Epidemiology Of Invasive Aspergillosis (IA) During Induction Therapy In Adults With Acute Lymphoblastic Leukemia (ALL): A Graall-2005 Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1394-1394
Author(s):  
Clara Mariette ◽  
Anne Thiebaut ◽  
Jean-Yves Cahn ◽  
Didier Hocquet ◽  
Agnes Huynh ◽  
...  
Keyword(s):  
Median Time ◽  
Induction Therapy ◽  
High Efficiency ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Phase Iii ◽  
Particulate Filter ◽  
Attributable Mortality ◽  
Control Group ◽  
Aspergillus Antigen

Abstract Background IA is a major cause of morbidity and mortality for patients with hematological malignancies and has been mainly reported in patients with acute myeloblastic leukemia (AML) and stem cell transplantation. Much less is known about the role of IA during the treatment of lymphoproliferative diseases like ALL. Here, we retrospectively evaluated the characteristics of patients and the incidence of IA occurring during the induction course in adult ALL patients enrolled in the GRAALL-2005 trial. Methods We collected the data of 36 patients with IA during induction chemotherapy. All were included between May 2006 and October 2012 in the multicentric GRAALL-2005 phase III trial. According to ALL characteristics, these patients were treated in 3 different substudies: GRAALL, GRAALL-Rituximab (GRAALL-R) for CD20+ ALL, GRAAPH for Philadelphia (Ph) chromosome-positive ALL. IA was defined retrospectively using the EORTC modified criteria (De Pauw, CID 2008). Results Among the 969 patients enrolled, 36 (3.7%) developed IA during induction therapy. The median age was 30 years for all patients receiving induction and 47 years (range, 18 to 59) for patients with IA. We observed 18 IA (3%) by the GRAALL protocol (593 patients enrolled), 16 (8.3%) by the GRAALL-R protocol (191 patients enrolled), and 2 (0.7%) by the GRAAPH protocol (270 patients enrolled). In the GRAALL-R protocol, IA was diagnosed in 6 patients randomly assigned to receive rituximab and in 10 patients treated in the control group. The median time between first day of induction therapy and IA diagnosis was 20 days (range, -2 to 71). The median time between the first day of neutropenia and IA diagnosis was 18 days (range, 0 to 76). At the time of IA diagnosis, 13 patients were hospitalized in laminar airflow rooms, 10 patients in rooms with overpressure, 1 patient in a room with high-efficiency particulate filter, 5 patients in conventional rooms, 1 patient received home care and the type of hospitalization was unknown for the 6 remaining patients. Four patients with IA (11%) had received antifungal drug for invasive fungal infection (IFI) prophylaxis: one patient received fluconazole, one received caspofungin, and two received liposomal amphotericin B. All patients with IA presented pulmonary symptoms associated with a sinusal or cutaneous localization in 1 and 2 patients respectively. The diagnosis of IA was classified as possible in 7 episodes (19 %), probable in 22 episodes (61%), proven in 4 episodes (11%), and indeterminate in the remaining 3 episodes. Detection of Aspergillus antigen in serum by latex agglutination was positive in 24 cases (67%). Chest CT scans were taken for 33 patients (92%): nodules were found in 19 patients, halo sign in 20 patients, and “air crescent sign” in 1 patient. Bronchoalveolar lavage was performed in 11 patients (31%): culture was positive in 7 of them and Aspergillus antigen was positive in 2 of them. Biopsies where positive in 4 cases: in pulmonary biopsy in 3 patients and in cutaneous biopsy in 1 patient. Of all the Aspergillus isolates identified to the species level, Aspergillus fumigatus was isolated from 4 patients and Aspergillus flavus from 1 patient. Overall and IA-attributable 12-week mortality was 8 (0.8%) and 6 (16.7%) patients respectively. Conclusion IA is less frequently observed during induction therapy in adult ALL as compared to adult AML patients. However, the attributable mortality appears to be high in these patients. They are as at risk patients for IA and should be included in prophylactic and empirical antifungal clinical trials. Disclosures: No relevant conflicts of interest to declare.

A Plateau after 30 Months of Follow-Up in B -Lineage Childhood Acute Lymphoblastic Leukemia (ALL) with t(1;19)(q23;p13)/E2A-PBX1?.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1441-1441
Author(s):  
André Baruchel ◽  
Sylvie Chevret ◽  
Anne Auvrignon ◽  
Paola Ballerini ◽  
Gérard Michel ◽  
...  
Keyword(s):  
Median Time ◽  
Burkitt Lymphoma ◽  
Lymphoblastic Leukemia ◽  
Fusion Transcript ◽  
Wilcoxon Test ◽  
Response To Treatment ◽  
Control Group ◽  
Childhood All ◽  
Secondary Tumor ◽  
B Lineage

Abstract Late events are observed in B-lineage ALL with no plateau seen if a sufficient observation period is provided. The prognosis of childhood ALL associated to the t(1;19)(q23;p13)/E2A-PBX1 translocation has improved over the two last decades. The purpose of this study is to define the kinetics of relapse in a large cohort of children and to raise the possibility of a plateau in that entity. We identified 110 children treated for a B-lineage ALL harbouring a t(1;19(q23;p13) and/or E2A-PBX1 fusion transcript from 1987 to 2004 in the FRALLE protocols (FRALLE 83: n= 3, FRALLE 87–89: n=18, FRALLE 92 (phase II): n=10, FRALLE 93: n=48, FRALLE 2000 (still opened: n=31). Analysed features included: male sex (50, 45%), age (median: 6.9y; Q1–Q3: 3.5–12), CNS disease (4, 3.5%), leucocytosis (median: 21.4 G/L; Q1–Q3: 10.8–53.4), D8 poor prednisone response (PPR) (5/79, 6%), M1 D21 marrow response (103, 94%), and CR (108, 98%). For an accurate comparison, the subgroup of pts with t(1;19) included in the FRALLE 93 protocol (n=48) was compared to the 1,147 children aged more than 1 y with B- lineage ALL treated in the same protocol. Significant differences in the t(1;19) cohort were: excess of girls (65% vs. 46%; p= .01), and older age (median: 7 vs. 4.7; p= .01)). No differences in early response to treatment (D8, D21, D35) were seen. All the 110 patients received chemotherapy only, except 3 who received an autologous BMT for D8 PPR as recommended by the FRALLE 93 protocol. At a median FU of 65 months, 18 events have been recorded including 17 relapses (bone marrow: 13, CNS: 4) and 1 secondary tumor (abdominal Burkitt lymphoma) giving a 5 y and 10 y EFS of 78.7%. If “modern era” only is considered (> 1992), 5 y and 10 y EFS is 85.5%. Relapses occurred at a median time of 422 days (range: 72–899) in the whole t(1;19) cohort. In those from FRALLE 93, the median time to relapse (MTTR) was 280 days, that is significantly lower than the one observed in the control group defined above (MTTR = 894 days, Wilcoxon test, p = .01). Conclusions: We confirm that a high cure rate is now associated to that subgroup of childhood ALL. The main finding is that no event except from the secondary Burkitt lymphoma (1705 d) was registered after 30 months from diagnosis in that cohort of 110 children with t(1;19)/E2A-PBX1 translocation associated ALL. It is then conceivable to announce cure at 36 months in that subgroup with an extremely low possibility of mistake, thus much earlier and with more confidence than in the other B-lineage ALL.

The Serum Fas and Fas Ligand levels in Childhood Acute Leukemias.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4724-4724
Author(s):  
Alev Kiziltas ◽  
Bulent Antmen ◽  
Ilgen Sasmaz ◽  
Yurdanur Kilinc ◽  
Mustafa Yilmaz ◽  
...  
Keyword(s):  
Fas Ligand ◽  
Conflicts Of Interest ◽  
Cytotoxic T Cells ◽  
Lymphoblastic Leukemia ◽  
Serum Levels ◽  
Control Group ◽  
Extrinsic Pathway ◽  
Acute Leukemias ◽  
Mean Values ◽  
The Mean

Abstract Abstract 4724 Aim Abnormalities and alterations in apoptosis mechanism may lead to cancer development. Cystean proteases enzymes, called caspases, appear to be involved in both the initial signaling events. There are many proteins that trigger intrinsic and extrinsic pathway and induce apoptosis signals. Fas and its specific ligand that known as Fas Ligand are the best defined dead receptors and have functions in apoptosis regulation with many tumor types. Fas binds the ligand on the cytotoxic T cells and start apoptosis. Objectives of this study were to determine serum levels of Fas and Fas Ligand at the time of diagnosis in childhood acute leukemias that may be play important role in apoptosis mechanism. Patients and Methods In this study, we investigated serum Fas and Fas Ligand levels by using ELISA method in childhood acute leukemias. Twenty-nine cases with acute lymphoblastic leukemia and twenty-three cases with acute myeloblastic leukemia at the ages of 1-18 years are included this study. The age distrubition of the control group varied 1-15 years consisted of twenty-seven children. We investigated serum Fas and Fas Ligand levels at the time of diagnosis from peripheral blood samples. Results The comparison of the mean values of Fas and Fas Ligand levels in acute leukemia patients groups and control group have shown important difference as statistically (p<0,05). The mean values of Fas and Fas Ligand levels were higher in ALL and AML patients. The comparison of the mean values of Fas and Fas ligand levels in ALL and AML patients have shown no difference (p>0,05). The comparison of the Fas levels in ALL patients according to immunophenotypes; CALLA(+) B-ALL have higher mean level than T-ALL and shown important difference as statistically (p<0,05). The comparison of the mean values of Fas level at the diagnosis in ALL patients who had relapsed and patients who had remission have shown important difference (p<0,05). The mean values of Fas level were found higher in relapsed ALL patients. In these results showed that Fas and Fas ligand may play important role in apoptosis mechanism. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Combination of quinine as a potential reversing agent with mitoxantrone and cytarabine for the treatment of acute leukemias: a randomized multicenter study

Blood ◽  
1996 ◽  
Vol 88 (4) ◽  
pp. 1198-1205 ◽  
Author(s):  
E Solary ◽  
B Witz ◽  
D Caillot ◽  
P Moreau ◽  
B Desablens ◽  
...  
Keyword(s):  
Multicenter Study ◽  
Ex Vivo ◽  
Lymphoblastic Leukemia ◽  
Group Versus ◽  
Phase Iii ◽  
Control Group ◽  
Acute Leukemias ◽  
Blastic Transformation ◽  
Poor Risk

A phase III prospective randomized multicenter study was performed to determine whether quinine could improve the response rate of poor-risk acute leukemias (ALs) to standard chemotherapy including a multidrug resistance (MDR)-related cytotoxic agent. The rationale of the study was based on the negative prognostic value of MDR phenotype in ALs and the ability of quinine to reverse this phenotype both in vitro and ex vivo. Three hundred fifteen patients (median age, 49 years; range, 16 to 65) with relapsed (n = 108) or refractory (n = 32) acute myeloblastic leukemia (AML), relapsed (n = 27) or refractory (n = 9) acute lymphoblastic leukemia (ALL), secondary AL (n = 22) or blastic transformation of myelodysplastic syndrome ([MDS] n = 74) or myeloproliferative syndrome ([MPS] n = 43) were randomly assigned to receive mitoxantrone ([MXN] 12 mg/m2/d, days 2 to 5) and cytarabine ([Ara-C] 1 g/m2/12 h, days 1 to 5) alone or in combination with quinine (30 mg/kg/d, days 1 to 5; continuous intravenous infusion beginning 24 hours before MXN infusion). Side effects of quinine were observed in 56 of 161 quinine-treated patients and disappeared in all but four cases after one or two 20% dose decreases. Sera from quinine-treated patients showed increased MXN uptake in an MDR-positive cell line compared with matched sera obtained before quinine infusion. Quinine induced a significant increase in the incidence of nausea, vomiting, mucositis, and cardiac toxicity. A complete response (CR) was observed in 85 of 161 patients (52.8%) from the quinine-treated group versus 70 of 154 patients (45.5%) in the control group (P = .19). The most important differences between quinine and control group CR rates were observed in patients with refractory AMLs and blastic transformation of MDS and MPS. The CR rate was higher in P-glycoprotein-positive cases, although the difference was not significant. Failure of the regimen due to blastic persistence or blast number increase was higher in the control group (61 of 154 patients) than in the quinine group (45 of 161, P = .04). Early death was observed in eight cases (four in each arm) and death in aplasia in 27 cases (20 in quinine group v seven in control group, P = .01). The significant increase of toxicity in the quinine arm could have masked the clinical benefit of MDR reversion in poor- risk ALs.

scholarly journals Concomitant granulocyte colony-stimulating factor and induction chemoradiotherapy in adult acute lymphoblastic leukemia: a randomized phase III trial

Blood ◽  
1995 ◽  
Vol 86 (2) ◽  
pp. 444-450 ◽  
Author(s):  
OG Ottmann ◽  
D Hoelzer ◽  
E Gracien ◽  
A Ganser ◽  
K Kelly ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Induction Chemotherapy ◽  
Lymphoblastic Leukemia ◽  
Phase Iii ◽  
Control Group ◽  
Simultaneous Administration ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Adult Acute Lymphoblastic Leukemia ◽  
Stimulating Factor

This prospective multicenter study examined whether simultaneous administration of granulocyte colony-stimulating factor (G-CSF; Filgrastim) and induction chemotherapy for adult acute lymphoblastic leukemia (ALL) could prevent treatment-related neutropenia, infections, and resulting treatment delays. Seventy-six patients were randomly assigned to receive either G-CSF (n = 37) or no growth factor (n = 39) in conjunction with a uniform chemotherapy consisting of cyclophosphamide, cytarabine, mercaptopurine, intrathecal methotrexate, and cranial irradiation. The median duration of neutropenia (absolute neutrophil count &lt; 1 x 10(9)/L) during chemotherapy was 8 days in patients receiving C-CSF, compared with 12.5 days in the control group (P &lt; .002). A similar reduction from 11.5 to 7 days was observed in patients with T-ALL receiving additional mediastinal irradiation (P = .13). Infections occurred in 43% and 56% of patients in the G-CSF and control arm, respectively (P = .25); the incidence of nonviral infections was reduced by 50%, from 32 episodes in the control arm to 16 episodes in the G-CSF arm. Prolonged interruptions of chemotherapy administration were less frequent, with delays of 2 weeks or more occurring in only 24% of patients receiving G-CSF as opposed to 46% in the control arm (P = .01). Accordingly, chemotherapy was completed significantly earlier with the use of G-CSF (39 v 44 days, P = .008). With a median follow-up of 20 months, the probability of disease-free survival was 0.45 in the G-CSF group and 0.43 in the control group (P = .34). In conclusion, adult ALL patients appear to benefit by the simultaneous administration of G-CSF with induction chemotherapy because of a significant reduction in the duration of neutropenia, a trend to fewer infections, and a more rapid completion of chemotherapy.

Bortezomib (Velcade)-Melphalan-Prednisone (VMP) Versus Velcade- Thalidomide-Prednisone (VTP) in Elderly Untreated Multiple Myeloma Patients: Which Is the Best Partner for Velcade: An Alkylating or An Immunomodulator Agent?

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 651-651 ◽  
Author(s):  
Maria-Victoria Mateos ◽  
Albert Oriol ◽  
Joaquín Martínez ◽  
Ma Teresa Cibeira ◽  
Raquel de Paz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Median Time ◽  
Induction Therapy ◽  
Response Rate ◽  
Haematological Toxicity ◽  
Phase Iii ◽  
Induction Treatment ◽  
Induction Phase ◽  
Weekly Schedule ◽  
To Receive

Abstract Melphalan – Prednisone (MP) has been the Standard of care for elderly multiple myeloma patients in the past 40 years. However, bortezomib and thalidomide-based combinations have demonstrated to improve the efficacy in terms of both response rate and time to events as compared to MP. In two recent Phase II and phase III trials we have shown (Mateos et al. Blood 2006; San Miguel JF et al. EHA 2008) that the combination VMP is highly effective, but it remains to be elucidated which agent is the optimal partner for bortezomib: an alkylating or an immunomodulatory drug. In order to answer this question in April 2006, Spanish Myeloma Group (PETHEMA/GEM) activated a phase III trial comparing VMP versus VTP in untreated MM patients older than 65 years. Patients in the VMP arm received intravenous bortezomib 1.3 mg/m2 twice weekly (days 1, 4, 8, 11; 22, 25, 29 and 32) for one 6-week cycle (8 doses per cycle), followed by once weekly (days 1, 8, 15 y 22) for five 5-week cycles (4 doses per cycle) in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1–4 of each cycle. Patients in the VTP arm received the same bortezomib and prednisone regimen, but instead of melphalan they received continuous thalidomide at dose of 100 mg daily. For both groups, treatment continued for a maximum of 6 cycles (31 weeks) unless disease progression or unacceptable treatment-related toxicity occurred. The primary endpoint was overall response rate (ORR) after induction therapy and secondary endpoints included time to progression (TTP), progression-free survival (PFS), overall survival (OS), time to and duration of response, and safety. As of July 30, 2008, 246 out of 260 planned patients have been included in the study and 167 are evaluables for response to induction therapy and adverse events (AEs). Efficacy and toxicity analyses were performed on an intention-to-treat basis. 80 patients were randomly assigned to receive VMP and 87 to receive VTP. Regarding baseline characteristics, including cytogenetic abnormalities, no significant differences were observed in both arms. No significant differences were observed in response rate: ≥ PR in 78% of patients in VMP and VTP groups respectively, with a CR rate of 18% vs 23% (p=NS) and CR/nCR of 38% vs 32% (P= NS). Only one patient prgressed under induction treatment in each arm. Median time to first response was similar in both arms (1,6 months) and there were not differences in the median time to achieve CR (4,4 vs 4,9 months). Regarding haematological toxicity, VMP resulted in higher incidence of ≥G3 neutropenia (34% vs 19%; p=0,009) and thrombocytopenia (21% vs 9%; p=0,01); in contrast, 157 related non-hematological AEs occurred in VTP arm vs 133 in VMP arm (p<0,005); and they were ≥G3 in 32% vs 25% (p=0,04). The most relevant toxicities included: ≥G3 cardiac toxicity reported in 7% of patients receiving VTP vs 0% in VMP arm; the incidence of ≥G3 thromboembolic events was 3,4% in VTP arm and <1% in VMP arm; finally, 15% of patients in VTP arm developed ≥G3 peripheral neuropathy and 9% in VMP arm. No significant differences were reported in other non-hematologic toxicities, including infections despite the higher incidence of neutropenia in VMP arm. Treatment discontinuation due to AEs was required in 8 patients in VMP arm and in 16 patients in VTP arm (p=0,08). Five patients in VMP arm and 7 in VTP group died during the induction phase due to AEs. In summary this initial analysis indicates that there are no significant differences in terms of efficacy between VMP and VTP, while the incidence of non-hematological AEs, specially cardiac events, was higher in the VTP arm, resulting in more serious AEs and treatment discontinuations.. These data suggest that thalidomide may not be the partner of choice for combination with bortezomib and other IMIDs such as lenalidomide should be explored. In addition, our data indicate that the modified VMP regimen used in this trial (weekly schedule after cycle 1 and only six cycles) is well tolerated although the CR rate is lower than in the VISTA trial.

Is Time of the Essence in Adult Acute Myeloid Leukemia (AML)? Time to Blast Clearance and Time to Induction Therapy Fail to Predict Overall Survival (OS).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1617-1617
Author(s):  
Holbrook E Kohrt ◽  
Samit Patel ◽  
Michelle Ho ◽  
Terri Owen ◽  
Ravindra Majeti ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
Induction Therapy ◽  
Mayo Clinic ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Cleveland Clinic ◽  
Risk Groups ◽  
Adult Patients

Abstract Abstract 1617 Poster Board I-643 Background A rapid decline of circulating blasts in response to induction therapy is one of the most important prognostic factors of clinical outcome in childhood acute lymphoblastic leukemia. However, the prognostic significance of time to blast clearance in adult AML has not been well-established. The Mayo Clinic recently reported improved OS with early clearance ('3 days) of peripheral blood (PB) blasts among 86 adult patients with AML. In a separate series, age is suggested to modify the effect of time with shorter interval from diagnosis to induction therapy (TDT) predicting improved OS in younger but not older AML patients. We retrospectively reviewed the Stanford Leukemia Database to validate the prognostic relevance of time and age as a putative effect modifier with respect to OS in AML. Methods From 1993 to 2008 outcomes of 1,909 adult patients with leukemia were reviewed to select eligible patients with previously untreated AML (non-acute promyelocytic leukemia) having received cytarabine-based induction regimens. We defined the day of PB blast clearance (the first day after initiating induction chemotherapy that PB blasts were absent), and three “blast risk groups” (good, intermediate and poor, according to PB blast clearance on or before day 3, on days 4 or 5, or on day 6 or beyond, respectively) identical to the Mayo Clinic model. A 100 cell manual slide differential count was evaluated from the first day of induction through nadir with PB blasts enumerated unless the WBC was less than 0.5 ×109/L. For purposes of TDT analysis, patients receiving therapy on day of diagnosis were excluded (24 patients) as performed in the Cleveland Clinic-MD Anderson (CC-MDA) model. We defined delayed versus immediate treatment (delayed meaning more than 5 days from day of diagnosis to first day of induction therapy) identical to the CC-MDA model. Results Among 333 patients (55% males; median age 53y, range 18-88, including 224 patients<60y) with previously untreated AML, the median and range of white blood cell count (WBC), PB blast percent, and TDT were 10 × 109/L (range: 0.1–332), 23.0% (range: 0–98), and 4 days (range: 0-91) respectively. Karyotype was classified as favorable, intermediate and unfavorable in 9.7%, 59.3% and 31% of cases, respectively. At the time of analysis, 56% had died, primarily of relapse. Median OS was 59 weeks (range: 0-558) in all patients, 76.2 (range: 3.4-558) and 38.3 (range: 0-342) weeks in patients younger than 60 years, and older patients, respectively. The median time to PB blast clearance was six days (range: 1– >11). The distribution of good, intermediate and poor blast risk groups was 28.3%, 26.1%, and 45.6%, without significantly different median OS of 63.8, 56.2, and 51.6 weeks, respectively (Fig 1, p=0.61). In univariate analysis there was no relationship between TDT and OS among all patients as a continuous variable (p=0.791) or classified as delayed versus immediate treatment (Fig 2, p=0.92). When stratified by older and younger AML patients, age did not modify the effect. Conclusion In adults with non-APL AML, both TDT and PB blast clearance after induction chemotherapy with cytarabine-based regimens failed to predict OS. Current practice standards should not be modified until further studies validate the significance of time from diagnosis to treatment and to clearance of circulating blasts. Disclosures No relevant conflicts of interest to declare.

Preclinical Evaluation of Tysabri as a Novel Adjuvant Therapy against Drug Resistant B-ALL.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3089-3089 ◽  
Author(s):  
Yao-Te Hsieh ◽  
Enzi Jiang ◽  
Carlton Scharman ◽  
Ella Waters ◽  
Eugene Park ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Adjuvant Therapy ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Scid Mice ◽  
Prolonged Survival ◽  
Control Group ◽  
Drug Resistant

Abstract Abstract 3089 Poster Board III-26 Novel treatment strategies for pediatric acute lymphoblastic leukemia (ALL) have turned a rapidly deadly diagnosis into a highly treatable entity, but we are still failing 25% of our pediatric ALL patients who die of recurrent ALL. Definitive studies have demonstrated that adhesion of leukemia and lymphoma cells to extracellular matrices or stromal cells protects them against the toxicity of cytoreductive chemotherapy drugs. In this context, a specific role for CD49d, a dominant adhesion molecule for normal lymphocytes, was demonstrated for acute myeloid leukemia (AML) and other malignant hematopoietic cells. The finding that CD49d blockade sensitizes AML cells to chemotoxicity may be of therapeutic potential, as is suggested by recent findings for AML cells engrafted in NOD/SCID mice. CD49d is and is similarly expressed on acute lymphoblastic leukemia (ALL) cells, but our knowledge about CD49d adhesion-mediated chemoprotection of B-ALL is limited. We hypothesized whether similar to primary AML blasts, xenografted ALL cells resistant to chemotherapy can be sensitized to chemotherapy by disrupting their CD49d-mediated adhesive interaction with stroma. To test our hypothesis we used as a CD49d inhibitor the humanized anti-human CD49d antibody natalizumab, or Tysabri®, which is in clinical use for the treatment of relapsing or refractory Multiple Sclerosis. To determine the potential of Tysabri as a single agent to decrease leukemia progression, we engrafted 5-7 weeks old NOD/SCID mice with primary drug resistant B-ALL labeled with lentiviral luciferase to allow monitoring of leukemia using noninvasive bioluminescent imaging. Tysabri administered upon detection of engraftment on Day15 post-injection of leukemia in the dose of either 1 mg (n=3) or 6 mg (n=3) led to remarkably slower leukemia progression regardless of the dose compared to the control group treated with saline only (n=2). Additional administration of Tysabri on day 29 and day 37 did not result in further containment of leukemogenesis but still showed a marked reduction in progression compared to the saline treated control group. In addition, we determined in vivo that a weekly administration of Tysabri in the dose of 5mg/kg/d resulted in prolonged survival compared to the treated control (p<0.05). Next, we assessed the effect of adjuvant anti-CD49d antibody-mediated dislodgement of ALL cells of drug resistant patients in combination with chemotherapy. The group treated for 4 weeks with chemotherapy including Vincristine, Dexamethasone and L-Asparaginase (VDL) in combination with Tysabri (5mg/kg/d) admistered once weekly showed decreased progression of leukemia and significantly prolonged survival (p<0.05) compared to the VDL only treated control group. No toxicity of Tysabri treatment was observed. Taken together, our data indicates the potential of Tysabri as a novel adjuvant therapy for treatment of drug resistant B-ALL. Given the availability of clinical-grade CD49d blocking antibody, clinical studies can follow immediately, should our hypothesis be confirmed in further in vitro an in vivo studies. Disclosures No relevant conflicts of interest to declare.

Severe Telomeric Erosion In Ph-Negative Hematopoiesis After Successful CML Treatment: Association with Acquired Cytogenetic Lesions and Hematological Toxicity.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3375-3375
Author(s):  
Chiara Lobetti Bodoni ◽  
Ferrero Dario ◽  
Elisa Genuardi ◽  
Roberto Passera ◽  
Elisa Bernocco ◽  
...  
Keyword(s):  
Median Time ◽  
Conflicts Of Interest ◽  
Strong Association ◽  
Previous History ◽  
Hematological Toxicity ◽  
Control Group ◽  
Treatment Schedule ◽  
Telomere Shortening ◽  
Over Time ◽  
Telomere Erosion

Abstract Abstract 3375 Introduction. Telomere are effective sensors of cell integrity and their accelerated shortening is a marker of genetic and/or proliferative stress in several tissues including the hematopoietic compartment. Severe telomere attrition has been indeed observed in aplastic anemia and post-transplant setting. Little is currently known on the genetic integrity of Ph-negative hematopoietic cells (HCs) repopulating the bone marrow (BM) after successful chronic myeloid leukemia (CML) treatment. We thus decided to verify whether severe telomere shortening might occur in this setting and to assess whether its presence might correlate to genetic and functional impairment of Ph-negative hematopoiesis. Patients and methods. We investigated 81 CML patients with persistent (≥12 months) complete cytogenetic remission (CCyR). Median age was 62 years (23-88), M/F ratio was 1.5. Median time from diagnosis and CCyR were 4 years (1-18) and 3 years (1-12) respectively. 15 patients had acquired cytogenetic abnormalities (CA) (del7: 4 patients, +8: 5 patients, del5q: 2 patients, del or +Y: 2 patients, other CA: 2 patients). Telomere length (TL) analysis was performed by Southern Blotting on polymorphonucleates (PMN) and on monocyte-depleted PBMC (MD-PBMC) to monitor both the myeloid and lymphoid compartments. As control group we analyzed 76 age-matched healthy donors. Prospective follow-up monitoring of TL was performed on 56 CML patients with a median time of 22 months from the first determination (range 12–20). Results. PMN (but not MD-PBMC) from CML patients showed a major erosion of their telomeric DNA (median loss 1294 bp p<0.001). Correlations were sought by using a multivariate general linear model on the whole population (CML patients and controls) and then exclusively on the CML population. In the whole population a previous history of CML was a predictor of TL attrition together with age (both p <0.001). In the CML-only population we found no association between TL and sex, Sokal score, or treatment schedule. Most notably we found a correlation between TL attrition and presence of acquired CA (p=0.02, figure 1A), particularly in case of del7 and +8. Somehow more surprisingly we found an increased TL shortening among patients lacking complete molecular remission (CMolR) (p=0.001). The physiological correlation between age and TL persisted also among CML patients (p=0.003). Moreover we found an association between the presence of short telomeres and G≥2 hematological toxicity of any kind (p=0,005), anemia (p=0,007) and a trend with the presence of neutropenia (p=0,080). The association persisted also when G1-4 toxicities were considered (hematological toxicity of any kind p=0.030, anemia p=0.010). We than made a prospective assessment of the telomere dynamics over time performing a second TL determination after at least 12 months on 56 patients. The overall population showed further significant ongoing telomere shortening that was superior to the expected yearly loss for healthy subjects (median annual telomeric loss of 261 bp). We then performed a patient by patient analysis of TL dynamics over time. None of the patients had evidence of telomere recovery. Moreover even considering the maximal recorded interassay variability of 300 bp and the maximal physiological annual telomeric loss (50 bp), a non-physiological telomeric loss was observed in 17 patients (30% of CML population, median loss of 534 bp, range 1290-357 bp, figure 1C). Conclusions. i) Ph-negative HCs display severe telomeric loss, compared to healthy controls; ii) telomere erosion is more pronounced in patients with CA and without CMolR; iii) a strong association between shorter telomeres and hematological toxicity (particularly anemia) was observed; iv) telomere loss is persistent over time in the whole population. Moreover one third of them has a clear evidence of ongoing telomere erosion during the remission phase. Our results indicate that Ph-negative hematopoiesis emerging after successful CML treatment suffers from severe and ongoing telomeric stress whose biological and clinical consequences need to be carefully investigated. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Results of a Phase III Double-Blind Study of the Addition of Tocilizumab Vs. Placebo to Cyclosporin/Methotrexate Gvhd Prophylaxis after HLA-Matched Allogeneic Stem Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 368-368 ◽  
Author(s):  
Glen A Kennedy ◽  
Siok-Keen Tey ◽  
Cameron Curley ◽  
Jason P Butler ◽  
Ashish Misra ◽  
...  
Keyword(s):  
Median Time ◽  
Research Funding ◽  
Acute Gvhd ◽  
Phase Iii ◽  
Control Group ◽  
Double Blind ◽  
Free Survival ◽  
Entire Cohort ◽  
Gvhd Prophylaxis ◽  
Grade Ii

Background: IL-6 mediates graft-vs.-host disease (GVHD) in experimental models of allogeneic stem cell transplantation. The addition of a humanized anti-IL-6R mAb (Tocilizumab; TCZ) to standard GVHD prophylaxis has shown in promise in reducing the incidence of acute GVHD in two prospective phase I/II clinical studies. Aims: To determine the efficacy of TCZ in preventing grade II-IV acute GVHD in patients with acute leukaemia or myelodysplasia undertaking 8/8 matched related sibling (MSD) or matched unrelated donor (MUD) allogeneic HPCT after myeloablative (MAC) or reduced intensity conditioning (RIC) across five Australian transplant centers. Methods: 145 patients (50 MSD and 95 MUD) were randomly assigned to either placebo or TCZ (8mg/kg; max dose 800mg) on day-1 of conditioning. Patients and physicians were both blinded to treatment. RIC patients all received Flu/Mel (n=81, 56%) while MAC patients received Cy/TBI (n=46, 32%) or Bu/Cy (n=18, 12%). All patients received T-replete PBPC grafts, and standard GVHD prophylaxis cyclosporine and day 1 (15mg/m2), 3, 6 and 11 (10mg/m2) methotrexate. The primary endpoint was incidence of grade II-IV acute GVHD. A planned substudy analyzed the MUD cohort. Secondary endpoints included day 180 grade II-IV acute GVHD free-survival (GVHD-FS), transplant-related mortality (TRM), progression-free survival (PFS), overall survival (OS), time to engraftment and rates of infection. The study was powered to observe a 50% reduction in the incidence of grade II-IV acute GVHD at day +100 for the entire and MUD cohorts, assuming a 50-55% baseline in the control group. Competing risk (death) regression adjusted hazard ratio (HR) was estimated to evaluate the GVHD-related outcomes in TCZ vs. placebo groups. Results: With a median follow up of 746 days, the overall incidence of grade II-IV GVHD at day 100 for the entire cohort was 36% vs. 27% for placebo vs. TCZ respectively (HR: 0.69; 95% CI 0.38-1.26; p=0.23), and 45% vs. 32% (HR: 0.61; 95% CI 0.31-1.22; p=0.16) for the MUD subgroup. The incidence of grade II-IV GVHD at day 180 for the entire cohort was 40% vs. 29% for placebo vs. TCZ respectively (HR: 0.68; 95% CI 0.38-1.22; p=0.19), and 48% vs. 32% (HR: 0.59; 95% CI 0.30-1.16; p=0.13) for the MUD subgroup. The incidence of severe grade III/IV GVHD at day 100 for the entire cohort was similar, 13% vs. 14% for placebo vs. TCZ respectively (HR: 1.04; 95% CI 0.42-2.61; p=0.93), and 10% vs. 14% for the MUD subgroup (HR: 1.42; 95% CI 0.41-4.95; p=0.59). A trend to improved GVHD-FS was noted in the TCZ-treated MUD subgroup, 52% vs. 68% for placebo vs. TCZ treated (HR: 1.70; 95% CI 0.86-3.37; p=0.13). For the entire cohort, TRM occurred in 8% of placebo-treated vs. 11% of TCZ-treated patients respectively (HR: 1.37; 95% CI 0.48-3.96; p=0.56); Progressions were similar at 25% vs. 33% (HR:1.44; CI 0.78-2.63, p=0.24) and OS was 79% vs. 71% (HR: 0.69; CI 0.35-1.34, p=0.27). No significant differences were seen in these outcomes in the MUD cohort. Day to neutrophil engraftment was marginally delayed in TCZ-treated patients, with median time to neutrophil ≥0.5 of 15 days (range 11-24 days) vs. 18 days (range 9-35 days) for placebo vs. TCZ-treated patients respectively (95% CI 1.3-4.7; p=0.001). Time to platelet engraftment was also marginally delayed in TCZ-treated patients, with median time to plts≥20 of 16 days (range 9-36 days) vs. 19 days (range 11-389 days) (95% CI 0.4-5.6; p=0.022). The median time to neutrophil and platelet engraftment in TCZ-treated patients were each 2 days slower in the MUD cohort (p=0.016 and p=0.22 for neutrophils and plts respectively). Two TCZ-treated patients died beyond day 30 (at day 31 and 32) with incomplete neutrophil recovery. The incidence of 1 or more grade 3 or higher liver toxicity (LT) was similar between groups, occurring in 14% of placebo-treated patients vs. 15% of TCZ-treated patients respectively (OR: 1.14; 95% CI 0.45-2.88; p=0.79). Grade 2 or higher infection adverse events occurred in 64% of placebo-treated patients vs. 71% of TCZ-treated patients respectively (OR: 1.34; 95% CI 0.67-2.71; p=0.41). Conclusion: In a phase III randomized, double-blind trial, TCZ administered at D-1 showed non-significant trends to reduced incidence of grade II-IV GVHD and improved acute GVHD-free survival in recipients of HLA-matched MUD donors, but no improvements in long term-survival. Study power was compromised by lower rates of acute GVHD in the control group than anticipated. Disclosures Ritchie: Novartis: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; BMS: Research Funding; Takeda: Research Funding; Beigene: Research Funding; Imago: Research Funding; Sanofi: Honoraria. Gottlieb:Novartis: Consultancy; AbbVie: Consultancy; University of Sydney: Employment; Merck: Consultancy; Gilead: Consultancy; Haemalogix P/L: Membership on an entity's Board of Directors or advisory committees, Research Funding. Paul:Novo Nordisk: Consultancy, Research Funding; Sanofi: Consultancy, Speakers Bureau; Roche: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Hill:Roche: Other: Investigator driven trial funding; Pharamcyclics: Consultancy, Research Funding; CSL: Consultancy, Research Funding; Implicit Bioscience: Consultancy, Research Funding. OffLabel Disclosure: Use of Tocilizumab for the prevention of acute GVHD

scholarly journals Clinical Utility of Morphological Evaluation of Day 14 Bone Marrow Biopsies in Acute Myeloid Leukemia Patients Undergoing Standard Induction Chemotherapy: Time to Change Practice?

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1004-1004 ◽  
Author(s):  
Yehuda E. Deutsch ◽  
German Campuzano-Zuluaga ◽  
Matthew P Salzberg ◽  
Alexandra Gomez Arteaga ◽  
Justin M. Watts ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Induction Chemotherapy ◽  
Induction Therapy ◽  
Predictive Value ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Response To Treatment ◽  
Bone Marrow Biopsies ◽  
Count Recovery

Abstract Introduction Early bone marrow (BM) evaluation (during aplasia or at “day 14” (D14)) in patients with AML undergoing conventional induction therapy has been adopted from clinical practice in pediatric acute lymphoblastic leukemia (ALL). While it has been shown that early persistence of AML correlates with decreased complete remission (CR) rates and overall survival (OS), unlike in ALL, there are no data to indicate that early initiation of re-induction therapy based on these findings will positively influence outcome. In fact, early re-induction, especially in older patients, may increase morbidity and mortality from prolonged cytopenias, infectious complications, and longer hospital stays. Moreover, it can be challenging to determine the nature of scattered blasts identified in a hypocellular BM at D14, as they may represent normal recovering marrow elements or malignant blasts. Even if malignant, the chemosensitivityof these cells will only be fully determined by later assessment of the BM at the time of expected count recovery (“day 28”). For these reasons, early re-induction therapy may not be advisable. In this retrospective study, we sought to evaluate the validity of D14 BM assessments as post-therapy prognostication to guide treatment decisions in AML. Methods We conducted a retrospective institutional study (2006-2014) of AML patients undergoing routine induction chemotherapy where diagnostic, interim (around D14) and recovery (D21-42) BM evaluations were available for review. Clinical information and pathology data were retrieved from our institutional database. Responses at D14 were categorized morphologically into three categories: optimal response (OR, blasts ≤5%), indeterminate response (IR, blasts 6-19%), and residual leukemia (RL, blasts ≥20% or a relative decrease in blast count from baseline of <20%). Published response criteria were used to define responses at marrow recovery. Suboptimal response (SOR) at D14 was defined as either IR or RL during the assessment period. Mann-Whitney's U test was used to compare non-normally distributed variables. The Fisher's exact test was employed to assess for associations between response to treatment at D14 and likelihood of recovering in CR. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of a D14 BM to predict CR were calculated for patients that were observed without re-induction. Results Evaluable patients (n=98) had a mean age of 51 years (20-73), and 45% were male. The median BM blast percentages at diagnosis, D14 and recovery were respectively 54.5%, 0% and 2.5% (Figure 1). There was a significantly greater absolute decrease in blast percentage from diagnosis to D14 in patients who recovered in CR compared to those who did not achieve CR (median: 53.5% vs 23.0%, P = 0.001). In patients that got early re-induction therapy for SOR at D14, the relative differential in baseline and D14 BM blasts was significantly lower compared to patients with D14 SOR who did not get re-induction therapy (median: 21.8% vs 77.8%, P=0.004) Ninety patients did not receive early re-induction therapy. Of these, 86 (95.6%) achieved CR and 4 patients (4.4%) recovered counts with residual leukemia. Fourteen (14.3%) patients were classified as SOR at D14. Of these, 6 (6.7%) did not receive re-induction therapy and 4 of these 6 patients (67%) achieved a CR. Eight patients received early re-induction therapy based on SOR at D14 (IR = 2, RL = 6); of these, 4 patients (50%) achieved CR at count recovery. Achieving an OR at D14 was predictive of achieving CR at recovery (sensitivity = 95.3%, PPV = 97.6%). However, not achieving an OR at D14 had low specificity (50%) and NPV (33.3%) for achieving CR (P = 0.021). Conclusions Our results indicate that a SOR at the D14 BM evaluation does not uniformly identify patients with primary induction failure (low NPV) and should not be used to dictate the timing of re-induction therapy. We confirmed the PPV of achieving an OR at D14 as previously reported, but we argue that no additional prognostic data is provided by an OR at D14, beyond what can already be predicted by pre-treatment variables (e.g., age and chromosomal abnormalities). We suggest that the D14 BM should be omitted from the routine evaluation of AML patients during induction therapy outside the context of a clinical trial. Figure 1 Figure 1. Progression and percentage of blasts at diagnosis, day 14 and recovery assessments (n = 98). Disclosures No relevant conflicts of interest to declare.

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