scholarly journals Impact of Central Nervous System Involvement in Adult Patients with Acute Lymphoblastic Leukemia Treated in a Pediatrics-Inspired Protocol - a Graall Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 215-215
Author(s):  
Corentin Orvain ◽  
Sylvain Chantepie ◽  
Xavier Thomas ◽  
Martine Escoffre-Barbe ◽  
Francoise Huguet ◽  
...  
Keyword(s):  
Blood Cells ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
White Blood Cells ◽  
Clinical Signs ◽  
Adult Patients ◽  
High Dose ◽  
Cns Involvement ◽  
The Impact ◽  
To Receive

Abstract Background: The prognosis of central nervous system (CNS) involvement in adult patients with acute lymphoblastic leukemia (ALL) has been historically associated with a dismal outcome. Whereas the prognosis of adult patients with ALL has greatly improved since the advent of pediatrics-inspired regimens, the prognostic impact of CNS involvement has not been formerly reevaluated. We report herein the impact of CNS involvement in patients included in the pediatric-inspired prospective GRAALL-2005 study. Methods: All patients received a 5-drug induction therapy with native E. Coli-ASP intravenous injections. Patients in complete remission (CR) received two consolidation courses with alternating cycles including high dose cytarabine (2g/m2/12h on days 1 and 2), high dose methotrexate (3 g/m2 on day 1), and cyclophosphamide. All patients in persistent CR and with no indication for allogeneic stem cell transplantation (SCT) received late intensification, followed by one last consolidation course. Patients with initial CNS involvement, clinically and/or cytologically (cerebrospinal fluid), were recommended to receive an increased number of triple intrathecal therapy, CNS irradiation, and were eligible for allogeneic SCT in first CR. They received less Asp injections during induction therapy to avoid CNS adverse events. CNS irradiation included two lateral fields encompassing the skull, facial, the base of the skull, and the first two cervical vertebrae at a dose of 24 grays for those not receiving allogeneic SCT and 15 grays for those receiving allogeneic SCT. Results: Between 2006 and 2014, 784 adult patients with newly diagnosed Philadelphia-negative ALL were included with 55 (7%) having initial CNS involvement. These patients were more likely to be of T-phenotype (51 versus 32%, p=.004) and had more white blood cells at diagnosis (median 23 G/l versus 11 G/l, p=.02). Most patients (36 pts, 66%) were classified as CNS-3 (> 5 white blood cells/µl and a positive cytospin and/or clinical signs) whereas 5 patients (9%) were CNS-2 (< 5 white blood cells/µl and a positive cytospin), and 14 (25%) have data pending. Among patients with details regarding CNS involvement, 25/41 (61%) had clinical signs including trigeminal anesthesia (9 pts, 36%), facial paralysis (4 pts, 16%), extremities paresthesia (4 pts, 16%), visual signs (2 pts, 8%), meningeal syndrome (2 pts, 8%), and motor deficit (2 pts, 8%), and 4/18 (22%) had radiological signs. Induction death, CR1 rate, and negative minimal residual disease after induction were similar whether patients had CNS involvement or not (6 vs 6%, 89 vs 89%, 73 vs 62%, 26 vs 22%, respectively). Patients with CNS involvement had a worse outcome than those without with a median event-free survival (EFS) of 391 days (versus not reached for patients without CNS involvement, HR: 1.7, 95% CI: 1.2 - 2.5, p=.002) and a median overall survival (OS) of 608 days (versus not reached for patients without CNS involvement, HR: 1.8, 95% CI: 1.3 - 2.6, p=.001) (figure). Similar results were observed when patients who received allogeneic SCT in CR1 were censored at the time of graft. As recommended, patients with CNS involvement were more likely to receive allogeneic SCT than those without (53 versus 34%, p=.01), with a median time of 169 days. A 150-day landmark analysis, excluding 12 patients with an EFS event before 150 days, was performed to study the impact of allogeneic SCT on the outcome of patients with CNS involvement. Allogeneic SCT had no impact on either EFS (HR: .5, 95% CI: .2 - 1.2, p=.15) or OS (HR: .8, 95% CI: .3 - 1.8, p=.53). Conclusion: Despite improved outcome in young adult ALL patients with pediatrics-inspired protocols, CNS involvement remains a poor-risk feature. The historical use of allogeneic SCT does not improve outcome. Specific regimens should be developed for adult ALL patients with CNS involvement. Figure 1 Figure 1. Disclosures Huguet: Amgen: Other: Advisor; BMS: Other: Advisor; Celgene: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Novartis: Other: Advisor; Pfizer: Other: Advisor. Barbieux: ASTRA-ZENECCA: Consultancy. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Boissel: Bristol-Myers Squibb: Honoraria, Research Funding; Servier: Consultancy, Honoraria; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; JAZZ Pharma: Honoraria, Research Funding; CELGENE: Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria. Mathilde: ABBVIE: Consultancy; SERVIER: Consultancy.

Pediatric ALL-like Therapy in Adults with T-Cell Lymphoblastic Lymphoma: Results of the Graall-Lysa LL03 Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 371-371
Author(s):  
Stephane Lepretre ◽  
Aurore Touzart ◽  
Thomas Vermeulin ◽  
Jean-Michel Picquenot ◽  
Aline Tanguy-Schmidt ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Prognostic Value ◽  
Lymphoblastic Leukemia ◽  
Multivariable Analysis ◽  
Lymphoblastic Lymphoma ◽  
Adult Patients ◽  
High Dose ◽  
Genetic Profile ◽  
Cns Involvement

Abstract Background: It has been suggested that using an acute lymphoblastic leukemia (ALL) rather than non-Hodgkin lymphoma protocol to treat patients with lymphoblastic lymphoma (LL) might be associated with better results (Hoelzer, Best Pract Res Clin Haematol 2002). To address this issue, the GRAALL and LYSA groups have conducted the Phase 2 LL03 trial in adult patients with LL, using the GRAALL-2003 protocol, which yielded good results in adult patients with ALL (Huguet, JCO 2009). Patients and Methods: Between 2004 and 2012, 155 patients aged 18-59 years were enrolled, including 131 evaluable patients with T-cell LL (T-LL). The pediatric-inspired ALL treatment included a corticosteroid prephase, a 5-drug induction with sequential cyclophosphamide, high dose consolidation, late intensification, CNS prophylaxis with IT injections and cranial irradiation, and a 2-year maintenance. Response, including complete remission (CR) and unconfirmed CR (CRu), were assessed using Cheson criteria (Cheson, JCO 1999). Allogeneic stem cell transplantation (SCT) was offered to CR/CRu patients with high-risk disease (defined as need for a second-induction salvage course and/or CNS disease) and a donor. Results: Of 131 T-LL patients (median age, 33 years; M/F ratio 4.0; mediastinal enlargement, 95%; CNS involvement, 5%), 119 patients (91%) reached CR/CRu (30 patients needing a salvage course) and 34 relapsed. Response evaluation was based on CT scan, as PET scan was performed in only 73/131 and 20/30 patients after first induction and salvage, respectively. At 5 years, estimated DFS, EFS and overall survival were 71%, 61% and 66%, respectively. The lymphoma IPI-score had no prognostic value, but increased serum LDH level (observed in 71% of the patients) was associated with a significant decrease in EFS (HR = 2.8 [1.3 – 6.1]) and OS (HR = 3.5 [1.4 – 9.1]) in multivariable analysis. Of note, need for a salvage course was not associated with shorter DFS in CR/CRu patients. In a subset of 49 patients studied for oncogenetic markers, the 4-gene risk classifier (based on NOTCH1, FBXW7, N/K-RAS and PTEN status) we have recently reported to be a powerful predictor in T-ALL patients (Trinquand, JCO 2013) also demonstrated strong prognostic value in T-LL. Among these patients, 29 (60%) had a high-risk genetic profile (defined as no NOTCH1/FBXW7 mutation and/or N/K-RAS mutation and/or PTEN deletion). At 3 years, the high-risk genetic profile was predictive of shorter EFS (HR = 14.3 [1.9 – 107.8]), DFS (HR = 9.5 [1.2 – 74.3]) and OS (HR = 11.5 [1.5 – 87.5]) in univariable analysis, as well as in multivariable analysis after adjustment on age, ECOG-PS and LDH level (HR = 20.5 [2.6 – 164.1], 12.6 [1.5 – 104.8] and 17.0 [2.1 – 136.8], respectively. A total of 30 CR/CRu patients were eligible for allogeneic SCT (25 for late CR/CRu, 4 for CNS involvement, and 1 for both criteria) and 17 of them were actually transplanted in first CR/CRu. When analysed as a time-dependent event, allogeneic SCT was not associated with prolonged DFS in these high-risk patients. Finally, Grade III/IV adverse events were those commonly observed with the GRAALL regimen. Overall, 46 patients died during the study (37 after relapse or progression; 5 during induction; 3 from allograft toxicity and 1 after a highway accident). Conclusion: As compared to historical studies, we report here a relatively good outcome in T-LL patients treated with a pediatric-inspired ALL strategy. Very interestingly, the NOTCH1/FBXW7/RAS/PTEN T-ALL risk classification was also a strong prognostic factor in these T-LL patients. Allogeneic SCT did not appear to significantly influence the outcome of selected T-LL patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals A Comparative Study of Biosimilar Filgrastim Versus Originator G-CSF for CD34+ Cells Mobilization and Autografting in Hematological Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2183-2183 ◽  
Author(s):  
Lucia Brunello ◽  
Luisa Giaccone ◽  
Maria Josè Fornaro ◽  
Matilde Scaldaferri ◽  
Valter Redoglia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Blood Cells ◽  
Research Funding ◽  
Hematological Malignancies ◽  
Advisory Board ◽  
High Dose ◽  
Historical Cohort ◽  
Cd34 Cells ◽  
The Impact ◽  
Biosimilar Filgrastim

Abstract INTRODUCTION: Autografting (auto-HSCT) is widely used for the treatment of hematological malignancies. Since 2010, Biosimilar Filgrastim (Nivestim™, Pfizer Inc.) (BioG-CSF) has been approved and introduced into clinical practice to mobilize hematopoietic stem cells (CD34+cells) and to reduce the duration of chemo-induced neutropenia. This single institution study was designed to evaluate its safety and efficacy in the setting of "real life" medical practice. METHODS: We designed a "mixed retrospetive-prospective study" to evaluate the impact of BioG-CSF on CD34+ cells collections and engraftment kinetics after autografting. Patients who received BioG-CSF were compared with a historical cohort treated with Originator G-CSF (Filgrastim or Lenograstim). Primary endopoints were CD34+ mobilizations and post auto-HSCT engraftment kinetics. Secondary objectives included transfusions requirements, duration of hospitalization and 1-year overall survival (OS). Leukapheresis (LA) was initiated when circulating CD34+ count was at least 20/uL. Day of neutrophil engraftment was defined as the first of 3 consecutive days of absolute neutrophil count (ANC) ≥ 500/ul whereas day of platelet engraftment was defined as the first of 7 consecutive days without transfusion support. RESULTS: Initially,187 patients (137/187 affected by multiple myeloma) have been enrolled in the cohort under evaluation for CD34+ mobilization kinetics. Overall, 138 and 49 patients received originator and BioG-CSF (5-10 ug/kg/day) to collect CD34+cells. All but two patients underwent chemotherapy for mobilization (high-dose cyclophosphamide in 157/187 patients). Less than 3% of patients were poor mobilizers in both cohorts. No differences between Originator and BioG-CSF cohort were observed in time from chemotherapy to first day of LA (median day 11 vs day 11 p=0.473), CD34+/ul (mean 157.3/ul vs 166.2/ul, p=0.59) and CD34+*10^6/kg recipient harvested on the first day of LA (mean 10.5*10^6/kg vs 11.1*10^6/kg, p=0.323). A higher count of white blood cells on the first day of LA was observed in patients treated with BioG-CSF (mean originator 18.6*10^9/L vs BioG-CSF 27.1*10^9/L, p=0.001). A further analysis was conducted on 175 patients (126/175 affected my multiple myeloma) for a total of 220 auto-HSCTs, evaluable for hematological recovery and clinical outcomes. Overall, 137 and 83 patients received Originator and BioG-CSF, respectively. All patients were hospitalized and prepared for the autograft with a high-dose conditioning (Melphalan 200mg/sqm in 171/220 auto-HSCTs). Infused CD34+ cells were 5*10^6/kg recipient (IQR 3.8-5.1) and 4.1*10^6/kg recipient (IQR 3.5-5.3) in the Originator and BioG-CSF cohorts. After the autograft, patients were prescribed 30-34 milliion units (MU) of Originator G-CSF and 30 MU dose of BioG-CSF starting on day +1/+3. Day +25 cumulative incidences of ANC and platelets recovery were 99.3% and 98.5% and 97.6% and 90.2% in the Originator and BioG-CSF groups, respectively (p=0.786, p=0.006). Of note, by Mann-Whitney test, no differences between cohorts were found in a)median duration of neutropenia (median 7 and 6 days, p=0.355), platelets (median 1 pool/patient in both, p=0.894) and red blood cells (median 0/patient in both, p=0.704) transfusion requirements, hospital stay (median 20 days and 21 days, p=0.33). Serial measurements of complete blood counts were performed from discharge to day +90 post auto-HSCT; no significant differences were found at any time point between the two groups. No severe adverse reactions attributable to G-CSFs were documented. Thrombocytopenia lasted longer for patients treated with BioG-CSF, however this finding did not translate into a higher transfusion requirement or bleeding episodes. Finally, 1-year OS was comparable between cohorts (p=0.699). CONCLUSIONS: In this sizable study, BioG-CSF was as effective as Originator G-CSF in mobilizing CD34+ cells as well as in treating post-transplant neutropenia in patients with hematological malignancies. Moreover, the extensive use of BioG-CSF led to a significant cost containment. Disclosures Massaia: Janssen: Other: advisory board; Gilead: Other: advisory board; Roche: Other: advisory board, research support. Cavallo:JANSSEN: Honoraria; CELGENE: Honoraria; ONYX: Honoraria. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Boccadoro:Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Mundipharma: Research Funding; Abbivie: Honoraria; SANOFI: Honoraria, Research Funding; BMS: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding.

Capizzi-Style Methotrexate with Pegasparagase (C-MTX) Is Superior to High-Dose Methotrexate (HDMTX) in T-Lineage Acute Lymphoblastic Leukemia (T-ALL): Results from Children's Oncology Group (COG) AALL0434

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 794-794 ◽  
Author(s):  
Stuart S. Winter ◽  
Meenakshi Devidas ◽  
Si Chen ◽  
Barbara Asselin ◽  
William L. Carroll ◽  
...  
Keyword(s):  
Young Adults ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Adolescents And Young Adults ◽  
Phase Iii ◽  
High Dose ◽  
Cns Involvement ◽  
Leucovorin Rescue ◽  
To Receive

Abstract Early intensification with MTX is a key component of most treatment regimens used for children, adolescents and young adults with ALL. We have previously shown that HDMTX is superior to C-MTX in B-ALL in COG Study AALL0232. Because there are differences in sensitivity to MTX and pegaspargase (PEG-ASNase) between B- and T-ALL that might affect outcome, we conducted a front-line, Phase III study for patients with T-ALL. COG AALL0434 was a 2 x 2 pseudo-factorial randomization comparing the COG augmented BFM (ABFM) regimen with C-MTX without leucovorin rescue to ABFM with HDMTX plus leucovorin rescue in T-ALL, and randomizing patients with T-ALL and T-lymphoblastic lymphoma to therapy with/without six, five-day courses of nelarabine. Study subjects with T-ALL received either block of MTX therapy during the 8-week Interim Maintenance (IM) phase; those with CNS3 status were non-randomly assigned to receive HDMTX. The T-ALL patients all received prophylactic (1200 cGy) or therapeutic (1800 cGy for CNS3) cranial irradiation (cXRT), except for the ~10% with low-risk T-ALL (NCI standard risk, CNS1 without extramedullary disease, and Day 29 minimal residual disease <0.1%), who did not receive cXRT. AALL0434 accrued 1,895 study subjects between 2007 and 2014. One thousand thirty-one T-ALL subjects without CNS3 status were randomized to receive ABFM with C-MTX or HDMTX. Subjects randomized to C-MTX (n= 518) received cXRT during Consolidation (Week 4 of protocol therapy), while subjects randomized to HDMTX (n=513) received cXRT during Delayed Intensification (DI) Week 26 of protocol therapy. The 4-year disease-free survival rates (DFS) were 89.3% (SE 1.5%) overall and 92.5% (SE 1.8%) for the C-MTX regimen vs. 86.1% (SE 2.4%) for the HDMTX regimen (p = 0.0173) (Figure 1). Interim monitoring resulted in the early release of efficacy results showing that C-MTX is superior to HDMTX, but data for the nelarabine randomization (n = 659) have not yet matured enough to assess its impact. The C-MTX regimen had 11 relapses; 7 without CNS, and 4 with CNS involvement, all occurring after Week 21 in DI phase therapy. In contrast, among those randomized to HDMTX, there were 24 relapses, 14 without CNS and 10 with CNS involvement, 6 with CNS before delivery of HDMTX and cXRT. This result is directly opposite to what we observed in B-ALL (Larsen et al, ASCO 2011), emphasizing the different biology and treatment sensitivities of B- and T-ALL. The reasons for these differences are uncertain, but may be related to different sensitivities to MTX with/without leucovorin rescue, differences in PEG-ASNase scheduling, or near universal use of cXRT in AALL0434 with different timings of cXRT administration between study arms. In conclusion, AALL0434 produced a 4-year DFS rate of 89.3% (SE 1.5%) in children, adolescents, and young adults with T-ALL, and established that ABFM with C-MTX was superior to ABFM plus HDMTX. Figure 1. Figure 1. Disclosures Hunger: Bristol-Myers Squibb: Employment; Jazz Pharmaceuticals; Sigma Tau Pharmaceuticals; Erytech: Honoraria.

Can Less Intensive Chemotherapy and an Autotransplant Cure Adult T-Cell Acute Lymphoblastic Leukemia?

2019 ◽  
Vol 143 (2) ◽  
pp. 131-139 ◽  
Author(s):  
Elena Parovichnikova ◽  
Vera Troitskaya ◽  
Andrey Sokolov ◽  
Olga Gavrilina ◽  
Zalina Akhmerzaeva ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Blood Cells ◽  
Lymphoblastic Leukemia ◽  
White Blood Cells ◽  
High Dose ◽  
Consolidation Chemotherapy ◽  
Free Survival ◽  
Number Of Patients ◽  
Cell Acute Lymphoblastic Leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is a rare disease usually treated with intensive, high-dose consolidation chemotherapy followed by an allotransplant in a substantial number of patients. The data of the RALL-2009 study on 125 adult T-ALL patients suggest that similar total chemotherapy doses given less intensively over a longer interval without interruptions and with an auto- rather than an allotransplant produce outcomes like current more intensive protocols and an allotransplant: 9-year cumulative incidence of relapse (CIR), leukemia-free survival (LFS), and survival were 24% (95% CI 16–33%), 70% (95% CI 59–79%) and 62% (95% CI 51–72%). In a landmark analysis, subjects achieving a complete remission and receiving an autotransplant had a lower 9-year CIR (9% [95% CI 2–22%] vs. 29% [95% CI 16–43%]; p = 0.0076) and better LFS (91% [95% CI 79–98%] vs. 58% [95% CI 41–74%]; p = 0.0009) and survival (92% [95% CI 77–99%] vs. 60% [95% CI 44–77%]; p = 0.001) compared with subjects not receiving an autotransplant. In a multivariate analysis, white blood cells ≥100 × 109/L at study entry were significantly associated with worse LFS (HR = 2.842 [95% CI 1.131–7.143]; p = 0.0263) and survival (HR = 6.085 [95% CI 1.918–19.3]; p = 0.0022) because of more early deaths (HR = 2.42 [95% CI 1.04–5.67]; p = 0.041). Receiving an autotransplant correlated with a lower CIR (HR = 0.23 [95% CI 0.07–0.73]; p = 0.0136) and better LFS (HR = 0.27 [95% CI 0.08–0.85]; p = 0.0256) and survival (HR = 0.158 [95% CI 0.045–0.550]; p = 0.0037).

scholarly journals The Omission of High-Dose Cytarabine during Consolidation Therapy of Ph-Positive ALL Patients Treated with Nilotinib and Low-Intensity Chemotherapy Results in an Increased Risk of Relapses Despite Non-Inferior Levels of Late BCR-ABL1 MRD Response. First Results of the Randomized Graaph-2014 Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 512-512
Author(s):  
Philippe Rousselot ◽  
Yves Chalandon ◽  
Sylvie Chevret ◽  
Jean-Michel Cayuela ◽  
Francoise Huguet ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Primary Endpoint ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Cell Transplant ◽  
Advisory Committees ◽  
High Dose Cytarabine ◽  
To Receive

Abstract On behalf of the GRAALL group. Introduction. Tyrosine kinase inhibitors (TKIs) have dramatically improved the outcome of patients diagnosed with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). In a previous randomized trial (GRAAPH-2005; Chalandon Y., Blood 2015), our group demonstrated that anthracycline and cyclophosphamide could be safely omitted during the first Hyper-CVAD chemotherapy cycle when combined to imatinib. In the present GRAAPH-2014 trial, we investigated whether the use of nilotinib, a 2 nd generation TKI, would allow further decreasing chemotherapy intensity through the omission of high-dose cytarabine (HD-AraC) during consolidation cycles 2 and 4. Methods. From March 2016, patients aged 18-60 years old were randomized frontline to receive 4 cycles (1=3, 2=4) of chemotherapy combined with continuous nilotinib 400 mg bid. Cycle 1 and 3 were similar in both arms, identical to the less-intensive first cycle of the previous GRAAPH-2005 trial with weekly vincristine and dexamethasone and nilotinib instead of imatinib. Cycle 2 and 4 differed between control arm A (MTX 1 g/sqm over 24h, HD-AraC 3 g/sqm/12h for 2 days) and experimental arm B (MTX 1 g/sqm over 24h only). Marrow minimal residual disease (MRD) was assessed by both BCR-ABL1 and IG-TCR qPCR after each cycle (MRD1-4). Patients in complete remission (CR) after cycle 4 were eligible to receive allogeneic stem cell transplant (alloSCT). Non allografted patients had the option to receive autologous SCT (autoSCT) if a major molecular response (MMolR) (MRD4 BCR-ABL1 &lt;0.1%) was achieved. AlloSCT and autoSCT were followed by a 2-year imatinib maintenance. The randomization was stratified on age (≤40y, &gt;40y) and BCR-ABL1 breakpoint region (M/m-bcr). MMolR rate at MRD4 was the primary endpoint of this non-inferiority study, with a margin set at 0.15. In February 2019, the study DSMB decided to stop the randomizations after an unplanned analysis demonstrating a significant excess of relapse in arm B (without HD-AraC). An intention-to-treat analysis is provided. All patients gave informed consent. The study is registered at EudraCT under the number: 2014-002146-44. Results. A total of 156 patients were randomized (77 in arm A, and 79 in arm B). Median age was 47.1 years old (range 18.1-59.9). One-hundred and ten patients had the m-bcr (70.5%) and 46 (29.5%) the M-bcr. An IKZF1 intragenic deletion was found in 87/153 (56.9%). Median follow-up was 2.8 years (95%CI 2.6-3.1). All evaluable patients reached CR after a maximum of two cycles. Three patients died during cycle 1 (2 in arm A, 1 in arm B), and 2 during cycle 2 (1 per arm). Most patients received the 4 scheduled cycles (n=143, 91,7%). AlloSCT was performed in 91 patients (58.3%), whereas 41 patients received an autoSCT (26.3%) with no difference in allo/autoSCT rates between arms. A non-inferiority in late MRD response (MRD4) between the two arms was observed (primary endpoint). MMolR was reached in 55/75 (73.3%) and 61/78 (78.2%) of CR patients in arm A and B, respectively, with an estimated 95% CI of difference of -11% to +16% (-9.2% to +20.8% in the ITT analysis treating missing data as failures). At 3 years, overall survival (OS) was 86.0% in arm A versus 74.2% in arm B (p=.08, Figure A). Progression-free survival (PFS) was 79.6% in arm A versus 57.2% in arm B (p=.008, Figure B). Thirty-one patients experienced hematological relapse (8 in arm A and 23 in arm B). Twenty-height out of 31 relapsed patients were tested for the acquisition of BCR-ABL1 mutations, 20/28 (71%) had at least one mutation and 10/28 (36%) had a T315I mutation. At 3 years, the cumulative incidence of relapse (CIR) was 21.3%, significantly higher in arm B than in arm A (30.8% vs 10.6%, p=.007). When analyzing the CIR considering alloSCT as a competing event for relapse, a significant higher CIR was still observed in arm B as compared to arm A (Figure C). Conclusion. Four cycles of the combined administration of nilotinib and chemotherapy is very efficient for bridging younger adults with Ph-positive ALL to SCT. However, omitting HD-AraC is associated with a higher relapse incidence despite non-inferior levels of BCR-ABL1 MRD4. Figure 1 Figure 1. Disclosures Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Vincent: Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Raffoux: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ASTELLAS: Consultancy; ABBVIE: Consultancy. Boissel: Amgen: Consultancy, Honoraria, Research Funding; CELGENE: Honoraria; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria; JAZZ Pharma: Honoraria, Research Funding. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. OffLabel Disclosure: Nilotinib as a therapy for PH-positive acute lymphoblastic leukemia

scholarly journals The Histone Deacetylase 1 and 2 (HDAC1/2) Inhibitor ACY-957 Increases Epsilon (HbE) and Gamma (HbG) Globin mRNA in the Peripheral Blood of Non-Anemic Rats and Monkeys

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3378-3378 ◽  
Author(s):  
Jeffrey R Shearstone ◽  
Apurva Chonkar ◽  
Kailash Bhol ◽  
Simon S Jones ◽  
Matt Jarpe
Keyword(s):  
Peripheral Blood ◽  
Blood Cells ◽  
Plasma Levels ◽  
White Blood Cells ◽  
Clinical Signs ◽  
High Dose ◽  
Employment Equity ◽  
Once Daily ◽  
Equity Ownership ◽  
Baseline Levels

Abstract Elevated levels of HbG mRNA, leading to the formation of fetal hemoglobin, is known to ameliorate disease severity in sickle cell and β-thalassemia patients. We have previously shown that the small molecule ACY-957 is a selective inhibitor of HDAC1/2 which induces HbE and HbG in cultured human primary CD34+ cells (Shearstone et al, ASH Annual Meetings 2012-14). In this work, we describe the pharmacokinetics and HbE/HbG induction following once daily oral dosing of ACY-957 in rat and monkey. To determine the duration of ACY-957 exposure required to induce HbE and HbG in vivo, we first tested ACY-957 in drug washout experiments performed in cultured primary erythroid progenitors. The aminobenzamide class of HDAC inhibitors, such as ACY-957, are known to have slow on rates for HDAC1/2 (Kral et al, Biochemistry 2014; Lauffer et al, J Biol Chem 2013). We found that a 6 h pulse of ACY-957 (1 μM) resulted in undetectable increases in histone H3 lysine 9 acetylation (H3K9ac) and that 4 or 8 h pulses of ACY-957 (1 μM) resulted in undetectable HbE and HbG induction. However, continued exposure resulted in a 2.5-fold and 7-fold increase in H3K9ac after 24 and 48 h of incubation, respectively, leading to a time-dependent increase in HbE and HbG. Based on this data, we hypothesized that in vivo studies would require ACY-957 levels of 1 μM for 24 h in order to observe elevated HbE and HbG. Non-fasted Sprague Dawley rats or cynomolgus monkeys received a single oral dose of 20 mg/kg or 12.5 mg/kg ACY-957, respectively, and pharmacokinetic analysis yielded comparable results with T1/2 = 11.8 and 10.9 h, Cmax = 7.8 and 2.4 μM, and Tmax = 5.3 and 4.0 h, in rat and monkey, respectively. At 24 h post dose, ACY-957 plasma levels in rat and monkey were 1.6 and 0.6 μM, respectively. These findings suggested that the targeted drug exposure could be met with a single daily oral dose of ACY-957. Since ACY-957 induced HbE in cultured human primary erythroid progenitors, we attempted to measure HbE induction in rat as a surrogate marker for HbG in primate. Rats were dosed with 0, 10 or 30 mg/kg (n=4 per group) by oral gavage, once daily for 6 days, followed by a 13 day washout period. Peripheral blood was sampled every 3 days for isolation of total RNA. Complete blood counts were performed on day 0, 6 and 18. The low and high dose groups showed ACY-957 plasma levels of 1.3 or 5.2 μM, respectively, at 24 h post final dose. No abnormal clinical signs were found during the in-life phase, although a minor, reversible delay in rat weight gain was observed in the high dose group. White blood cells were suppressed by 33% and 68% at day 6 in low and high dose groups, respectively, but recovered to baseline levels by day 18. ACY-957 administration led to a dose-dependent increase in HbE relative to HbB that was detectable at day 3, peaked at day 6, and returned to baseline levels by day 9. Maximum induction of HbE was 2-fold and 5.6-fold for the low and high dosing groups, respectively, relative to animals receiving vehicle only. Next, monkeys were dosed at 0, 25 or 75 mg/kg (n=3 per group) by oral gavage, once daily for 5 days, followed by a 14 day washout period. Peripheral blood was sampled every 2 to 3 days for isolation of total RNA and analysis of complete blood counts. The low and high dose groups showed ACY-957 plasma levels of 1.9 or 8.0 μM, respectively, at 24 h post final dose. No abnormal clinical signs were found during the in-life phase. White blood cells were suppressed by 25% and 61% at day 5, but recovered to baseline levels by day 9. ACY-957 administration led to a dose-dependent increase in HbE and HbG relative to HbB that was detectable at day 5, peaked at day 7, and returned to baseline levels by day 12. Maximum induction of HbG was 2.2-fold and 7.2-fold for the low and high dosing groups, respectively, relative to animals receiving vehicle only. These results demonstrate that ACY-957 induces HbE in rat and HbG in monkey to a similar extent. ACY-957 appeared well tolerated in both animals, although a reversible suppression of white blood cells was observed. Together, these findings suggest that optimization of dose and schedule could be performed in rats by monitoring HbE as a surrogate for HbG in primates. The optimized regime could then be validated in cynomolgus monkey. Accordingly, we have initiated experiments that explore the effects of several different ACY-957 dose schedules on HbE induction and white blood cell suppression in rats during a 4 week dosing and 2 week recovery period, which will also be presented. Disclosures Shearstone: Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership. Chonkar:Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership. Bhol:Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership. Jones:Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership. Jarpe:Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership.

scholarly journals Expanded Access Program of Graspa for Treatment of Patients with Acute Lymphoblastic Leukemia Unable to Receive Other Form of L-Asparaginase - a Status Update (NCT02197650)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4877-4877 ◽  
Author(s):  
Yves Bertrand ◽  
Hervé Dombret ◽  
Bruno Quesnel ◽  
Jean-Louis Stephan ◽  
Claudine Schmitt ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Blood Cells ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Clinical Activity ◽  
Allergic Reactions ◽  
Advisory Committees ◽  
Expanded Access Program ◽  
To Receive ◽  
Access Program

Abstract Background L-asparaginase (L-ASP) is a key drug in the treatment of acute lymphoblastic leukemia (ALL). However the toxicity profile, especially hypersensitivities up to acute allergic reactions is a major drawback. GRASPA (eryaspase (proposed INN) or E-Coli L-Asparaginase encapsulated into red blood cells) is a new product under development with the aim of improving the tolerance of this enzyme. Asparagine is actively transported through the membrane of red blood cells (RBC) where it is hydrolyzed by the encapsulated L-ASP, the erythrocytes acting as "bioreactors". The RBC membrane shields against the anti-L-ASP antibody then avoiding binding to encapsulated L-ASP. Recently, a Phase III pivotal study of GRASPA in combination with COOPRALL chemotherapy protocols in patients with relapsed ALL demonstrated highly significant safety profile and clinical activity compared to control. However, there is an unmet medical need for patients who cannot receive current formulations of L-ASP. An expanded access program has recently been initiated in France to provide access for treatment with GRASPA in patients who are unable to receive other forms of L-ASP. Methods: This is a non randomized multicenter open label study, currently initiated in France. The primary objective of the EAP is to evaluate the tolerability of GRASPA. Patients under 55y of age presenting with de novo, relapsed or refractory ALL who are at risk to receive any other available L-ASP formulation are enrolled into this program. Patients with known allergic reactions to E.Coli L-ASP are also eligible. GRASPA is administrated every 2 to 3 weeks at a dose equivalent to 150 IU/kg of L-ASP during all chemotherapy courses intended to contain an asparaginase. Chemotherapy protocols are given according to the Investigator's choice. Patients are assessed regularly for safety and tolerability. The primary endpoint is tolerability; Key secondary endpoints include asparaginase activity, asparagine depletion, and clinical remission rates. An independent Safety Monitoring Board (DSMB) is set up, which will assess toxicities on yearly basis. Results As of time of June 2015, 13 patients were enrolled into the program. The first DSMB meeting reviewed the outcome of the first 7 patients enrolled into the program. Of the 7 pts (range 3 - 49 years), 5 males and 2 females were enrolled. Four pts presented with refractory disease and 3 with relapse, with all patients had evidence of allergies to 2 prior asparaginases (double allergies). There were 2 pts presenting with limiting toxicities, in the form of myelosupression, and streptococcal infection. There was no modification to the protocol recommended by the first DSMB An updated safety and clinical activity information on all patients will be provided. Conclusion: The EAP provides a potential treatment alternative for ALL patients, who are unable, or at risk of developing hypersensitivity reactions to prior asparaginases. The initial results from this program suggests that GRASPA is well tolerated, and may have a potential benefit in patients with double allergies. The program will be expanded to other European countries Disclosures Bertrand: ERYTECH Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dombret:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Recher:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Research Funding; Amgen: Research Funding; Sunesis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Salako:ERYTECH Pharma: Employment. Godfrin:ERYTECH Pharma: Employment. El Hariry:ERYTECH Pharma: Employment.

Time to Minimal Residual Disease (MRD) Negativity Is Independently Predictive of Outcome in Adults with Acute Lymphoblastic Leukemia (ALL) Receiving Hyper-CVAD

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2498-2498
Author(s):  
Ryan D. Cassaday ◽  
Philip A. Stevenson ◽  
Brent L. Wood ◽  
Pamela S. Becker ◽  
Paul C. Hendrie ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
White Blood Cells ◽  
Philadelphia Chromosome ◽  
Time Dependent ◽  
Secondary Malignancy ◽  
Fisher Exact Test ◽  
Inadequate Response ◽  
The Impact

Abstract Background: MRD is an established prognostic/predictive factor in ALL. Achieving MRD negativity (MRDNeg) early during treatment is associated with superior outcomes with pediatric regimens. However, little is known about how to use MRD assessments with hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with methotrexate and cytarabine), one of the most commonly used regimens in adults with ALL. MRDNeg at 3 months has been shown to be predictive of outcome with hyperCVAD + tyrosine kinase inhibitor (TKI) in Philadelphia chromosome (Ph)+ ALL (Ravandi, Blood, 2013, p. 1214), but this is relatively late in the treatment course. We hypothesized that achieving MRDNeg earlyduring treatment would be associated withbetter outcomes with hyperCVAD. Methods: We performed a retrospective analysis of our center's experience since 2005 under an IRB-approved protocol. We included pts with ALL (excluding Burkitt and mixed-phenotype) age >18 years (yrs) who received hyperCVAD as initial therapy. MRD was assessed primarily by either multiparameter flow cytometry or BCR-ABL quantitative PCR on bone marrow, though other techniques (e.g., cytogenetics [CG]) were considered if obtained. Timing and nature of assessments were left to treating physicians. Pts were not defined as MRDNeg until all assays performed were unable to detect any disease. Clinical risk at diagnosis was defined by age (> 35 yrs), white blood cells (WBC; > 30 for B-ALL, > 100 for T-ALL), and CG (Ph+, MLL rearranged, -7, +8, complex, low hypodiploid, and near triploid). Events included morphologic or MRD recurrence, change in treatment due to inadequate response, death from any cause, or secondary malignancy. Frequencies of characteristics between groups were compared using a Fisher exact test. Cox proportional hazards (PH) models were used to investigate associations between variables. A test of PH was used to assess the impact of time on the association between MRD and outcome, in which MRD was modeled as a time-dependent covariate with left-truncation. Clinical follow-up was updated as of June 2015. Results: We identified 142 pts for this analysis: 18% T-ALL, 73% > 35 yrs, 24% had high WBC (6 unknown), and 48% had high-risk CG, 71% of which (34% of total) were Ph+ (11 unknown). Sixty-five pts (46%) underwent hematopoietic cell transplantation (HCT) in first remission (CR1): 32% with reduced-intensity and 68% with myeloablative conditioning. All Ph+ pts received TKI with hyperCVAD: 23 (48%) received imatinib and 25 (52%) received dasatinib. Median time of 1st MRD assessment (relative to start of treatment) was 37 days, with 27% occurring by 21 days and 85% by 90 days; 42% were MRDNeg at 1stassessment, 26% became MRDNeg later, and 32% did not become MRDNeg during treatment with hyperCVAD. Incidences of age > 35 yrs (P = 1), high-risk CG (P = 0.08), Ph+ (P = 0.72), and high WBC (P = 0.38) were not significantly different in MRDNeg pts. HCT in CR1 was more common in MRDNeg pts (P = 0.05). In Cox PH models adjusted for HCT in CR1, CG, and WBC, MRDNeg pts had significantly better overall survival (OS; hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.23-0.81; P = 0.01; 48 events) and event-free survival (EFS; HR 0.27, 95% CI 0.16-0.46; P < 0.01; 84 events). Through an exploratory landmark analysis, the benefit of MRDNeg on EFS became more pronounced after 8 weeks: pts who were MRDNeg by 8 weeks had significantly better EFS (HR 0.53, 95% CI 0.32-0.89; P = 0.02) than those who were not. Further, achieving MRDNeg earlier during treatment was associated with better EFS. In a test of PH on the time-dependent Cox PH model, time to MRDNeg had a significant impact on the association between MRD status and EFS (P = 0.02) but not OS (P = 0.19). This is depicted in Fig 1, where being MRDNeg earlier after treatment initiation is associated with a smaller beta (i.e., significantly less hazard for an event). Conclusions: MRDNeg is an independent predictor of superior OS and EFS in adults receiving hyperCVAD for ALL. Further, achieving MRDNeg earlier during treatment was associated with better EFS. When considering the time-dependent nature of MRD status relative to EFS, 8 weeks after initiation of hyperCVAD may represent an important prognostic time point. If confirmed in an independent dataset, this may prove to be a useful surrogate in both routine clinical practice and future clinical trials with this regimen. Disclosures Cassaday: Pfizer: Research Funding; Seattle Genetics: Research Funding.

Central Nervous System (CNS) Relapse in Adult Patients with Acute Lymphoblastic Leukemia (ALL): Frequency and Prognosis in 467 Patients without Cranial Irradiation for CNS Prophylaxis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1841-1841
Author(s):  
Juan-Manuel Sancho ◽  
Josep-Maria Ribera ◽  
Albert Oriol ◽  
Jesus-Maria Hernandez-Rivas ◽  
Concepcion Rivas ◽  
...  
Keyword(s):  
High Risk ◽  
Predictive Factors ◽  
Lymphoblastic Leukemia ◽  
Cranial Irradiation ◽  
Adult Patients ◽  
High Dose ◽  
Cns Involvement ◽  
Cns Prophylaxis ◽  
Cns Relapse ◽  
Ldh Value

Abstract Background. Recurrence of ALL in CNS in adults is considered a poor prognostic feature but few studies have analyzed this issue. The objective of this study was to analyze the frequency, prognosis and predictive factors of CNS involvement and recurrence in adult patients with ALL treated with 4 PETHEMA protocols not including cranial irradiation for CNS prophylaxis. Methods. From June 1989 to December 2003, 467 adult patients (≥ 15-years-old) diagnosed with ALL were treated with one of the four consecutive protocols of PETHEMA group: ALL-89 (standard and high risk, n=108), ALL-93 (high risk, n=222), ALL-96 (standard risk, n=84), and ALL-97 (Burkitt’s leukemia, n=53). CNS prophylaxis consisted of intrathecal (IT) injection of methotrexate (12 mg), cytarabine (30 mg) and hydrocortisone (20 mg), for 12–14 courses, together with high-dose systemic methotrexate and cytarabine during the early intensification phase. Cranial or craniospinal irradiation was not used in any case. Results. The median (SD) age was 33 (16) years and 272 (58%) were males. ALL type according to the FAB classification was: L1 28%, L2 61%, L3 11%. Immunological subtypes were: early-pre-B 15%, common 45%, pre-B 5%, mature B 11% and T 24%. CNS involvement at diagnosis was observed in 18 (3.9%) patients. Predictive factors for CNS involvement at diagnosis were: L3/mature B ALL (p<0.0001) and testicular involvement (p=0.006). Overall, complete remission (CR) was achieved in 381 (81%) of the patients, of whom 159 (42%) relapsed: 137 (36%) in bone marrow (BM) and 22 (5.8%) in CNS (14 isolated and 8 combined CNS and BM). The median (range) CR duration prior to CNS recurrence was 1.06 yr (95%CI0.11–2.01) for isolated CNS relapse, 0.6 yr (95%CI o.30–0.89) for combined relapse and 0.93 (95%CI 0.78–1.07) for BM relapse (p=0.76). No correlation was found between initial CNS involvement and CNS relapse. An initial LDH value > 1,000 U/L was the only factor associated with higher risk of CNS relapse (p<0.001). Treatment of CNS relapse consisted of systemic and IT therapy in the 22 cases (cranial irradiation was added to one) and CR was attained in 7 (32%) out of 22 of these patients. Stem cell transplantation was performed in 4 patients and 3 patients developed a second CNS recurrence. The median overall survival (OS) after recurrence was 0.7 yr for isolated CNS relapse, 0.13 yr for combined relapse and 0.41 yr for BM relapse (p=0.11). Conclusions. The frequency of CNS relapse in adult ALL patients receiving IT and systemic therapy for CNS prophylaxis is similar to that observed in protocols including cranial irradiation. An initial LDH value > 1,000 U/L was the only factor associated with higher risk of CNS relapse. Adult patients with CNS recurrence have a poor prognosis, although it is not different from that observed in BM relapses.

A Randomized, Double Blinded Study of Risedronate Versus Placebo for the Prevention of Bone Loss in Patients Receiving High Dose Corticosteroids for the Treatment of Acute Lymphocytic Leukemia and Lymphoblastic Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1486-1486 ◽  
Author(s):  
Kyle Cash ◽  
Robert Gagel ◽  
J Lynn Palmer ◽  
Deborah A. Thomas ◽  
Gloria Mattiuzzi ◽  
...  
Keyword(s):  
Lumbar Spine ◽  
Bone Loss ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Lymphoblastic Lymphoma ◽  
Lymphocytic Leukemia ◽  
Adult Patients ◽  
High Dose ◽  
Mineral Density ◽  
Dexa Scan

Abstract Abstract 1486 Background: Corticosteroid therapy is a well-known cause of osteoporosis. Studies have shown that the use of bisphosphonates such as risedronate can prevent bone loss in patients receiving moderate to high doses of corticosteroids. Patients with acute lymphoblastic leukemia and lymphoblastic lymphoma (ALL/LL) are at high risk of bone loss due to both leukemia and high dose steroids used in chemotherapy regimens. Objectives: The primary objective was to determine whether the use of risedronate decreases the amount of bone loss in adult patients with ALL/LL receiving chemotherapy with high dose corticosteroids when compared to placebo. Methods: Adult patients with newly diagnosed ALL/LL receiving Hyper-CVAD or BFM were randomly assigned to receive either risedronate 35 mg weekly or placebo. Both patients and physicians were blinded to the treatment assignment. Patients in both arms were given vitamin D and calcium. Bone mineral density (BMD) using DEXA scan was measured at baseline and at 6 months. Patients who lost more than 10% BMD when compared to baseline measurements were taken off the study and unblinded. We excluded patients with osteoporosis. Results: 36 patients were randomized to each treatment arm. Median age was 29 years in the risedronate arm and 42 years in the placebo arm (p=0.06). 22 patients had an available 6 month DEXA scan in the risedronate arm and 29 in the placebo arm. Patients on the placebo arm had a greater decrease in BMD at the left hip (mean −0.12) and right hip (mean −0.11) when compared to baseline than patients in the risedronate arm (left hip mean −0.08; right hip mean −0.078) and this was statistically significant (p=0.03 and p=0.04, respectively). There were no significant differences observed in the lumbar spine between the two groups. 11/22 (50%) patients in the risedronate arm were taken off study for significant % decrease in BMD at any site, and 18/29 (62%) patients in the placebo arm (p=0.28). Two patients, 1 in each arm, experienced a vertebral fracture during the first 6 months of chemotherapy. Conclusions: Adult ALL/LL patients receiving high dose corticosteroids with HyperCVAD have profound bone loss and should be monitored for this while receiving chemotherapy. Risedronate significantly reduced bone loss at the hips, but did not have a significant effect at the lumbar spine. Despite treatment with risedronate, 50% of patients had profound bone loss during the first 6 months of chemotherapy, thus a more potent bisphosphonate may be necessary to preserve bone mass, particularly at the lumbar spine. Whether a potent bisphosphonate or an agent such as a monoclonal antibody to RANK ligand will reduce fractures and improve quality of life should be studied in future clinical trials. Disclosures: Hu: Amgen: Research Funding, Speakers Bureau. Cabanillas:Procter and Gamble: Research Funding.

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