Response to Front-Line Imatinib Treatment in Children and Adolescents with CML - Data from a Large Pediatric Cohort

Abstract Purpose Results of the prospective trial "CML-PAED-II" assessing treatment efficacy and side effects in children and adolescents with newly diagnosed chronic myeloid leukemia (CML) are reported. Patients and Methods 156 patients (age range 1.3-18.0 years, 91 male) with newly diagnosed CML (N= 146 chronic phase (CML-CP), N= 3 accelerated phase (CML-AP), N= 7 blastic phase (CML-BP)) received imatinib upfront (300 mg/m², 400 mg/m², 500 mg/m², respectively). Therapy response, progression-free survival, causes of treatment failure and proportion of patients undergoing stem cell transplantation were analyzed in 148 patients with complete data. Results Event-free survival rate at 18 months for pediatric patients diagnosed in CML-CP (median follow-up time 25 months, range: 0.1-120) was 97% (95% CI, 94.2%-99.9%). According to the 2006 ELN-criteria complete hematologic response at month 3, complete cytogenetic response (CCyR) at month 12, and molecular response (MR3.0) at month 18 were achieved in 98%, in 63%, and 59% of the patients, respectively. At month 36 on continuous first line imatinib or 2nd generation tyrosine kinase inhibitor treatment, 86% of the patients achieved CCyR and 74% achieved MR3.0. 66% of the patients experienced at least one side effect. Imatinib-related anemia was the most frequent toxicity observed if all grades were considered (N=98; 66%) while neutropenia was the most frequently reported grade 3/4 hematologic adverse effect (N=22; 15%). Among non-hematologic toxicities, all grades of gastrointestinal toxicity were observed most frequently (N=57, 38%), however, it occurred at lower grades 1/2 in all but one patient. Higher grade 3/4 musculoskeletal pain was also frequent (N=53, 36%). Twenty-seven patients (18%) had to discontinue treatment temporarily while nine patients permanently terminated imatinib due to non-tolerable side effects (neutropenia N= 4, muscle cramps N= 3, skin N= 1, liver N= 1). Thirty-eight patients (27%) experienced imatinib failure because of unsatisfactory response (N= 27) or intolerance (N= 9). 28/148 patients (19%) underwent stem cell transplantation (SCT). In the SCT sub-cohort 2/23 patients diagnosed in CML-CP, 0/1 in CML-AP, and 2/4 in CML-BP, respectively, died of relapse (N=3) or SCT-related complications (N=2). Conclusion This large pediatric trial provides evidence confirming that first line imatinib in children is highly effective. Observed adverse effects are acceptable and mainly comprise hematological side effects. Long term outcome and effects of a potentially life-long TKI treatment have to be registered in cooperation with adult hematologists in extended surveillance follow-up studies. Disclosures Suttorp: Novartis: Research Funding. Schrappe: JAZZ Pharma: Consultancy, Research Funding; Baxalta: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; SigmaTau: Consultancy, Research Funding; Medac: Consultancy, Research Funding. Thiede: Novartis: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Roche: Consultancy; Agendix: Employment.

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Frontline Therapy with Bortezomib, Lenalidomide, and Dexamethasone (VRD) Induction Followed by Autologous Stem Cell Transplantation, VRD Consolidation and Lenalidomide Maintenance In Newly Diagnosed Multiple Myeloma Patients: Primary Results of the IFM 2008 Phase II Study

Blood ◽

10.1182/blood.v116.21.624.624 ◽

2010 ◽

Vol 116 (21) ◽

pp. 624-624 ◽

Cited By ~ 10

Author(s):

Murielle Roussel ◽

Hervé Avet-Loiseau ◽

Philippe Moreau ◽

Anne Huynh ◽

Lotfi Benboubker ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Autologous Stem Cell Transplantation ◽

Research Funding ◽

Response Rate ◽

Phase Ii Study ◽

Newly Diagnosed ◽

Grade 3 ◽

Stem Cell Collection

Abstract Abstract 624 Background: Autologous Stem Cell Transplantation (ASCT) is a standard of care for eligible MM patients (pts). Introduction of new drugs in this setting have markedly increased survival rates within the last 10 years. Efforts to further improve response and survival in those pts are still needed, mainly by increasing the depth of tumor reduction and the duration of response through more effective induction, consolidation and maintenance therapies. Therefore, the IFM (Intergroupe Francophone du Myélome) decided to evaluate the Bortezomib (Bor), Lenalidomide (Len) and Dexamethasone (Dex) regimen as induction and consolidation therapy followed by Len maintenance in the transplant setting for newly diagnosed pts. Methods: This open-label phase II study was conducted at 10 IFM transplant centers, with enrollment between September and December 2009. Pts under 65 with symptomatic de novo MM were enrolled to receive three 21-day induction cycles of VRD= Bor 1.3 mg/m2 (days 1, 4, 8, 11), Len 25 mg (days 1–14), and oral Dex 40 mg (days 1, 8 and 14). Stem cell collection was planned for all pts after high dose cyclophosphamide (3g/m2). All pts then proceeded to intensification prepared with melphalan 200 mg/m2 followed by ASCT. Two months after hematological recovery, pts could receive two 21-day consolidation cycles of VRD (same schedule) followed by 1 year of maintenance with Len at 10–15 mg/day. All patients received, unless contraindicated, aspirin prophylaxis or alternative anticoagulation for prevention of deep-vein thrombosis (DVT), anti-viral therapy (valacyclovir) for herpes zoster prevention. Pts with ≥ grade 2 peripheral neuropathy (PNY) were excluded. The primary endpoint was the best response achieved 1 month after consolidation. The secondary endpoints were the response rate after 3 cycles of VRD, after ASCT and after consolidation; the safety profile of the program, the feasibility and quality of stem cell collection and dthe uration of response (DOR), PFS, OS. Response was assessed according to International Uniform Response Criteria including stringent Complete Response (sCR). Flow cytometric analysis of bone marrow plasma cells was performed before and after ASCT, and after consolidation. Toxicities were graded using the CTCAEv4. Patients: Thirty-one pts with symptomatic MM were enrolled. Baseline characteristics of the pts were: median age = 58 (range 33–65); 55% were women; 55%/32%/13% had IgG/IgA/light chain MM; ISS= 1 in 52%, 2 in 32% and 3 in 16% of pts; chromosome 13q deletion in 41% over 27 assessable pts; chromosome 17p del in 18% and t(4;14) translocation in 11%. Results: All pts but one remain on study program at data cut-off (01/08/10). The one pt had discontinued treatment at time of ASCT due to mobilization failure. Therefore, 31 pts are evaluable for response rates after induction therapy, 30 after ASCT and 13 after consolidation. All results are summarized in table 1. In Intent To Treat analysis, the overall response rate (ORR) after ASCT was 94%, including 32% VGPR, 13% CR and 23% sCR. Nine serious AEs were reported. There was no treatment-related mortality. The most common toxicities were: sensory PNY (45%), including 29% grade 1 and 16% grade 2; neuropathic pain (13%); GI tract symptoms (42%) including diarrhea (16%) and constipation (10%); fatigue (10%) and erythrodermia (9%). There was no grade 3/4 PNY. Grade 3/4 hematological toxicities included neutropenia (26%), and thrombocytopenia (6%). No DVT or pulmonary embolism was reported.Six of 31 pts (19%) have had difficulty with mobilization but only 1 pt did not undergo ASCT. Stem cell collection with plerixafor was successful in 4 pts. Median stem cell collection was 7.7 × 106 CD34+ cells/kg. Conclusions: VRD induction followed by ASCT and VRD consolidation produce high quality responses and is well tolerated in newly diagnosed MM pts under 65. Updated efficacy and safety data will be presented at the meeting. Disclosures: Roussel: Janssen: Consultancy, Research Funding, orator; Celgene: Consultancy, Orator, Research Funding. Off Label Use: bortezomib, lenalidomide as induction and consolidation therapies in frontline MM pts. Leleu:Celgene: Consultancy, Research Funding; Janssen Cilag: Consultancy, Research Funding; Leo Pharma: Consultancy; Amgen: Consultancy; Chugai: Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Attal:celgene: Consultancy, Research Funding; johnson and johnson: Consultancy, Research Funding.

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A Phase III Study Of ASCT Vs Cyclophosphamide-Lenalidomide-Dexamethasone and Lenalidomide-Prednisone Maintenance Vs Lenalidomide Alone In Newly Diagnosed Myeloma Patients

Blood ◽

10.1182/blood.v122.21.763.763 ◽

2013 ◽

Vol 122 (21) ◽

pp. 763-763 ◽

Cited By ~ 16

Author(s):

Antonio Palumbo ◽

Francesca Gay ◽

Andrew Spencer ◽

Francesco Di Raimondo ◽

Adam Zdenek ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Phase Iii ◽

Study Endpoint ◽

Newly Diagnosed ◽

Advisory Committees ◽

Grade 3 ◽

To Receive

Abstract Background High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). The introduction of novel agents challenged the role of ASCT at diagnosis. We conducted a multicenter 2X2 randomized trial comparing conventional chemotherapy plus lenalidomide with ASCT followed by maintenance with lenalidomide-prednisone (RP) or lenalidomide (R) alone in newly diagnosed young MM (NDMM) patients. Methods Eligible patients with NDMM ≤ 65 years were enrolled. All patients received Rd induction (four 28-day cycles of lenalidomide 25 mg day 1–21 and low-dose dexamethasone 40 mg day 1,8,15,22) followed by stem cell mobilization. Patients were randomized to receive consolidation with CRD [six 28-day cycles of cyclophosphamide (300 mg/m2 day 1,8,15), dexamethasone (40 mg days 1,8,15,22) and lenalidomide (25 mg days 1–21)] or MEL200-ASCT (melphalan 200 mg/m2 with stem-cell support). Patients were randomly assigned to receive subsequent maintenance with RP (28-day cycles of lenalidomide 25 mg days 1–21 plus prednisone 50 mg every other day) or R alone (28-day cycles of lenalidomide 25 mg days 1–21). Primary study endpoint was progression-free survival (PFS); secondary endpoints included safety, responses and overall survival (OS). Data cut off was May 30th, 2013. Results Three-hundred and eighty-nine patients were enrolled in the trial. Patient characteristics were well balanced between CRD (n=194) and MEL200-ASCT (n=195), and between R (n=195) and RP (n=194) arms. Median follow-up was 31 months. In the intent to treat (ITT) analysis, the median PFS was not reached with MEL200-ASCT and 28 months with CRD (the respective 3-year PFS was 60% vs. 38%, HR=0.62, 95%CI: 0.49-0.85, P=0.003). Median time from enrolment to maintenance was 14 months. In the population of patients eligible for maintenance, 2-year PFS from the start of maintenance was 73% for RP and 56% for R patients (HR= 0.57, 95%CI: 0.34-0.93; P=0.03). In the subgroup of patients who received MEL200-ASCT, 2-year PFS from the start of maintenance was 83% for patients who received RP and 64% for those who received R alone (HR=0.36 95%CI: 0.15-0.87, P=0.02). In the subgroup of patients who received CRD, 2-year PFS from the start of maintenance was 64% for patients who received RP and 47% for those who received R alone (HR=0.75, 95%CI: 0.40-1.39, P=0.36). At present, no differences in OS were noticed between patients randomised to received CRD or MEL200-ASCT, and between patients who received RP or R maintenance. As expected, the rates of grade 3-4 hematologic (85% vs. 26%, P<0.001) and non-hematologic (35% vs. 19%, P=0.003) adverse events (AEs) were higher in the MEL200-ASCT arm compared with the CRD arm. The main non-hematologic AEs were infections (18% vs. 5%, P=0.001) and gastrointestinal AEs (18% vs. 3%, P<0.001). Rates of grade 3-4 hematologic (8% vs. 7%, P=0.85) and non-hematologic (12% vs. 13%, P=0.88). AEs were similar in the RP and R arms. The main non-hematologic AEs in both RP and R groups were infections (3% vs. 3%). At present, 6 second primary malignancies and 3 cases of cutaneous basalioma have been reported. Conclusions MEL200-ASCT significantly prolonged PFS in comparison with CRD. At present no difference in OS was reported, this may be due to the low number of events and to the length of follow-up. The increase in toxicity with MEL200-ASCT did not adversely impact on efficacy. The addition of prednisone to lenalidomide maintenance significantly reduced the risk of progression in comparison with lenalidomide alone, without increasing the toxicity. Updated data with longer follow-up will be presented at the meeting. Disclosures: Palumbo: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Gay:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Spencer:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Larocca:Celgene: Honoraria. Caravita:Celgene: Honoraria, Research Funding. Petrucci:Celgene: Honoraria. Hajek:Celgene: Honoraria; Celgene: Consultancy. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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Bortezomib Maintenance Therapy after Induction with R-CHOP, ARA-C and Autologous Stem Cell Transplantation in Newly Diagnosed MCL Patients, Results of a Multicenter Phase II HOVON Study

Blood ◽

10.1182/blood.v126.23.339.339 ◽

2015 ◽

Vol 126 (23) ◽

pp. 339-339 ◽

Cited By ~ 14

Author(s):

Jeanette K Doorduijn ◽

Monique C. Minnema ◽

Marie Jose Kersten ◽

Pieternella J Lugtenburg ◽

Martin R. Schipperus ◽

...

Keyword(s):

Stem Cell ◽

Maintenance Therapy ◽

Phase Ii ◽

Research Funding ◽

Progressive Disease ◽

Induction Treatment ◽

High Dose ◽

Newly Diagnosed ◽

Grade 3

Abstract Introduction. The standard first-line treatment of young and fit mantle cell lymphoma (MCL) patients consists of a rituximab containing induction of CHOP and high dose ARA-C, followed by high dose consolidation and autologous stem cell transplant (ASCT). Thus far, almost all patients relapse after ASCT. Bortezomib is a proteasome inhibitor with activity in MCL. We investigated in a randomized phase II study whether there was any indication that maintenance therapy with bortezomib after ASCT could improve the outcome of treatment, measured as event free survival (EFS). Methods. Patients 18-65 years with newly diagnosed MCL were treated with 3 cycles of R-CHOP and 2 cycles of ARA-C (2 x 2 g/m2 iv d1-4) and rituximab (375 mg/m2, iv d11). Patients in PR or CR continued with ASCT after BEAM conditioning. Patients with a PR or CR after ASCT, with a neutrophil count > 0.5 x 109/l and platelets > 80 x 109/l were randomized between bortezomib and no further treatment. Bortezomib 1.3 mg/m2 iv was given once every two weeks, for 2 years, starting between 6 - 12 weeks after transplantation. Results . Between October 2007 and February 2012, 140 patients aged 34-66 years (median 57) were registered. Five patients were not eligible. The MIPI score was low, intermediate, high or unknown in 57%, 32%, 10% and 1% respectively. All eligible patients started induction treatment with R-CHOP. Two patients did not receive the first ARA-C cycle, because of progressive disease and physician decision. Hundred-fifteen patients (85%) received the BEAM and ASCT. Reasons to stop protocol treatment before ASCT were: progressive disease (PD) (n=6), inadequate stem cell harvest (n=3), excessive toxicity (n=3), other reasons (n=8). The response after ASCT was CR/CRu in 99 patients (86%), PR in 15 (13%), unknown in 1 (1%). Only 62 patients (45%), aged 34-65 years (median 56) were randomized between bortezomib maintenance and no further treatment. Two patients were randomized, but not eligible. Reasons for no randomization were: not eligible (n=30), patient refusal (n=14), excessive toxicity (n=2, and other reasons (n=7). In each treatment arm 30 patients were included. The patient characteristics were well balanced, except the MIPI score. In the no maintenance arm 21 patients (70%) had a low MIPI, compared to 15 patients (50%) in the bortezomib arm, and 6 (20%) versus 11 (37%) patients had an intermediate MIPI score. In both arms 3 patients (10%) had a high MIPI. Fifteen patients (50%) in the maintenance group continued bortezomib for 2 years. Reasons to stop earlier were excessive toxicity (n=6), PD/relapse (n=4), patients refusal (n=3) and other (n=2). The main adverse events during maintenance therapy were neurologic (CTC grade 2: 14%, grade 3: 4%), and infectious (grade 2: 11%, grade 3: 7%). Three patients developed a secondary malignancy: a basal cell carcinoma in the no maintenance group, a melanoma and a prostate carcinoma in the bortezomib group. With a median follow-up of the patients still alive of 50.9 months EFS at 4 years for all patients is 61%, and the overall survival (OS) 78%. The median follow-up of the randomized patients still alive is 42.9 months. The EFS at 4 years is 72% without maintenance versus 71% in the patients randomized for bortezomib maintenance. The OS at 4 years also shows no significant difference between the groups, 90% versus 93% respectively. Conclusion. There is no indication that bortezomib iv maintenance in a frequency of once every 2 weeks does improve the EFS of newly diagnosed MCL patients after intensive induction treatment with R-CHOP, double ARA-C and BEAM followed by ASCT. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Doorduijn: Celgene: Consultancy; Janssen: Consultancy; Roche: Consultancy. Off Label Use: bortezomib maintenance in MCL. Minnema:Celgene: Consultancy; Jansen Cilag: Consultancy; Amgen: Consultancy. Kersten:janssen: Honoraria, Research Funding; takeda millennium: Research Funding; roche: Honoraria, Research Funding. Lugtenburg:Mundipharma: Consultancy; Servier: Consultancy; Janssen-Cilag: Consultancy; Celgene: Consultancy; Roche: Consultancy. Schipperus:Novartis: Consultancy. Zijlstra:Celgene: Consultancy; Roche: Consultancy.

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Bortezomib-Based First Line Treatment for AL Amyloidosis Patients Who Are Not Candidate for Stem Cell Transplantaion

Blood ◽

10.1182/blood-2018-99-114099 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3256-3256

Author(s):

Joon Young Hur ◽

Kang Kook Lee ◽

Sang Eun Yoon ◽

Sehhoon Park ◽

Jangho Cho ◽

...

Keyword(s):

Stem Cell ◽

Research Funding ◽

The Body ◽

Autonomic Nerve ◽

Al Amyloidosis ◽

Line Treatment ◽

Newly Diagnosed ◽

First Line ◽

First Line Treatment

Abstract Introduction Systemic AL amyloidosis is characterised by deposition of misfolded immunoglobulin light chains within organs. Treatment for amyloidosis is generally derived from that for multiple myeloma (MM). Combinations of immunomodulatory drugs and proteasome inhibitors are standard frontline MM therapy, but there is little experience with such regimens in AL. For patients not receiving autologous stem cell transplantation (ASCT), bortezomib-based regimens have been first-line treatment in AL amyloidosis over the last few years. The purpose of this study is to investigate the efficacy of bortezomib-based regimens for patients with newly diagnosed AL amyloidosis Methods We performed a retrospective study of all newly diagnosed patients with AL amyloidosis treated at our center between 4/1/11 and 12/31/17. Data pertaining to demographics, diagnosis, treatment and follow-up were extracted from electronic medical records. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test. All statistical analyses were performed by using the SPSS 24.0 software. Time to progression (TTP) is defined as time from the date of diagnosis or the start of treatment for a disease until the disease starts to get worse or spread to other parts of the body. The primary endpoint was overall response rate and secondary endpoints were overall survival (OS) and TTP. Results A total 63 patients with newly diagnosed AL amyloidosis who did not receive ASCT were analyzed. Clinical characteristics are shown in Table 1. They included 32 men and 31 women with a median age of 66 years (range, 42-82). Autonomic nerve, Cardiac, peripheral nerve, renal, soft tissue, and liver involvement were found in 46 (73%), 41 (65.1%), 23 (36.5%), 20 (31.7%), 16 (25.4%), 4(6.4%), respectively. The Mayo 2012 stage was: Stage 2 3.8%, Stage 3 30.8% and stage 4 65.4%. Hematological responses were: complete response (CR) 33.3 %, VGPR 19.0%, partial response (PR) 12.6% and no-response (NR) 17.4%. Organ response was 26.9% (n=17). With a median follow-up of 34 months, median OS was 40 months (95% CI 30-50) (Figure 1A) and median TTP was 27 months (95% CI 18-36) (Figure 1B). The rate of early death within 6 months was 28.5% (n=18). Patients were classified according to first-line treatment; bortezomib-based regimens (VMP, n=37; VD (bortezomib and dexamethasone), n=9; VCD, n=8; VMD, n=8; VTD (bortezomib with thalidomide and dexamethasone, n=1). Hematological responses of VMP, VD, VCD, VMD, and VTD were: 75.6%, 55.5%, 50.0%, 50.0%, 100%, respectively. Organ responses of VMP, VD, and VMD were: 35.1%, 22.2%, 25.0%, respectively. Conclusions In this retrospective analysis, bortezomib-based regimens in newly diagnosed AL amyloidosis showed results that appear comparable to those seen at other centers. These findings therefore continue to support the emerging roles for bortezomib-based regimens for the purposes of improving response. Larger scale analyses in multi-center trials would be beneficial to further study these roles. Disclosures Kim: Kyowa-Kirin: Research Funding; Roche: Research Funding; Mundipharma: Research Funding; Novartis: Research Funding; Celltrion: Research Funding; J&J: Research Funding; Takeda: Research Funding.

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Upfront Autologous Stem Cell Transplantation for Newly Diagnosed Elderly Multiple Myeloma (MM) Patients: A Prospective Multicenter Study

Blood ◽

10.1182/blood.v126.23.1989.1989 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1989-1989

Author(s):

Laurent Garderet ◽

Cyrille Touzeau ◽

Anne-Marie Stoppa ◽

Denis Caillot ◽

Lionel Karlin ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Median Time ◽

Autologous Stem Cell Transplantation ◽

Research Funding ◽

Newly Diagnosed ◽

Advisory Committees

Abstract Introduction: Previous trials have shown that autologous stem cell transplantation (ASCT) is superior to conventional chemotherapy in terms of remission rate and PFS in younger MM patients. Concerns about toxicity and potential efficacy of ASCT in older MM patients lead most centers to limit ASCT indications to patients aged <65 years. However, at the era of novel induction regimens, and because of better patient selection and supportive care, ASCT may prove to be a valid treatment option even in older MM patients. Therefore, some investigators are questioning the widely used 65 years age limit. Patients and Methods: We prospectively analyzed the outcomes of 56 consecutive MM patients who had received ASCT between September 2012 and September 2014 in 6 institutions in France (protocol ClinicalTrials.gov Identifier: NCT01671826). Patients were newly diagnosed MM. For induction therapy, all patients received a bortezomib-based induction regimen (VD, VTD, VCD, or VRD, 4 to 6 cycles) according to center's local guidelines. Mobilization was performed with G-CSF or G-CSF+cyclophosphamide and plerixafor whenever needed. High-dose chemotherapy consisted of either 140 mg/m2 or 200 mg/m2 Melphalan. A short two months consolidation phase post ASCT was allowed (lenalidomide-dexamethasone, VD, VTD, VCD or VRD). No maintenance treatment was given. Response, disease progression and relapse were defined according to the IMWG uniform response criteria. All patients signed an informed consent form according to the EBMT guidelines. Results: At time of diagnosis, median age was 67 (range, 64-74) years with 23% of patients being >70 years. There were 30 males and 26 females. The immunoglobulin subtype was IgG (n=29), IgA (n=15), light chain (n=10), other (n=2). The Salmon and Durie stage was III in 89% of cases (n=47), and the ISS score was I (n=18; 35%), II (n=19; 37%), III (n=14; 27%). Patients had high risk cytogenetics features (t(4;14) and/or del17p) in 9 cases (16%). 10% of patients had a serum creatinine level >176 micromol/L. None of the patients underwent hemodialysis. The Sorror comorbidity score was 0 (34), 1 (6), 2 (2), 3 (6), 6 (1), unknown (7). The median age at time of ASCT was 68 years, and the median time from diagnosis to ASCT was 5 months. In an intention to treat analysis, out of 56 patients, 6 patients could not proceed to ASCT because of an early infectious death (n=1), serious comorbidity (n=2), disease refractoriness to induction (n=1), and failure to collect an adequate PBSC graft (n=2). A median of 5.31x106/Kg CD34+ cells could be collected. Disease status at time of ASCT was: CR (n=12; 24%), VGPR (n=19; 38%), PR (n=17; 34%), and SD/non-responding (n=2; 4%). The conditioning regimen consisted of 140mg/m² melphalan in 18 cases (36%) and 200mg/m2 in 32 patients (64%). Moreover, 4 patients (8%) received a tandem ASCT. The median time for neutrophils and platelets engraftment was 12 days. The day-100 post ASCT non-relapse mortality was 0% and the 2-year NRM was 4.2% (95% CI:[0.3-18.3]). The overall response rate at day 100 was 96% (CR: 34%, VGPR: 47%, PR: 15%, SD/non-responsive: 4%). At 3 months post ASCT, 82% patients were able to receive the planned post ASCT consolidation treatment. After a median follow-up of 12 months, the estimated progression-free (PFS) and overall survival (OS) rates at 2 years were 76% (95%CI: [61.6-94.1]) and 88% (95%CI: [76.7-100]), respectively. The incidences of infectious complications post ASCT, and response rates were comparable between the two melphalan dose levels (p=0.28). However, in the univariate analysis, the 200 mg/m2 melphalan conditioning group showed a better OS rate compared to the 140 mg/m2 group (1-year OS: 100% vs. 67%; p=0.012). Conclusion: These prospective multicenter results indicate that ASCT is a safe and effective treatment modality for elderly, but fit MM patients at the era of novel induction agents. Of note, patients above age 70 did not experience a worse prognosis. Thus, age per se should not be used as an exclusion criterion for ASCT. Longer follow-up data will be presented, but these results already set the frame for a randomized comparison to the non-transplant approaches in this patients' subgroup. Disclosures Garderet: Bristol-Myers Squibb: Consultancy. Touzeau:AbbVie: Research Funding. Stoppa:Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria. Karlin:Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau:Celgene, Janssen, Takeda, Novartis, Amgen: Membership on an entity's Board of Directors or advisory committees.

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The effect of first-line imatinib interim therapy on the outcome of allogeneic stem cell transplantation in adults with newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia

Blood ◽

10.1182/blood-2004-09-3785 ◽

2005 ◽

Vol 105 (9) ◽

pp. 3449-3457 ◽

Cited By ~ 145

Author(s):

Seok Lee ◽

Yoo-Jin Kim ◽

Chang-Ki Min ◽

Hee-Je Kim ◽

Ki-Sung Eom ◽

...

Keyword(s):

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Newly Diagnosed ◽

First Line

AbstractPreviously, we suggested that imatinib incorporation into conventional chemotherapy as an alternative (imatinib interim therapy) might be a useful strategy for bridging the time to allogeneic stem cell transplantation (SCT) for newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL). Here, we provide an updated report on this strategy in 29 patients. At the time of enrollment, 23 patients (79.3%) achieved complete remission (CR). After the first imatinib cycle, the median breakpoint cluster region–Abelson oncogene locus (BCR-ABL)/ABL ratios decreased by 0.77 log in 25 (86.2%) responders, and their BCR-ABL/ABL ratios decreased further by 0.34 log after the second imatinib cycle, which included 7 molecular CR. One patient (4.3%) relapsed during the imatinib therapy. The remaining 3 patients were primarily refractory to both imatinib and chemotherapy. Twenty-five (86.2%) of the 29 patients received transplants in first CR. With a median follow-up duration of 25 months after SCT, the 3-year estimated probabilities of relapse, nonrelapse mortality, disease-free survival, and overall survival were 3.8%, 18.7%, 78.1%, and 78.1%, respectively. In comparison to our historical control data, first-line imatinib interim therapy appears to provide a good quality of CR and a survival advantage for patients with Ph+ ALL. Further long-term follow-up is needed to validate the results of this study.

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Myelodysplastic Syndromes with NPM1 Mutations May Constitute a Unique Entity Associated with Improved Outcomes When Treated with AML-like Chemotherapy

Blood ◽

10.1182/blood.v128.22.3171.3171 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3171-3171 ◽

Cited By ~ 2

Author(s):

Guillermo Montalban-Bravo ◽

Ana Alfonso Pierola ◽

Koichi Takahashi ◽

Elias J. Jabbour ◽

Tapan M. Kadia ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Myelodysplastic Syndromes ◽

Research Funding ◽

Normal Karyotype ◽

Complete Response ◽

Hypomethylating Agents ◽

Free Survival ◽

Improved Outcomes

Abstract INTRODUCTION: Frequency of NPM1 mutations in patients with myelodysplastic syndromes (MDS) is <1%. Patients with acute myeloid leukemia and NPM1 mutations have favorable outcomes and high complete response (CR) rate with chemotherapy. In this study we analyzed the characteristics and clinical outcomes of patients with MDS and NPM1 mutations. METHODS: We analyzed the clinical characteristics of all patients with MDS and NPM1mut treated at MD Anderson Cancer Center from 2009 until 2016. Detection of exon 12 NPM1 mutations (W288fs*12) was performed by Sanger sequencing from 2009 until 2012 and by a 28 or 53 gene panel PCR-based next generation sequencing platform from 2012 to 2016. All clinical and demographic characteristics were obtained from clinical records. Response was defined following 2006 IWG criteria. The Kaplan-Meir product limit method was used to estimate the median overall survival (OS) and leukemia-free survival (LFS). Univariate Cox proportional hazards were used to identify association between variables and outcomes. RESULTS: A total of 22 patients with MDS had detectable W288fs*12 NPM1 mutations. Patient characteristics are detailed in Table 1. Median age was 58 years (range 19-86). Thirteen (59%) patients were classified as Int-1 and 9 (41%) as Int-2 by IPSS. Two (9%) patients had CMML and the remaining had MDS. Nineteen (82%) patients had normal karyotype. All patients had available FLT3, NRAS and KIT mutational evaluation with an additional 2 (9%) patients having sequencing data on 28 genes and 11 (50%) on 53 genes. A total of 2 (9%) patients had co-occurring FLT3-ITD mutations and 1 (4.5%) had a co-occurring FLT3 D835 mutation. Other detectable mutations included NRAS in 6/22 (27%) patients, DNMT3A and WT1 in 4/13 (31%), PTPN11, TET2 and IDH2 in 2/13 (15%) and RUNX1 and IDH1 in 1/13 (8%). A total of 15 (68%) patients were treated with azacitidine or decitabine based therapy, 6 (27%) with intensive chemotherapy and 1 (4.5%) with lenalidomide. Patients treated with chemotherapy tended to be younger (44 vs 62 years, p=0.023) and have higher bone marrow blasts (14% vs 8%, p=0.018). Seven (33%) patients underwent allogeneic stem-cell transplantation: 4 of the treated with chemotherapy and 3 of the patients treated with hypomethylating agents (p=0.12). Patients treated with chemotherapy had higher overall response rates (100% vs 38%, p=0.015) and complete response rates (84% vs 13%, OR 32.5, 95% CI 2.38-443.14, p=0.006) than patients treated with hypomethylating agents. A total of 6 patients had transformation to AML. Median follow up was 10 months (range 1-115). Median OS of all the population was not reached at current follow up. Median leukemia-free survival (LFS) was not reached at current follow up. Chemotherapy was associated with a trend to improved OS compared with hypomethylating agents (NR vs 58 months, p=0.086) as shown in Figure 1A. Allogeneic stem-cell transplant was associated with improved OS irrespective of treatment (NR vs 58 months, p=0.034) as shown in Figure 1B. By univariate analysis, presence of either FLT3-ITD or D835 mutation was associated with shorter median OS (6.9 vs 115.9 months, HR = 7.42, 95% CI: 1.03-53.45, p=0.047). No other mutations were found to significantly impact outcome. CONCLUSIONS: NPM1 mutations are extremely rare in the context of MDS and tend to appear in younger patients with excess blasts and normal karyotype. Our results suggest treatment of this subset of patients with AML-type chemotherapy followed by stem-cell transplantation could be associated with improved outcomes. Confirmation in larger studies is required. Table 1 Table 1. Figure 1 Figure 1. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. DiNardo:Novartis: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Agios: Research Funding; Daiichi Sankyo: Research Funding. Konopleva:Calithera: Research Funding; Cellectis: Research Funding.

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90-Yttrium Ibritumomab Tiuxetan (Zevalin) and BEAM Chemotherapy (Z-BEAM) Vs BEAM for Autologous Stem Cell Transplantation in Lymphoma: Toxicity and Long Term Outcome From a Retrospective Multicentric Study of 123 Patients.

Blood ◽

10.1182/blood.v120.21.2726.2726 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2726-2726

Author(s):

Louis Terriou ◽

Hanane Gasmi ◽

Salomon Manier ◽

Isabelle Plantier ◽

Marc Wetterwald ◽

...

Keyword(s):

Intensive Care Unit ◽

Stem Cell ◽

Intensive Care ◽

Stem Cell Transplantation ◽

Median Time ◽

Second Line ◽

First Line ◽

Ibritumomab Tiuxetan ◽

Grade 3

Abstract Abstract 2726 Background. There is a need for improving conditioning regimens in poor risk Non Hodgkin Lymphoma (NHL) patients (pts) eligible for autologous stem cell transplantation (ASCT). Incorporating radioimmunotherapy in the conditioning is an option. Bexxar-BEAM does not appear to be superior to BEAM in relapsed Diffuse Large B –cell lymphoma (DLBCL). The benefic risk ratio of 90-yttrium ibritumomab tiuxetan (Zevalin) BEAM remains to be established. Aims and methods. We analyzed retrospectively the efficacy and the toxicity of Zevalin combined with BEAM chemotherapy (Z-BEAM) compared with BEAM alone followed by ASCT. From January 2000 to November 2004 (BEAM group) and from June 2005 to December 2011 (Z-BEAM group), 55 and 68 pts respectively were treated in 6 French centers (male n=78, female n=45). Zevalin was administered on day-14 prior to ASCT with standard dose of 0.4 mci/kg (n=32) or 0.3 mci/kg (n=36) chosen according to bone marrow reserve. The efficacy and toxicity were compared between the two groups. Results. The study included 123 pts (median age: 53 years old; range 21–69) with different histological subtypes (58 DLBCL, 19 Mantle cell lymphomas, 37 follicular lymphoma, 3 marginal zone lymphoma, 4 MALT lymphoma and 2 B-lymphocytic lymphoma). Fifty-four pts were treated in first line (20 in the Z-BEAM group and 34 in the BEAM group) and 69 pts in second line (Z-BEAM, n=48; BEAM, n=21). The median time to platelets engraftment (>20000/mm3) was 9 days and 10 days in the Z-BEAM and BEAM group respectively (p=0.334), and the median time to neutrophil engraftment (>500/mm3) was 11 days and 12 days respectively (P=0.117). Grade 3/4 infectious events were more frequent in the Z-BEAM group (80.9%) than in the BEAM group (56.4%), p=0.0001. Grade 3/4 mucositis were observed in 42.6% in the Z-BEAM group Vs 12.7% in the BEAM group (p<0.0001). Admissions to intensive care unit were more frequent in the Z-BEAM group (20.6%) than in the BEAM group (7.3%), p=0.038. Transplant-related mortality (TRM) occurred in six (8.8%) patients in the Z-BEAM group and only one patient (1.8%) in the BEAM group (P=0.071). Median follow up was 73 months in the BEAM group (range 3.1–141 months) and 31 months in the Z-BEAM group (1.4–80.9 months). The 3-years OS is 80% (95%CI, 69–89%) and 78.1% (95%CI, 64.5–88%) in the Z-BEAM and the BEAM group respectively (P=0.864), and 3-years PFS was 65% (95%CI, 56–79%) and 63.4% (95%CI, 51–77%) respectively (P=0.539). Outcome was not statically different with Age (>60 y.o), histological subtype, first line treatment Vs second line, or IPI (0–1 Vs 2–3). In a subset analysis of the Z-BEAM group, female gender was associated with worse outcome; 3 years-OS was 69% (95%CI, 48–85%) in female and 93% (95%CI, 79–98%) in male (p=0.042); 3 years-PFS was 54% (95%CI, 34–73%) in female and 81% (95%CI, 65–91%) in male (p=0.032). Those results may be linked to a higher TRM, 23.1% Vs 0% (P=0.002), more respiratory complications 23.1% Vs 4.8 % ( P=0.047) and more admissions to intensive care unit 46,1% Vs 2 % (P< 0.0001) in female than in male group respectively. Conclusions. Z-BEAM is possibly as effective as BEAM alone as a conditioning regimen for ASCT with an increased toxicity. Surprisingly, our series report for the first time an increased toxicity and TRM in female. A longer follow up is needed to asses this results. Disclosures: No relevant conflicts of interest to declare.

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Lenalidomide Maintenance Following Non Myeloablative Allogeneic Stem Cell Transplantation In Patients with Multiple Myeloma: Results of the HOVON 76 Study

Blood ◽

10.1182/blood.v116.21.3502.3502 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3502-3502 ◽

Cited By ~ 1

Author(s):

Monique C. Minnema ◽

Evelien Kneppers ◽

Ronnie van Der Holt ◽

Marie Jose Kersten ◽

Sonja Zweegman ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Research Funding ◽

Maintenance Treatment ◽

Late Onset ◽

First Line ◽

Grade 3

Abstract Abstract 3502 The phase II HOVON 76 study examined the efficacy and safety of maintenance treatment with lenalidomide 10 mgr daily for 21 days in a 28 day cycle for a maximum of 24 cycles following non T-cell depleted non myeloablative allogeneic stem cell transplantation (NMA allo-SCT). Patients with newly diagnosed Multiple Myeloma who had received autologous stem cell transplantation (auto-SCT) and had a HLA identical sibling could be included. The NMA allo-SCT was performed within 2–6 months after the auto-SCT after conditioning with TBI 2Gy only. Immunosuppression consisted of mycophenolate mofetil and ciclosporin. From January 2008 until March 2010, 35 patients from 5 academic hospitals were included. In that same time period 13 patients with NMA allo-SCT first line could not be included due to acute graft versus host disease (GvHD) ≥ grade 2 (8 pts), refusal (3 pts) or failing other inclusion criteria (2 pts). Of those 35 included patients 5 never started with lenalidomide because the study was put on hold and later stopped prematurely. Median age of the remaining 30 patients was 53 years (range 37–65). Patients started with lenalidomide median 12 weeks (range 4–27) after NMA allo-SCT. During lenalidomide treatment 19 patients (63%) developed acute (late onset) GvHD. GvHD started median 18 days (range 4–247) after start of lenalidomide, 12 of these 19 patients developed GvHD during cycle 1. In 11 patients GvHD resolved completely. Blood samples were taken for cellular analysis and will be reported. The total of maximal CTCAE grade 3 and 4 toxicities reported were 53% and 23%, respectively and consisted of blood/bone marrow toxicity grade 3 in 27% and grade 4 in 17%, metabolic/laboratory 23% and 7% and dermatology grade 3 in 10%. Lenalidomide stopping criteria were development of GvHD ≥ 2 and other toxicities CTCAE grade ≥ 3. Eight patients (27%) went off protocol treatment after 1 cycle, mainly due to the development of GvHD. After cycle 2 another 4 patients (13%) stopped treatment and after 4 cycles just 12 pts (40%) could continue. Only 3 patients have completed 24 cycles and 1 pt is still on protocol treatment. In 10 patients responses improved after start of lenalidomide; from PR to VGPR in 3, from PR to CR in 2 and from VGPR to CR in 5. Nine patients have progressed. Two patients have died; one patient with graft failure due to neutropenic fever and another due to progression. Median follow up is 69 weeks (2-122) and estimated 2 years OS is 93% and PFS 60%. In conclusion, early lenalidomide treatment following NMA allo-SCT is not feasible mainly due to the development of acute (late onset) GvHD. The occurrence of GvHD was closely related with the start of lenalidomide treatment. In this preliminary analysis no improvement of PFS was demonstrated compared to the HOVON 54 study in which no maintenance treatment after NMA allo-SCT was given. Disclosures: Minnema: Ortho Biotech: Speakers Bureau. Off Label Use: Lenalidomide is in the netherlands not registered for first-line use. Lokhorst:ortho biotech: Research Funding; celgene: Research Funding.

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T-Bird (thalidomide, clarithromycin/[Biaxin®], lenalidomide/[Revlimid®], Dexamethasone) Therapy in Newly Diagnosed Symptomatic Multiple Myeloma

Blood ◽

10.1182/blood.v118.21.2937.2937 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2937-2937

Author(s):

Tomer M Mark ◽

Manan Shah ◽

Melissa Rodriguez ◽

Ryann Quinn ◽

Roger N Pearse ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Board Of Directors ◽

First Line ◽

Advisory Committees ◽

Free Survival ◽

Line Therapy ◽

Grade 3 ◽

Stem Cell Collection

Abstract Abstract 2937 Background: The addition of thalidomide to BiRD therapy (clarithromycin/[Biaxin®], lenalidomide/[Revlimid®], dexamethasone) may enhance anti-myeloma activity of the combination while not adding to overall regimen toxicity, given the different side effect profiles of thalidomide and lenalidomide. We now report an update of the phase 2 trial of T-BiRD (thalidomide/Thalomid®, clarithromycin/[Biaxin®], lenalidomide/[Revlimid®], dexamethasone) in up-front treatment of symptomatic multiple myeloma (MM). Methods: Twenty-six patients with newly diagnosed symptomatic MM received T-BiRD. T-BiRD is clarithromycin 500mg twice daily; dexamethasone 40mg on days 1, 8, 15, 22; and lenalidomide 25mg for days 1–21 of a 28-day cycle. Thalidomide was given at a dose of 50mg daily for the first week and thereafter at 100mg daily. All subjects had thromboprophylaxis with aspirin. Disease response evaluation was performed monthly with immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Treatment was continued as tolerated by the patients until disease progression. Results: Twenty-six patients were enrolled. The median number of T-BiRD cycles delivered was 6.5 (range 0–17). The overall response rate (ORR) to T-BiRD (audited at time of autologous stem cell transplant [ASCT] or other planned change in therapy) was 77% (4% progressive disease (PD), 19% stable disease (SD), 42% partial response (PR), 31% very good partial response (VGPR), 4% CR). Eight patients (31%) withdrew from study, including 4 (15%) early withdrawals prior to completion of cycle 2 (1 due to Grade 4 rash, 2 due to Grade 3 rash, and 1 due to renal failure secondary to MM). Excluding these early withdrawals, ORR was 86% (5% PD, 10% SD, 45% PR, 36% VGPR, 5% CR). In these patients, median time to PR was 1 cycle [range 1–5]; the median time to max response was 4 cycles [range 1–7]. All eighteen patients who electively underwent autologous stem cell collection were successful, with median 16.317 CD34+ cells/kg collected [range 5.8–43.9] over a median of 1.5 apheresis sessions [range 1–5]. Eleven subjects underwent ASCT as part of a first line of therapy with T-BiRD induction; ORR to first line therapy in these subjects was 100%, with 18% PR, 46% VGPR, and 36% CR. At 4 years of study follow-up for 1st line therapy, median progression free survival (PFS) and event free survival (EFS) was 135.6 and 65.3 weeks respectively. Median overall survival (OS) was not reached; at 4-year follow-up, 4 patients had died of progressive myeloma, giving an overall survival rate of 84.5%. Twelve patients experienced grade 3 non-hematologic toxicity (weakness: 4; rash: 3; popliteal vein thrombosis: 2; respiratory infection: 1; hyperglycemia: 1; anorexia/dysgeusia: 1; renal insufficiency: 1; dizziness: 1; psychomotor agitation: 1; myocardial infarction: 1). One subject had grade 4 rash during cycle 1. 1 subject died of progressive myeloma prior to completion of 10 days of cycle 1. Conclusions: T-BiRD is a highly active regimen in treatment-naïve multiple myeloma, with prolonged responses achieved; however, early treatment toxicity precluded extended use in up to a third of patients. Responding patients achieved PR within 1 cycle, indicating that this regimen may be useful when a swift drop in paraprotein is desired. T-BiRD allows for successful autologous stem cell collection and transplant outcomes. These data support the use of immunomodulatory-based regimens in the upfront treatment of MM and highlight the potential additive toxicities of the simultaneous administration of thalidomide and lenalidomide. Disclosures: Mark: Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: The combination of thalidomide and lenalidomide was tested in relapsed myeloma; the combination is not FDA-approved. Zafar:Celgene Corp: Speakers Bureau. Pekle:Celgene Corp: Speakers Bureau. Coleman:Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Niesvizky:Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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