for chemotherapy alone. The median time of WBC recovery to at least 1,000/mL was 19 days (range, 14 to 29 days), and the median time of platelet recovery to at least 100,000/mL was 22 days (range, 14 to 30 days). Death occurred in two patients, one for pulmonary bleeding on day 10, and the other for pneumonia on day 32. Interruption of imatinib was implemented for 11 patients (27%) for the following reasons; nausea in 4, GPT elevation in 3, pulmonary bleeding, pneumonia, fluid retention, ileus, amylase elevation in one patient, respectively; however, none of the 39 surviving patients dropped out the protocol due to intolerance of treatment. Four patients had a relapse during consolidation therapy after 4.0, 4.5, 4.9 and 10.3 months of CR. Allogeneic HSCT was performed for 20 patients (9 from a sibling donor, 8 from an unrelated donor, and 3 from unrelated cord blood) during their first CR. The 1-year event-free survival (EFS) and OS rates were estimated at 78% and 88%. Outcomes were superior to those in ALL93 study, where patients were treated with chemotherapy alone, in terms of CR rate, EFS, and OS (P &lt; 0.0001, P &lt; 0.0001, and P = 0.0118, respectively). In summary, our study demonstrated that IDEAMOP produces high-quality CR for a majority of patients with newly diagnosed BCR-ABL positive ALL without an increase in toxicity. This is especially useful for providing patients with a better chance to receive allogeneic HSCT. Long-term efficacy will be addressed in the final analysis of this study.

A Phase II Trial of Combined Bendamustine, Bortezomib and Dexamethasone in Newly Diagnosed Multiple Myeloma (MM) Patients Who Are Not Candidates for High-Dose Chemotherapy: Results of a Planned Interim Safety Analysis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2943-2943 ◽  
Author(s):  
Jesus G. Berdeja ◽  
Daniel R. Couriel ◽  
Patrick Murphy ◽  
Ralph V. Boccia ◽  
Victor Priego ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Interim Analysis ◽  
Sensory Neuropathy ◽  
Response Rates ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Fish Analysis ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Grade 3

Abstract Abstract 2943 Background Despite significant advances, multiple myeloma is an incurable plasma cell disorder with an eventual fatal outcome. In newly diagnosed MM, combinations of bortezomib, steroids and alkylating agents, such as melphalan and prednisone, have achieved response rates in excess of 70% and have been established as a standard of care in patients (pts) who are ineligible for high dose chemotherapy. Bendamustine is a bi-functional alkylating agent with a purine-like benzimidazole ring effective as single agent and in combination with steroids, thalidomide and bortezomib for the treatment of MM. Pönisch et al reported an overall response of 61% and CR of 15% in pts with relapsed/refractory MM using the combination of bendamustine, bortezomib and prednisone. In this study, the combination of bendamustine, bortezomib and dexamethasone (BVD) was tested for efficacy and safety in newly diagnosed pts with active MM who are not candidates for high-dose chemotherapy. Methods Patients with newly diagnosed active multiple myeloma who were not candidates for high-dose chemotherapy and met standard eligibility criteria with regards to renal, hepatic and hematologic function were enrolled. Pts were treated with bendamustine 80 mg/m2 on days 1, 4, bortezomib 1.3 mg/m2 on days 1, 4, 8, 11 and dexamethasone 40 mg on days 1, 2, 3, 4 every 28 days for a total of 8 cycles or 2 cycles beyond documented CR, whichever occurred first. Responses were assessed using the IMWG criteria. We report on the preliminary efficacy and safety results of a planned interim analysis of the BVD combination. Results Between May 2010 and February 2011, 18 pts were enrolled, all evaluable for toxicity. The median age was 75 (range 56–82); nine (50%) pts were DS stage III; seven (39%) pts had a B2M ≥ 5mg/L. Cytogenetics and FISH analysis for 13 del, t4;14, t14;16, and 17p del were available for all but 1 pt; 8 (44%) pts had at least 1 chromosomal abnormality, while 9 (50%) pts had none. At the time of data cut off, pts completed a median of 5.5 cycles (range 1–8); with 11 (61 %) receiving at least 4 cycles; and 5 (28%) receiving 8 cycles. Seven (39%) pts remain on study and 10 have discontinued therapy (1 disease progression and 3 deaths on study [2 cardiac arrest, 1 pulmonary emboli; all 3 determined to be unrelated to treatment], 1 MD discretion, 1 non-compliance, 1 pt request, 2 poor tolerance, 1 intercurrent illness) and 1 completed treatment. The most common grade 3/4 adverse events, occurring in more than 10% of pts, were leucopenia (17%), neutropenia (11%), myalgia (17%) and sensory neuropathy (11%). Twelve pts had treatment emergent sensory neuropathy: 5 (28%) grade 1, 5 (28%) grade 2 and 2 (11%) grade 3. Of the 17 patients evaluable for response, 15 had at least a PR for an ORR of 88% (9 (53%) VGPR, 6 (35%) PR, 2 (12%) SD). The presence of cytogenetic abnormalities did not seem to have a strong impact on response rates, with 88% of pts with 1 or more abnormalities responding compared to 88% with none. The median time to best response was 9 weeks. Conclusions In this planned interim analysis, the combination of BVD produced a high ORR, however the current schedule is relatively toxic in this pt population. The majority of the non-hematological toxicities appear to be related to bortezomib and dexamethasone. For this reason, the protocol was amended where bortezomib and dexamethasone are now dosed weekly (days 1, 8, and 15). The amended trial is currently accruing. Disclosures: Off Label Use: Bendamustine in myeloma. Flinn:Cephalon and Millenium: Research Funding.

scholarly journals Intensive Chemotherapy and Immunotherapy in Patients With Newly Diagnosed Primary CNS Lymphoma: CALGB 50202 (Alliance 50202)

2013 ◽  
Vol 31 (25) ◽  
pp. 3061-3068 ◽  
Author(s):  
James L. Rubenstein ◽  
Eric D. Hsi ◽  
Jeffrey L. Johnson ◽  
Sin-Ho Jung ◽  
Megan O. Nakashima ◽  
...  
Keyword(s):  
Primary Cns Lymphoma ◽  
Whole Brain Radiotherapy ◽  
Progression Free Survival ◽  
Complete Response ◽  
Remission Induction ◽  
Cns Lymphoma ◽  
High Dose ◽  
Newly Diagnosed ◽  
Brain Radiotherapy ◽  
Myeloablative Chemotherapy

Purpose Concerns regarding neurocognitive toxicity of whole-brain radiotherapy (WBRT) have motivated development of alternative, dose-intensive chemotherapeutic strategies as consolidation in primary CNS lymphoma (PCNSL). We performed a multicenter study of high-dose consolidation, without WBRT, in PCNSL. Objectives were to determine: one, rate of complete response (CR) after remission induction therapy with methotrexate, temozolomide, and rituximab (MT-R); two, feasibility of a two-step approach using high-dose consolidation with etoposide plus cytarabine (EA); three, progression-free survival (PFS); and four, correlation between clinical and molecular prognostic factors and outcome. Patients and Methods Forty-four patients with newly diagnosed PCNSL were treated with induction MT-R, and patients who achieved CR received EA consolidation. We performed a prospective analysis of molecular prognostic biomarkers in PCNSL in the setting of a clinical trial. Results The rate of CR to MT-R was 66%. The overall 2-year PFS was 0.57, with median follow-up of 4.9 years. The 2-year time to progression was 0.59, and for patients who completed consolidation, it was 0.77. Patients age > 60 years did as well as younger patients, and the most significant clinical prognostic variable was treatment delay. High BCL6 expression correlated with shorter survival. Conclusion CALGB 50202 demonstrates for the first time to our knowledge that dose-intensive consolidation for PCNSL is feasible in the multicenter setting and yields rates of PFS and OS at least comparable to those of regimens involving WBRT. On the basis of these encouraging results, an intergroup study has been activated comparing EA consolidation with myeloablative chemotherapy in this randomized trial in PCNSL, in which neither arm involves WBRT.

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