Results of the Interim Analysis of the “HUSOM” Trial: Hungarian Study of Maintenance After Rituximab Pretreatment, A Multicentre, Phase III, Open-Label Study Evaluating the Benefit of a Long-Term MabThera (rituximab) Maintenance Therapy in Patients with Advance Follicular Lymphoma After Induction of Response (CR(u) or PR) with a MabThera (rituximab)-Containing First Line Regimen

Abstract Abstract 2714 Background: The addition of immunotherapy–rituximab–to the treatment regimen of follicular lymphomas has led to a significant improvement in therapeutic efficacy. In the mid-2000's, immuno-chemotherapy was approved by European authorities as part of the induction treatment for untreated and relapsed follicular lymphomas followed by maintenance therapy. Data about efficacy and safety of rituximab maintenance following first-line induction with R-CVP or R-CHOP have not been available. Therefore the Hungarian National Working-Group initiated a trial: Hungarian Study of Maintenance after Rituximab Pretreatment. Methods: Between July 2005 and December 2008 126 newly diagnosed patients with follicular lymphoma who had achieved partial or complete remission after induction treatment with either R-CVP or R-CHOP were treated with two years of rituximab maintenance. In this open-label, single-arm study rituximab was administered in standard dose (375 mg/m2) every 8 weeks, 12 times in total. Results: 126 patients have been included. Data of 99 patients are available for this interim analysis. Average age of the 30 male (30%) and 69 female (70%) patients were 53.2 (29–80) years. Histological subtypes were grade-1 in 32% of patients, grade-2 in 49%, and grade-3a in 19%. Twenty-eight percent of patients had tumors with size over 7 cm. Sixty-four percent of patients were in the moderate risk group (FLIPI: 1–2) and 36% in the high risk group. Fifty-six percent of patients received R-CVP and 44% R-CHOP induction treatment. After induction 61% achieved complete remission and 39% partial remission. With respect to induction treatment regimen, patients treated with R-CVP 52% showed CR and 48% PR. In patients treated with R-CHOP 75% had CR and 25% had PR. Fourteen patients (37%) in PR converted to CR during or after rituximab maintenance therapy. Three-year OS after initiation of maintenance was 94%, EFS was 84%, and PFS was 88%. With respect to FLIPI, OS rates were 97% and 89% for moderate and high risk groups respectively. Patients treated with R-CHOP achieved significantly better PFS (98% vs. 80%; p=0.0096) and EFS (93% vs. 76%; p=0.0332) than those treated with R-CVP. Patients achieving CR compared to PR showed significantly higher PFS (100% vs. 68 %; p<0.0001) and EFS (95 % vs. 65 %; p<0.0001) values respectively. Safety: Four patients experienced SAEs. Three patients died (due to causes other than lymphoma). Two hepatitis B reactivations occurred. Conclusion: These data confirm that rituximab maintenance is a safe and effective treatment for patients after induction with rituximab based immuno-chemotherapy. Interestingly those patients who were treated with more intense induction regimen R-CHOP and those who achieved a better remission status seemed to have a favorable outcome. Thirty-seven percent of patients receiving rituximab maintenance converted from PR to CR. Therefore these data support the use of rituximab maintenance in 1st line treatment. Disclosures: No relevant conflicts of interest to declare.

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A Phase IIIb Study of Rituximab Maintenance Therapy in Patients with Follicular Non-Hodgkin’s Lymphoma Who Have Responded to Induction Therapy - MAXIMA-Protocol.

Blood ◽

10.1182/blood.v108.11.4706.4706 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4706-4706 ◽

Cited By ~ 1

Author(s):

Manfred Hensel ◽

Mathias Witzens-Harig ◽

Peter Dreger ◽

Anthony D. Ho ◽

Daniel Thurley ◽

...

Keyword(s):

Overall Survival ◽

Complete Remission ◽

Maintenance Therapy ◽

Follicular Lymphoma ◽

Induction Therapy ◽

Randomized Trials ◽

Phase Iii ◽

First Line ◽

Free Survival ◽

Rituximab Maintenance

Abstract Five randomized trials (four Phase III and one phase II) have confirmed that rituximab maintenance therapy provides clinical meaningful improvements in terms of Progression Free Survival, Event Free Survival and response duration for patients. Two studies have also found an overall survival advantage for rituximab maintenance therapy (Hoechster et al. 2005, van Oers et al. 2005) and a third study could demonstrate a strong trend towards overall survival advantage (Dreyling et al. 2006). A Cochrane meta-analysis of several randomised Phase III trials (Schulz et al. 2005) demonstrated that rituximab plus-chemotherapy for first-line treatment of Follicular Lymphoma is superior to chemotherapy alone and significantly prolongs overall survival. To further broaden the available basis for maintenance treatment in the first-line and relapsed setting, the MAXIMA (MAintenance rituXImab in Follicular LymphoMA) trial has been started in August 2006 and will last 5 years. Patients with first line or relapsed/refractory advanced Follicular Lymphoma are included in this trial. In total 500 patients are planned for this international trial running in 23 countries. Patients who achieve a Complete Remission, Complete Remission unconfirmed or Partial Remission after rituximab containing induction therapy (rituximab with or without chemotherapy) are eligible to enter the study to receive rituximab maintenance therapy administered at the standard dose of 375 mg/m2 every 2 months for 2 years. This regimen is also investigated in the ongoing PRIMA study, and also in an ongoing SAKK study which investigates the benefit of rituximab maintenance therapy for up to five years. The previous five randomized trials did not detect significant safety issues for rituximab maintenance therapy. The main objective of the MAXIMA trial is to confirm this safety data in a wider patient population. Secondary objectives of the study include standard time dependent parameters (PFS, EF, OS). In addition, the effect of rituximab maintenance therapy on improving response quality (PR =>CR) after induction therapy will be evaluated.

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Risk Stratification in Acute Promyelocytic Leukemia Based on Elevated White Cell Count and Reduced Platelet Count Does Not Identify Subsequent Relapses: A Retrospective Review of 60 Patients.

Blood ◽

10.1182/blood.v104.11.4522.4522 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4522-4522

Author(s):

Richard T. Doocey ◽

Stephen H. Nantel ◽

Michael J. Barnett ◽

Donna L. Forrest ◽

Donna E. Hogge ◽

...

Keyword(s):

High Risk ◽

Complete Remission ◽

Maintenance Therapy ◽

Risk Group ◽

White Cell Count ◽

High Risk Group ◽

Low Risk ◽

Intermediate Risk ◽

Risk Patients

Abstract Acute promyelocytic leukemia (APL) has become one of the more readily treatable subtypes of acute myeloid leukemia on the basis of its particular sensitivity to anthracyclines and the introduction of the differentiating agent all-trans retinoic acid (ATRA). Unfortunately some patients will ultimately relapse after achievement of complete remission. A PETHEMA and GIMEMA (PETH/GIM) cooperative group joint study sought to identify risk factors associated with relapse and developed a predictive model based on white cell count (WCC) and platelet count (Plt) at diagnosis. This model for relapse free survival was capable of segregating patients into low risk (WCC < 10 x 109/L / Plt > 40 x 109/L), intermediate risk (WCC < 10 x 109/L / Plt < 40 x 109/L), and high risk (WCC > 10 x 109/L). A subsequent follow up study demonstrated improved outcomes for intermediate and high risk group patients treated with an anthracycline and ATRA based risk adapted strategy. We reviewed 60 cases of adult de novo APL treated at Vancouver General Hospital from August 1995 to December 2003. Thirty five females (58%) and 25 males (42%) were treated with a standard induction and consolidation protocol consisting of 3 cycles of Daunorubicin (60 mg/m2 OD for 3 days), Cytosine arabinoside (100 mg/m2 BID for 7 days), and ATRA (45 mg/m2/day until complete remission or a maximum of 60 days). In 2000 maintenance therapy was introduced and ATRA and/or varying doses of Methotrexate and 6-Mercaptopurine were then instituted for up to 2 years duration. At the completion of induction chemotherapy complete morphological and cytogenetic remission was achieved in 55/60 patients (92%) with 4 induction failures and only 1 death during induction treatment. Subsequently during and after consolidation and maintenance therapy at a median follow up of 34 months there were a total of 10 episodes of relapse (18%) in these 55 patients. When the 55 patients in complete remission were stratified at diagnosis by the PETH/GIM risk group there were 18 low risk patients (33%), 26 intermediate risk patients (47%), and 11 high risk patients (20%). The number of relapses was 6 in the low risk group (33%), 4 in the intermediate risk group (15%) and no relapses were identified in the high risk group. In our experience the predictive model for relapse free survival developed by the PETH/GIM cooperative group does not identify those at most likelihood for subsequent relapse after achieving an initial complete remission. The greatest number of relapse was seen in the low risk group with no relapses in the high risk group. These variations may be explained in part by the different chemotherapy treatment protocols with variable maintenance therapy. Future investigation will focus on the prognostic role of immunophenotype, additional cytogenetic abnormalities and molecular isoforms in determining outcome in APL.

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High-Dose Chemotherapy with Bendamustin and Melphalan Improves the Rate of Complete Remission in Myeloma Patients in First Remission Compared to Standard Melphalan Alone

Blood ◽

10.1182/blood-2020-141545 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Sarah Farag ◽

Ulrike Bacher ◽

Myriam Legros ◽

Daniel Betticher ◽

Jean-Marc Lüthi ◽

...

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

Complete Remission ◽

Median Time ◽

Maintenance Treatment ◽

Induction Treatment ◽

High Dose ◽

First Line ◽

Term Survival ◽

Pulmonary Failure

Introduction: Consolidation of first-line induction treatment in myeloma (MM) patients (pts) with 200 mg/m2 melphalan chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) was established as standard of care three decades ago. However, definite cure in myeloma patients remains exceptional due to residual disease escaping intensive treatment, and almost all patients will ultimately relapse at earlier or later time points following ASCT. Thus, improving efficacy of HDCT in MM remains an unresolved issue. Methods: We performed a phase-II randomized trial comparing standard 200 mg/m2 Melphalan (Mel) HDCT to experimental HDCT treatment with 200 mg/m2 bendamustine, a bifunctional alkylating agent, given at days -4 and -3, combined with 200 mg/m2 melphalan split on days -2 and -1 at 100 mg/m2 (BenMel) before ASCT in MM pts. Patients had up to four cycles of first-line induction treatment with bortezomib, lenalidomide and dexamethasone. After ASCT, pts received lenalidomide maintenance treatment for two years. The primary endpoint was to show a 15% improvement of the rate of complete remission (sCR+CR) after HDCT with BenMel compared to Mel alone. MRD assessment from the bone marrow was performed by multiparameter flow cytometry after hematological engraftment following HDCT/ASCT. MRD negativity was defined as clonal plasma cells below 10(-5). Results: We randomized 120 myeloma pts (60 patients in each arm), with high-risk genetic abnormalities present in 21.3% of the patients. The median age was 63 years (range 35-74). The sCR/CR rate after ASCT before initiation of lenalidomide maintenance treatment was better in the BenMel arm compared to Mel alone (70.0% vs 51.7%; p=.039). The post-ASCT remission rates in detail were sCR 40.0% vs 31.7% (p=.341); CR 30.0% vs 20.0% (p=.205); VGPR 16.7% vs 33.3% (p=.035); and PR 13.3% vs 15.0% (p=.793). MRD negativity assessed in the bone marrow by flow cytometry was observed in 26 (45.6%) of the BenMel treated pts compared to 22 (37.9%) of the Mel pts. Median time until neutrophil engraftment was 11 days after BenMel vs 12 days after Mel (p=.096), and median time until platelet engraftment was 13 days in both arms (p=0.367); all pts had full engraftment of both cell lineages. Prolonged hospitalization duration was seen in BenMel pts (median 19 vs 18 days; p=.006) due to the longer BenMel treatment administration. Fully reversible acute renal insufficiency occurred in three (5%) BenMel pts compared to none of the Mel pts (p=.250). No treatment-related mortality was seen in both groups. ICU admissions were necessary in 3 pts (5%) in the BenMel group (ARDS, septic shock, pulmonary failure), and 2 Mel treated pts (3.3%; due to pulmonary failure and decompensated cardiomyopathy). The PFS rates at 12 months were 95% in BenMel pts and 91% in Mel treated pts (p=.551). OS at 12 months was 96% for both groups (p=.262), and median PFS and OS were not reached in both groups. Conclusions: Our data confirm that high-dose bendamustine combined with melphalan HDCT before ASCT in MM patients is safe and well tolerated. In particular, bendamustine-associated renal toxicity was manageable and reversible in all patients, and hematopoietic engraftment was comparable to standard melphalan HDCT. HDCT with BenMel improves the sCR/CR rate compared to standard melphalan alone. Thus, BenMel HDCT before ASCT warrants further investigation aiming to improve the long-term survival rates of MM patients, eventually combined with new maintenance strategies in the post-transplant period. Figure 1 Disclosures No relevant conflicts of interest to declare.

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Anlotinib Plus Toripalimab and Nab-Paclitaxel in Patients with Locally Advanced or Metastatic Pancreatic Cancer: Study Protocol for An Open-Label, Non-Randomized, Phase II Study (ATNPA)

10.21203/rs.3.rs-1076724/v1 ◽

2021 ◽

Author(s):

Jingwen Chen ◽

Yiqian Liu ◽

Yizhi Zhu ◽

Shiyun Cui ◽

Chongqi Sun ◽

...

Keyword(s):

Pancreatic Cancer ◽

Maintenance Therapy ◽

Kinase Inhibitor ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Metastatic Pancreatic Cancer ◽

Second Line ◽

First Line ◽

Open Label ◽

Combination Strategy

Abstract Background There have not been standard second-line or maintenance regimens with definite survival benefits so far for patients with pancreatic carcinoma who have lost the opportunity of curable resections or failed first-line chemotherapy. Anlotinib, a potent small-molecule tyrosine kinase inhibitor, exhibits anti-angiogenic and anti-tumour effects by specifically binding to multiple targets such as VEGFR, FGFR, PDGFR, c-Kit and Ret. Toripalimab, a novel anti-PD-1 mAb, has been proved to significantly prolong progression-free survival (PFS) and overall survival (OS) in various solid tumours with manageable toxicities when combining with cytotoxic chemotherapy. We design this study to assess the combination of anlotinib, toripalimab and nab-paclitaxel as a second-line or maintenance therapy for locally advanced pancreatic cancer (LAPC) or metastatic pancreatic cancer (MPC). Patients and Methods: This is an open-label, non-randomized, single-arm phase Ⅱ study, aimed at evaluating the efficacy and safety profile of the above-mentioned combination strategy in first-line therapy-failed LAPC or MPC. Totally 53 patients are to be enrolled and receive anlotinib (12 mg, po. qd.) plus toripalimab (240 mg, ivgtt. q3w.) and nab-paclitaxel (125 mg/m2, ivgtt, d1, d8) every 3 weeks as a cycle until disease progression or intolerable adverse events. The primary endpoint is PFS. Secondary end points include OS, disease control rate (DCR), object response rate (ORR), quality of life (QoL) and safety. Enrollment started in April 2021, and follow-up will be finished in April 2023. Discussion and Significance: Combination of anlotinib, toripalimab and nab-paclitaxel may promote vessel normalization and drug delivery, and activate the immune response, thus exerting synergistic anti-tumour effects and counteracting the immunosuppressive microenvironment of pancreatic cancer. As the first intending to assess this combination in pancreatic cancer, this study will provide comprehensive evidence for second-line or maintenance therapy of LAPC and MPC. Trial registration: ClinicalTrials.gov: ATNPA, NCT04718701. Registered January 22, 2021. (https://clinicaltrials.gov/ct2/show/NCT04718701?term=NCT04718701&draw=2&rank=1)

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Rituximab Consolidation and Maintenance Immunotherapy Improve Outcome in B-Cell Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v110.11.2035.2035 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2035-2035 ◽

Cited By ~ 1

Author(s):

Giovanni Del Poeta ◽

Maria Ilaria Del Principe ◽

Luca Maurillo ◽

Francesco Buccisano ◽

Gianfranco Catalano ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Maintenance Therapy ◽

B Cell ◽

Response Duration ◽

Lymphocytic Leukemia ◽

Induction Treatment ◽

Hematologic Toxicity ◽

Grade 3 ◽

Cell Chronic Lymphocytic Leukemia

Abstract Monoclonal antibodies in combination with chemotherapy allowed us to obtain more responses and longer response duration in B-cell chronic lymphocytic leukemia (B-CLL), reducing disease burden to levels detectable only by flow cytometry. Moreover, it has been reported that low-dose rituximab decreases CD20 antigen loss via shaving and promotes enhanced targeting in CLL (Williams, 2006). We performed a phase II study that added rituximab to fludarabine (Flu) as therapy for symptomatic, untreated CLL. Remission status was assessed by a multiparametric flow cytometric method based on the detection of CD19+CD5+CD79b– residual B-CLL lymphocytes. VH mutational status, CD38, ZAP-70 and cytogenetics were obtained in all pts before treatment. We defined as “high risk” pts having at least two of the following markers: unmutated IgVH, CD38>30%, ZAP-70>20%, intermediate/unfavorable cytogenetics (trisomy 12 or del11q or del17p). Eighty-two CLL pts, median age 61 years, received six monthly courses of Flu (25 mg/m2 for 5 days) and four weekly doses of rituximab (375 mg/m2) starting after completion of Flu therapy. According to modified Rai stages, 8 pts had a low stage, 70 an intermediate stage and 4 a high stage. Based on NCI criteria, 66/82 (80%) pts achieved a complete remission (CR), 12/82 (15%) a partial remission (PR) and 4/82 (5%) no response or progression. Hematologic toxicity included mainly neutropenia (grade 3 and/or 4 in 42 pts) and thrombocytopenia (grade 3 and/or 4 in 4 pts). Thirty-five pts in clinical CR or PR, either with CD5+CD19+CD79b– bone marrow (BM) cells >1% (MRD+, n=20 pts) or MRD negative but presenting CD5+CD19+ peripheral blood lymphocytes (PBL) >1000/microl (n=15 pts) within 1 year after completion of the induction treatment, underwent consolidation/maintenance therapy with four monthly cycles of rituximab at 375 mg/m2 followed by twelve monthly doses of rituximab at 150 mg/m2. The median follow-up duration was 46 months. Noteworthy, all B-CLL pts experienced a long progression-free survival (PFS) from the end of induction treatment (68% at 5 years). Nevertheless, CLL pts that underwent consolidation and maintenance therapy (n=35) showed a significant longer response duration (85% at 5 years, Figure). On the other hand, BM and PBL persistently MRD negative (>1 year) pts (n=29) showed a response duration similar to that of the consolidated pts (87% at 5 years). A significant shorter PFS was observed within CD38+ pts (39% vs 78% at 5 years, P=0.002), unmutated pts (45% vs 94% at 2.5 years, P=0.001) and ZAP-70+ pts (36% vs 88% at 6 years; P=0.00002). Notably, within the “high risk” subset (n=30), considering only MRD+ pts in CR or PR (n=20), MRD+ consolidated pts (n=11) showed a significant longer response duration (64% vs 13% at 2 years, P=0.006) in comparison with MRD+ unconsolidated pts (n=9). In conclusion, consolidation/maintenance therapy with rituximab prolongs significantly the response duration in B-CLL, improving also the outcome of the “high risk” subset. Figure Figure

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Influence of Race and Nutritional Status on the Long Term Event Free Survival in Childhood Acute Lymphoblastic Leukemia (ALL): A 14-year Follow-up with a Reduced BFM-Based Treatment Protocol (GBTLI ALL-93)

Blood ◽

10.1182/blood.v112.11.13.13 ◽

2008 ◽

Vol 112 (11) ◽

pp. 13-13

Author(s):

Silvia Regina Brandalise ◽

Maria Pombo-de-Oliveira ◽

Vitoria Régia Pereira Pinheiro ◽

Maria Jose Mastellaro ◽

Waldir Veiga Pereira ◽

...

Keyword(s):

High Risk ◽

Complete Remission ◽

Nutritional Status ◽

Risk Group ◽

Treatment Protocol ◽

Low Risk ◽

Event Free Survival ◽

Free Survival ◽

All Treatment

Abstract Background: Different event-free survival rates (EFS) of childhood ALL treatment regarding race, were published in the literature. However, a better consensus exists considering the bad prognosis of undernutrition. Taking into account the social economic reality of a low-income country such as Brazil, the systematic evaluation of these variables is of utmost importance, while inserted in a modern ALL treatment protocol. Objective: To compare, prospectively, the long-term EFS rates of previously untreated children with ALL, according to race and nutritional status at diagnosis. Methods: Patients were classified as Low Risk and High Risk according to NCI Criteria. Treatment schedule: Low Risk group: Remission induction therapy with DEXA 6mg/m2/d × 28 days, VCR 1.5 mg/m2/wk × 4, Daunomycin 25 mg/m2/wk × 4, L-ASP 10.000 U/m2/dose × 8, Ara-C 75mg/m2/dose × 8 and TIT therapy (day 0,28 and 42). Intensification therapy with MTX 2g/m2/wk × 4, 24 h continuous infusion with LCV rescue 15mg/m2/dose × 4, 6MP-50mg/m2 d × 21days and TIT therapy (x 4). Re-induction therapy: Dexa 6mg/m2 d × 21days, VCR 1.5mg/m2/wk × 4, L-ASP 10.000 U/m2/d × 4, 6-MP 50mg/m2/d × 14days, Ara-C 75 mg/m2/d × 4 and TIT therapy (x3). Central randomization was done for maintenance therapy duration (130 vs 103 wk). Maintenance: 6-MP 50mg/m2/d, MTX 25mg/m2/wk and TIT therapy every 8 weeks during all treatment. No CNS radiation was done. For High Risk patients, an induction intensification with intermediate dose of AraC (750 mg/m2/d × 6) was introduced, as well as, a rotational maintenance therapy with different pair of drugs were proposed (AraC 750mg/m2 × 4/Asp 6 000 U; Dexa/VCR/wk × 3 and 6-MP 75 mg/m2/d × 21 days/MTX 40 mg/m2/wk × 3). Prophylatic CNS radiation(18Gy) was done at wks 19–21 of therapy. Statistical analysis: EFS is defined as the time from diagnosis till any failure, relapse, death, or the development of a second malignancy. Continuous complete remission duration (CCR) is defined as EFS, contingent upon induction of a complete remission. EFS and CCR rates have been estimated by Kaplan and Meier’s method. Results: From October 1993 to September 1999, 867 patients were consecutively enrolled in the protocol GBTLI ALL-93. Fourteen pts were excluded (1.5%), due to wrong diagnosis or previous corticosteroid treatment. 853 pts were evaluated in this study. 447 pts were classified as Low Risk group (52%) and 406(48%) as High Risk. According to race, 226 pts (26.5%)were classified as black and 627 (73.5%) as white. Overall undernutrition was diagnosed among 7.0 % of the patients. In the black population 10.4% were undernourished, comparing with 5.7% in the white group. The 14yrs-EFS for all the study patients is 80% ± 2% and 55% ± 2.5% for the Low Risk and High Risk pts, respectively. Concerning race, the 14yrs-EFS is of 71.7% ± 4.5% for the black children, comparatively to 83% ± 2.1% for the white ones (p=0.01). According to the nutritional status, the EFS is of 70.2%± 1.7% and 53.0%± 6.8% for the nourished and undernourished children, respectively. Malnutrition had the worst desfavorable impact among the High Risk pts, with a 14yrs-EFS of 40.1% ± 8.7%, compared to those without malnutrition of 57.8% ± 2.7% (p = 0.05). Social and economical issues directly involved with treatment, were provided by means of free medical attention and drugs supplies. Treatment abandon was < 1%. Conclusion: The black race and undernutrition had significant adverse effect on the long-term EFS among the patients of this study.

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Reduced Intensity Conditioning with Thiotepa and Fludarabine for Allogeneic Transplantation: Evidence for Low Toxicity and Long-Lasting Disease Control in MDS with Low/Intermediate-1 IPSS Score and in AML from MDS in Complete Remission.

Blood ◽

10.1182/blood.v112.11.3285.3285 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3285-3285

Author(s):

Emilio Paolo Alessandrino ◽

Luca Malcovati ◽

Giorgio La Nasa ◽

Paolo de Fabritiis ◽

Massimo Bernardi ◽

...

Keyword(s):

High Risk ◽

Complete Remission ◽

Cox Regression ◽

Risk Group ◽

Prognostic Score ◽

Conditioning Regimen ◽

Disease Status ◽

Risk Groups ◽

High Risk Group ◽

Valvular Stenosis

Abstract This study investigated Thiotepa (TT) and Fludarabine (Fluda) as a preparative regimen for allogeneic peripheral stem cell transplantation in patients with myelodysplastic syndrome (MDS) or acute leukemia from MDS (MDS-AML) older than 50 or with comorbidities contraindicating standard conditioning. Patients were prepared with TT, given over 3 hours as an i.v. infusion at a dose of 10 mg/kg over two days (day -8 and day -7) and Fluda at the dose of 125 mg/m2 i.v. over five days ( from day -7 to day -3). Fresh or cryopreserved allogeneic peripheral stem cells were infused on day 0 or +1. Graft-versus-Host Disease (GvHD) prophylaxis consisted of cyclosporine A (CyA) at the dose of 1.5 mg/kg day as a continuous iv infusion from day -5 until engraftment. The CyA was then administered orally at the dose of 3 mg/kg twice a day. Doses were adjusted to maintain plasma level concentrations between 150–350 mg/dL. From day +60, in the absence of acute GvHD, the CyA was tapered down by 20% every 2 weeks until withdrawal. In addition, patients received methotrexate 10 mg/m2 on day +1, and 8 mg/m2 on days + 3, +6 and +11 after transplantation. At the time of transplantation, patients were classified in two risk groups (low vs high risk) according to IPSS score (low/intermediate-1 vs. intermediate-2/high) for MDS patients, and disease status (CR vs. not CR) for MDS-AML. Kaplan-Meier survival analysis was carried out to compare Overall Survival (OS), Transplant-Related Mortality (TRM) and probability of relapse. Fifty patients (29 males, 21 females) entered the study; the median age was 54 years (range 38–71). Sixteen MDS patients had a low/intermediate 1 score according to the International Prognostic Score System (IPSS), 16 had an intermediate 2/high IPSS score, 18 had MDS-AML. Thirty patients underwent transplantation as front-line therapy, 20 received one or more cycles of chemotherapy before transplant. Among the latter, nine with MDS-AML were in complete remission at the time of their transplant, while four were in a partial remission. The interval from diagnosis to transplantation ranged from 1 to 52 months (median value 11 months). Contraindications to a standard conditioning regimen were liver disease, hypertrophic cardiomyopathy secondary to hypertension or valvular stenosis, cardiac arrhythmia, diabetes mellitus, hypothyroidism, previous CNS bleeding, and a history of sepsis. All but one patient achieved engraftment, with full donor chimerism by day +30. Patients were followed up for a median time of 21 months (range 0.2–87). TRM at 1 and 2 years after transplantation was 25% and 33%; the 5-year probability of relapse was 27%. Twenty-six patients are alive in complete remission, and the 5-year OS is 50%. The 5-year OS was 73% and 28% in low- and high-risk patients respectively (p=0.002). TRM at 1 and 2 years after transplantation was 13% and 21% in the low-risk group and 39% and 45% in the high-risk group (p=0.046); the 5-year probability of relapse was 10% and 50% in the low- and high-risk group respectively (p=0.015). In a multivariate Cox regression, risk group retained a borderline significance (HR=2.6, p=0.07) when adjusted by age at transplantation (p=0.03) and interval from diagnosis to transplant (n.s.). The combination of Thiotepa and Fludarabine is an effective and well-tolerated conditioning regimen in patients with MDS or MDS-AML who are poor candidates for standard myeloablative transplantation, particularly in MDS patients with low/intermediate-1 IPSS score and MDS-AML patients in CR.

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Sequential Treatment with Rituximab and CHOP Chemotherapy in B-Cell PTLD - Moving Forward to a First Standard of Care: Results From a Prospective International Multicenter Trial.

Blood ◽

10.1182/blood.v114.22.100.100 ◽

2009 ◽

Vol 114 (22) ◽

pp. 100-100 ◽

Cited By ~ 3

Author(s):

Ralf Trappe ◽

Sylvain Choquet ◽

Stephan H.K. Oertel ◽

Veronique Leblond ◽

Daan Dierickx ◽

...

Keyword(s):

High Risk ◽

Complete Remission ◽

Risk Stratification ◽

Disease Progression ◽

Early Treatment ◽

Interim Analysis ◽

Research Funding ◽

Low Risk ◽

Sequential Treatment ◽

Risk Patients

Abstract Abstract 100 Purpose: This trial aimed to investigate the efficacy and safety of sequential treatment with rituximab and CHOP-21 in patients with PTLD unresponsive to reduction of immunosuppression. Methods: An ongoing prospective, multicenter, international phase II trial was initiated in January 2003. Initially patients were treated with a fixed sequence of rituximab at days 1, 8, 15 and 22 (4R) followed by four cycles of CHOP-21 combined with G-CSF support starting 4 weeks after the last dose of rituximab (sequential treatment, ST). Based on the results of an earlier interim analysis showing that the response to rituximab predicts OS the trial was amended in 2007 introducing risk stratification according to the response to 4R (risk stratified sequential treatment, RSST). In RSST patients achieving a complete remission after 4R (low risk) continue with four 3-weekly courses of rituximab monotherapy while patients in PR, SD or PD (high risk) are followed by four cycles of R-CHOP-21 + G-CSF. Results: This is a scheduled interim analysis after inclusion of a total of 104 patients. The median follow up is 34.0 months for ST (64 pts.) and 9.1 months for RSST (40 pts.). 61 ST and 35 RSST patients were diagnosed with monomorphic PTLD, 3/5 with polymorphic PTLD. 27/23 patients were kidney, 3/0 kidney+pancreas, 15/8 liver, 13/6 heart, 6/3 lung or heart+lung transplant recipients. Median age at diagnosis of PTLD was 53/60 years (mean age: 48/56 years). 59%/58% of patients had an advanced stage of disease (Ann Arbor III/IV) and 49%/47% of tumors were EBV positive. 75%/75% of patients had late PTLD (i.e. later than 1 year after transplantation). LDH was elevated in 71%/64% of patients, respectively. The overall response rate (ORR) to 4 initial courses of rituximab monotherapy (4R, N=104) was 54% with a CR-rate of 32% and the subsequent completion of treatment with CHOP or R-CHOP allowed a clear increase of the response (p<0.0001, Fig. 1). With ST the final ORR was 89% (CR rate: 69%). 86%, 75% and 75% of patients were without disease progression at one, two and three years, respectively (Fig. 2a). Disease free survival was 87%, 78% and 70% at one, two and three years. There were 6 early treatment associated deaths (9%) resulting from infections (1 from CMV-colitis, 1 from PcP-pneumonia, 1 from fulminant hepatitis, 3 from sepsis) and 2/64 patients died from refractory PTLD. Two further patients died due to hemorrhage during treatment. With RSST the ORR was 90% and 73% achieved a complete remission. 90% of patients were without disease progression at one year (Fig. 2a). There was one early treatment related death due to infection (2.5%). This patient died from sepsis secondary to intestinal perforation in response to R-CHOP treatment. 2/40 patients died from refractory PTLD. With 1 event in 16 patients in both, the ST and the RSST-arms, subsequent consolidation with rituximab monotherapy (RSST) seems not to be inferior to consolidation with 4 cycles of CHOP (ST) in patients with a CR after 4R. Up to now there is no difference in toxicity between CHOP and R-CHOP in ST/RSST. Patients failing to achieve a complete remission with 4R (72 patients) seem to benefit from the subsequent escalation from CHOP to R-CHOP (Fig. 2b). Conclusions: This is the largest prospective study in PTLD. Sequential treatment with rituximab and CHOP-21 + G-CSF is well tolerated and highly effective with a treatment related mortality of less than 10% and an efficacy of up to 90%. In comparison to historic series of rituximab monotherapy, significantly more patients achieve a CR with sequential treatment and time to progression (TTP) is very much prolonged. In comparison to historic series of CHOP, sequential treatment is much better tolerated. This may result from a lower tumor burden and a better patient fitness at the time chemotherapy is applied. Introduction of risk stratification according to the response to 4 courses of rituximab monotherapy might further improve these results restricting chemotherapy related toxicity to high risk patients while these data suggest that low risk patients can effectively be treated with extended rituximab monotherapy. Thus, risk stratified sequential treatment (RSST) might further improve OS in this difficult to treat disease. Disclosures: Trappe: Hoffmann La Roche Ltd.: Consultancy, Honoraria, Research Funding; AMGEN GmbH: Research Funding. Choquet:Hoffmann La Roche Ltd.: Consultancy, Honoraria. Oertel:Hoffmann La Roche Ltd.: Employment, Equity Ownership. Leblond:Hoffmann La Roche Ltd.: Consultancy, Honoraria, Research Funding. Ekman:Hoffmann La Roche Ltd.: Honoraria. Dührsen:Hoffmann La Roche Ltd.: Honoraria, Research Funding. Salles:Hoffmann La Roche Ltd.: Consultancy, Honoraria, Research Funding. Morschhauser:Hoffmann La Roche Ltd.: Honoraria. Riess:Hoffmann La Roche Ltd.: Consultancy, Honoraria, Research Funding; AMGEN GmBH: Consultancy, Honoraria, Research Funding.

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A Phase III Study to Determine the Efficacy and Safety of Lenalidomide in Combination with Melphalan and Prednisone (MPR) in Elderly Patients with Newly Diagnosed Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.613.613 ◽

2009 ◽

Vol 114 (22) ◽

pp. 613-613 ◽

Cited By ~ 17

Author(s):

Antonio Palumbo ◽

Meletios A. Dimopoulos ◽

Michel Delforge ◽

Martin Kropff ◽

Robin Foa ◽

...

Keyword(s):

Multiple Myeloma ◽

Maintenance Therapy ◽

Board Of Directors ◽

Primary Endpoint ◽

Interim Analysis ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

Time To Progression ◽

First Line ◽

Advisory Committees

Abstract Abstract 613 Background: Lenalidomide (Revlimid®) is an oral immunomodulatory agent with clinical efficacy in patients with multiple myeloma (MM). In patients with relapsed/refractory MM, lenalidomide plus dexamethasone improved time to progression (TTP) and overall survival (OS) in comparison with dexamethasone alone. In newly diagnosed MM patients, the current study compares the efficacy and safety of melphalan, prednisone and lenalidomide (MPR) with that of MP alone. Methods: Key inclusion criteria were: ≥65 years of age, newly diagnosed and symptomatic MM. 459 patients were randomly assigned to receive MPR followed by lenalidomide maintenance therapy or MPR followed by placebo maintenance therapy or MP followed by placebo maintenance therapy (Figure 1). The study induction and maintenance phases were followed by an open label lenalidomide extension and a follow-up phase. All patients received aspirin 100 mg/day as thrombo-prophylaxis. The primary endpoint of the study is progression free survival (PFS). The secondary endpoints are OS, time-to-progression, response rate, time to response, response duration, time-to-next anti-myeloma therapy, safety, quality of life and exploratory assessment of cytogenetic abnormalities. Primary comparison is based on the intent-to-treat population comparing PFS between MPR followed by lenalidomide with MP followed by placebo; secondary comparisons are between MPR followed by lenalidomide and MPR followed by placebo, and between MPR followed by placebo and MP followed by placebo. Results: The first patient was enrolled in February 2007. A pre-planned interim analysis to evaluate the efficacy and safety was performed at 50% information. An independent central adjudication committee determined the assessment and timing of progressive disease prior to the interim analysis. At the interim analysis, it was determined by the Data Monitoring Committee (DMC) that the study had crossed the O'Brien Fleming superiority boundary for the primary endpoint, demonstrating a highly statistically significant improvement in PFS for patients treated with MPR compared with MP as first-line treatment for MM patients. The topline results will be availabel at the time of the meeting. Conclusions: MPR is an effective and safe regimen for front-line use in MM. PFS was significantly improved in patients who received MPR followed by lenalidomide maintenance compared with those who received MP followed by placebo maintenance. MPR followed by lenalidomide maintenance is a new therapeutic option and can be considered a new standard for patients older than 65 years old. Disclosures: Palumbo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide is not approved for first line use in multiple myeloma. Dimopoulos:Celgene: Honoraria. Delforge:Janssen-Cilag: Consultancy, Honoraria; Celgene: Honoraria, Speakers Bureau. Kropff:Ortho Biotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Foa:Celgene: Membership on an entity's Board of Directors or advisory committees. Yu:Celgene: Employment. Herbein:Celgene: Employment. Mei:Celgene: Employment. Jacques:Celgene: Employment. Catalano:Celgene: Research Funding.

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Final Analysis of Induction Treatment with Fludarabine, Cyclophosphamide Plus Rituximab (FCR) Followed by Fludarabine Plus Rituximab (FR) and Remission Maintenance Therapy with Rituximab In Previously Untreated B-Chronic Lymphocytic Leukemia (B-CLL): The Chairos AGMT CLL4/Roche ML18434 Study

Blood ◽

10.1182/blood.v116.21.1380.1380 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1380-1380

Author(s):

Alexander Egle ◽

Lukas Weiss ◽

Thomas Melchardt ◽

Eberhard Gunsilius ◽

Andreas L Petzer ◽

...

Keyword(s):

Maintenance Therapy ◽

Research Funding ◽

Maintenance Treatment ◽

Response Assessment ◽

Response To Therapy ◽

Clinical Staging ◽

Induction Treatment ◽

Rituximab Maintenance ◽

Best Response ◽

Remission Maintenance

Abstract Abstract 1380 Introduction: Intensification of treatment in CLL, specifically with FCR, has yielded impressive remission rates across almost all risk groups, with the exception of disease with del17p. However, despite initial remission patients relapsed with a median PFS time of 51.8 months in the CLL8 German randomized FCR trial, making remission maintenance an interesting concept. Study design: Three cycles of FCR, used initially to break potential resistance, were followed by 3 cycles of FR, with the intent to limit toxicities. Maintenance treatment was rituximab 375mg/m2 in 3 monthly intervals for 2 years. Here we report final results from this phase II study in previously untreated patients with CLL. Primary objective was the analysis of CR rates, according to NCI-WG criteria. An interim analysis of the induction phase of the study had been presented at ASH 2007. Results: We present 43 patients as intention-to-treat (ITT) population. The median age was 60 years (36 to 81), Rai stages III and IV were present in 21%, median β2-MG levels were 3.35 mg/L and 60% had at least one high risk factor out of mutation state, CD38 or FISH. Median follow up is currently 32 months. All ITT patients are evaluable for toxicity and 33 patients are evaluable for response after induction. 10 patients failed to reach the staging after the end of induction: 4 for septicemia/neutropenia, 1 for rituximab intolerance, 2 for hemolysis and 3 due to unrelated adverse events. The currently presented response assessment includes stringent use of CT scan results and is thus corrected from the 2007 interim results, obtained using clinical staging only. The response rates at the end of induction treatment were 27% CR, 36% CRi, 6% CRu, 21% PR and 9% SD. The previously reported high rate of CRi with incomplete marrow recovery argues that following FCR by FR did not improve tolerability. Nevertheless 81% of ITT patients were able to receive 6 cycles of therapy. Overall response and toxicity results are comparable with previously presented large datasets on FCR. A completely novel experience, however, is presented regarding the rituximab maintenance phase. Of the 43 ITT patients, 31 (72%) received at least one dose of maintenance treatment (the maintenance population). Regarding the maintenance population 74% finished all 8 cycles. Reasons to stop maintenance were: infections in 13% (all of them grade 1 and 2, although one patient died from herpetic encephalitis, 4 months after maintenance treatment had been stopped for a grade 2 infection), leucopenia 3%, progressive disease in 3 % and patient wish in 6%. Surprisingly, only a maximal 10% drop in serum IgG or IgM levels was observed during 2 years of maintenance. Regarding response assessment 5/31 (16%) patients receiving maintenance treatment improved their responses and 7/7 patients in CRi after induction resolved their cytopenias during maintenance treatment. Progression-free survival (PFS) in the ITT population was 78% after 36 months and was not significantly influenced by age >60, mutation state, β2-MG > 3,5 mg/L, creatinine clearance <60ml/min or permitted comorbidities. However, positive DAT and best response to therapy as well as an early drop in measured MRD levels predicted PFS. Two patients with del17p had expected inferior PFS, while none of the 5 patients with del11q has relapsed yet. Considering only the maintenance population, the PFS at 36 months was 77% and an overall best response of CR/CRu during maintenance led to a PFS of 91% after 36 months. Conclusion: Induction with an FCR like-induction protocol followed by rituximab maintenance proved feasible. However, 28% of the ITT population did not start maintenance treatment and 18% (ITT) could not finish the maintenance treatment, although no severe toxicities were responsible for the latter. One toxic death was observed, which is in the range reported for FCR without maintenance. Noteworthy, we did not find an influence of mutation state or β2-MG on PFS as has been previously reported, making it interesting to speculate that maintenance may be able to overcome such risk factors at least in mid-term, while keeping in mind the limited size of our sample. We currently run a multi-national randomized trial comparing rituximab maintenance with observation after R-containing induction in 1st and 2nd line that may be able to more definitely answer these questions (NCT01118234). Disclosures: Egle: Roche: Honoraria, Research Funding, Speakers Bureau. Off Label Use: Rituximab maintenance therapy in CLL. Petzer:Roche: Honoraria. Fridrik:Roche: Honoraria, Speakers Bureau. Greil:Roche: Honoraria, Research Funding, Speakers Bureau.

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