Improved Remission Induction Rate of Childhood AML: Preliminary Results of the AML02 Trial.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 275-275 ◽  
Author(s):  
Jeffrey Rubnitz ◽  
Bassem Razzouk ◽  
Paul Bowman ◽  
Gary Dahl ◽  
Norman Lacayo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Low Dose ◽  
Single Agent ◽  
Remission Induction ◽  
Intrathecal Therapy ◽  
High Dose ◽  
Triple Combination Therapy ◽  
Cns Relapse ◽  
Low Dose Cytarabine ◽  
Bone Marrow Blasts

Abstract The multicenter AML02 trial randomly assigns patients to receive high-dose or low-dose cytarabine (A), daunorubicin (D), and etoposide (E) as Induction I; all subsequent therapy is risk-adapted. Pharmacokinetic, pharmacodynamic, and gene expression studies are performed after exposure to high-dose or low-dose cytarabine. Patients with no response (NR, ≥ 25% bone marrow blasts) to Induction I receive low-dose ADE + gemtuzumab ozogamicin (GO) as Induction II, whereas all others receive ADE. Minimal residual disease (MRD) is monitored by flow cytometry and is defined as ≥ 0.1% cells with leukemia-associated immunophenotypes among bone marrow mononuclear cells. Patients who are MRD+ after induction therapy receive GO as a single agent before consolidation chemotherapy or stem cell transplantation. Among the 112 patients enrolled since October 2002, 37 had -7, FAB M6 or M7, FLT3 internal tandem duplication (ITD), or MDS or treatment-related AML and were classified as high-risk (HR); 32 had AML1-ETO, CBFβ-MYH11, or MLL-AF9 (low-risk; LR); the remaining 43 were considered as standard-risk (SR). The rate of complete response (CR, <5% bone marrow blasts) was 84% after Induction I and 97% after Induction II. Of the 3 patients who did not attain CR, 2 had partial responses and 1 died of streptococcal sepsis during Induction II. CR rates differed according to risk group after Induction I (LR, 100%; SR, 91%, HR 61%) but not after Induction II (LR, 100%; SR, 98%, HR 94%). The association between risk groups and MRD (determined successfully in 95% of cases) was more striking: the rate of MRD negativity after Induction I was 88% in LR, 59% in SR, and 26% in HR patients; after Induction II, rates were 97%, 82%, and 53%, respectively. Response to initial therapy was particularly poor among patients with a FLT3-ITD: only 1 of 11 patients was MRD-negative after Induction I and only 3 were MRD-negative after Induction II. 5 of the 6 patients who had NR to Induction I attained CR after subsequent treatment with ADE + GO and all 6 had dramatic reductions in MRD levels (from a median of 26% to a median of 0.24%). An additional 14 patients with MRD levels 0.1% to 5.6% received GO at the beginning of consolidation: 9 became MRD-negative. Overall, there were 4 deaths from infection (2 bacterial, 1 fungal, 1 viral), which occurred during induction (1), consolidation (1), and after completion of chemotherapy (2). Because CNS relapse occurred in 3 of the first 33 patients treated, intrathecal therapy was changed from cytarabine alone to triple combination therapy with methotrexate, hydrocortisone, and cytarabine; none of the 79 subsequent patients has had a CNS relapse. The 1-year event-free and overall survival estimates are 76.8% (SE, 5.1%) and 89.1% (SE, 3.8%). In conclusion, AML02 therapy has produced a high overall remission rate and low treatment-related mortality, which we attribute to excellent supportive care and to the use of risk- and MRD-adapted therapy.

Phase I Study of the Combination of 5-Azacitidine Sequentially with High-Dose Lenalidomide in Higher-Risk Myelodysplastic Syndrome (MDS) and Acute Myelogenous Leukemia (AML)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2613-2613 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Naval G. Daver ◽  
Gautam Borthakur ◽  
Marina Konopleva ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Conflicts Of Interest ◽  
Single Agent ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Significant Activity ◽  
Monosomy 7 ◽  
Prior Therapy ◽  
Bone Marrow Blasts

Abstract Abstract 2613 The hypomethylating agents are standard of care in patients with higher risk MDS and used frequently in older AML. A number of strategies, including combination approaches, are being developed to improve results of single agent hypomethylating agent. For instance the combination of 5-azacitidine and lenalidomide (LEN) has been shown to be safe and active in a phase I trial (Sekeres JCO 2010; 28:2253–8). Recently the use of high dose LEN (50 mg orally daily) has been reported to have significant activity in older AML (Vij Blood. 2011;117:1828–33). We hypothesized that sequential combination of 5-azacitidine followed by LEN could be safe and active in patients with higher risk MDS and AML. To test this concept, we developed a phase I/II protocol of such combination. Here, we present results from the completed phase I portion of the study. Patients with refractory or relapsed AML and MDS (bone marrow blasts more than 10%) of any age or untreated patients older than 60 years with AML or MDS who refused or were not eligible for frontline therapy were eligible. Adequate performance status, liver function and renal function were requiered. All study participants were registered into RevAssist® program. Females of childbearing potential were required to have a negative pregnancy test. 5-azacitidine was administered at 75 mg/m2 IV daily for 1 to 5 day on a 28 day cycle. LEN was administered on day 6 for 5 or 10 days. The phase I portion of the study design followed a classic “3+3” design and only LEN was dose escalated. 28 patients were registered in the study. The following doses of LEN were used: 10 (N=5), 15 (N=3), 20 (N=3), 25 (N=3), 50 (N=4), 75 mg (N=3) orally for 5 days and 75 for 10 days (N=7). Median age was 65 (range 31 to 79); 19 patients had AML and 9 had MDS or CMML. Median baseline WBC was 1.95 K/μL (range 0.1 to 19.1), median platelet count 68 K/μL (4 to 328), median bone marrow blasts 23% (range 11% to 84%), 8 had diploid cytogenetics and 20 others including 5q- (8 patients), monosomy 5 (5 patients) and monosomy 7(7 patients), del 17 (4 patients), t(9:11)(2 patients) and t(3;5)(2 patients). FLT-3 and N-RAS mutations were seen in 2 patients each and NPM-1 mutation in 1 patient. 22 patients had received prior therapy. A total of 88 cycles of therapy have been administered with a median of 1.5 cycles (range 1 to 10). No dose limiting toxicity was documented and the maximal tolerated dose was therefore not reached. At the 75 mg × 10 days dose, one patient died unexpectedly and subsequently 6 additional patients were treated with no additional severe toxicities observed. Common non-hematological toxicities were fatigue, loss of appetite, constipation, skin rash, fevers and weight loss. Of 6 patients that had not received prior therapy, 5 were evaluable for response and 3 (60%) achieved a complete response at doses of 25 and 50 mg of LEN. No response was observed in previously treated patients but 9 (47%) had stable disease. In conclusion, the combination of 5-azacitidine with high dose LEN up to 75 mg orally × 10 days is safe in patients with AML/MDS. The study continues now in a phase II extension of N=40 patients with LEN at a dose of 50 mg daily × 10 days. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Low-dose versus high-dose methotrexate during remission induction in childhood acute lymphoblastic leukemia (Protocol 81-01 update)

Blood ◽  
1991 ◽  
Vol 78 (10) ◽  
pp. 2514-2519 ◽  
Author(s):  
CM Niemeyer ◽  
RD Gelber ◽  
NJ Tarbell ◽  
M Donnelly ◽  
LA Clavell ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Low Dose ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Remission Induction ◽  
High Dose ◽  
Childhood All ◽  
To Receive

We evaluated event-free survival (EFS) and leukemia-free interval (LFI) of children treated for acute lymphoblastic leukemia (ALL). Patients were randomized to receive either a low dose or high dose of methotrexate (MTX) as a single agent at the time of diagnosis. Five days later, multidrug therapy was begun. We assessed the early antileukemic efficacy of the two doses of MTX, as well as toxicity and long-term efficacy. An increase in cell kill, as indicated by a larger decrease in the percentage of viable cells in the bone marrow between days 0 and 5, was observed for the high-dose MTX group when compared with the low-dose MTX group (P = .04). At 7.1 years of median follow- up, the 38 children randomized to receive high-dose MTX had a better EFS and LFI compared with the 39 patients randomized to receive low- dose MTX. The 7-year percentages (+/- SE) for EFS were 82% +/- 6% for high-dose MTX and 69% +/- 7% for low-dose MTX (P = .13). The 7-year percentages for LFI were 91% +/- 5% and 69% +/- 7%, respectively (P = .01). We recommend that high-dose MTX be considered as an effective addition to induction therapy in childhood ALL.

A Limited Impact of Chemotherapy on Prolonged Survival in Myelodysplasia (MDS). An Analysis of 142 Patients with Advanced Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2677-2677
Author(s):  
Jaroslav Cermak ◽  
Antonin Vitek ◽  
Marcela Lukasova ◽  
Petr Cetkovsky ◽  
Pavel Klener
Keyword(s):  
Bone Marrow ◽  
Multivariate Analysis ◽  
Supportive Care ◽  
Median Survival ◽  
Combination Chemotherapy ◽  
Low Dose ◽  
Single Agent ◽  
Impact On Survival ◽  
Low Dose Chemotherapy ◽  
Bone Marrow Blasts

Abstract The influence of different clinical and laboratory parameters and various therapeutic approaches on the survival was retrospectively studied in a group of 142 adult patients with advanced forms of primary MDS: RAEB with > 10% blasts or RAEB-T. Univariate statistical analysis was performed using Kaplan-Meier curves and log-rank2 test. Independent variables for determining survival were studied using proportional hazards regression multivariate analysis. Median survival, estimated 1 year (ES1y) and 3 year (ES3y) survival of patients stratified according to different treatment modalities are shown in the table. Median survival and estimated 1 and 3 year survival of patients stratified according to different treatment approaches. treatment Nr.of patients median survival (months) ES1y (%) ES3y (%) allo SCT (+/− chemotherapy) 31 37,5 90,3 58,0 chemotherapy + auto SCT 6 21,5 100 33,3 combination chemotherapy 47 8,0 40,4 4,3 low-dose chemotherapy 18 5,5 22,2 11,1 demethylating agents 3 11,5 33,3 NE oral single agent chemoth. 6 2,8 0 0 supportive care only 31 3,0 3,2 0 Allogeneic stem cell transplantation (SCT) regardless to the number of bone marrow blasts at the time of conditioning or to whether the patients received combination chemotherapy prior SCT or not was the most significant parameter affecting survival in univariate analysis (χ2=46,3, P<0.00001). However, achievement of complete (CR) or partial (PR) remission (according to Cheson criteria) after combination or low-dose chemotherapy had also a significant impact on survival, whether followed by SCT (χ2=31.9, P<0.0001) or not (χ2=27,8, P=0.0001). Treatment by combination chemotherapy itself (χ2=13,7, P=0.001) and age < 55 years (χ2=13,4, P=0.001) were also parameters with significant beneficial impact on survival. A multivariate analysis revealed SCT as the only independent variable determining survival in the whole group of patients (χ2=44,4, P=0.00001), SCT performed in CR/PR was a significant variable affecting survival in patients < 55 years (χ2=3,9, P=0.04). In non-transplanted patients, only achievement of CR or PR had a significant impact on survival (χ2=16,4, P=0.001). Our results confirm previous data showing only limited benefit of combination chemotherapy in patients with advanced MDS. Despite a significant impact on survival compared to single agent therapy or supportive care (P=0.005), combination chemotherapy not followed by SCT had only minimal effect on prolonged survival that was not different from treatment with low-dose chemotherapy (P=0.4) even in patients who achieved CR or PR (estimated 3 years survival was only 4,3 %). On the other hand, achievement of CR or PR prior SCT was a significant factor affecting long-term survival in patients < 55 years (estimated 3 years survival for SCT in CR/PR was 75% compared to only 36% for those with > 5% bone marrow blasts prior SCT). Our data support the usefulness of combination chemotherapy followed by SCT as an optimal treatment regimen for younger patient with advanced MDS. In future studies, combination chemotherapy followed by treatment with demethylating agents might be a promising approach to prolong survival in patients with advanced MDS who are not indicated for SCT.

Phase I study of frequent low-dose administration of decitabine, alone or in combination with hyperCVAD, in relapsed or refractory acute lymphocytic leukemia (ALL)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7072-7072 ◽  
Author(s):  
H. Yang ◽  
D. A. Thomas ◽  
M. E. Rytting ◽  
P. A. Zweidler-McKay ◽  
D. L. Brown ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bone Marrow ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Low Dose ◽  
Single Agent ◽  
Molecular Studies ◽  
Level 1 ◽  
Bone Marrow Blasts

7072 Background: Aberrant DNA methylation is frequent in ALL. Decitabine, a hypomethylating agent, is a potent inducer of apoptosis in lymphoid leukemia cell lines. In vivo, treatment with decitabine results in transient induction of global hypomethylation. Therefore, a more frequent schedule of administration (i.e. every other week (QOW)) may have significant clinical activity. Methods: We have developed a phase I study of low decitabine administered QOW. Patients that do not respond or progress after decitabine can receive the combination of decitabine with hyperCVAD in a sequential phase of the study. Starting doses of decitabine are 10 mg/m2 IV daily×5 every other week, and 5 mg/m2 IV daily×5 concomitant with hyperCVAD. The studies follow a classic “3+3” design. Patients with relapsed/refractory ALL of any age are elegible. Molecular studies include the analysis of global and gene specific DNA methylation and gene expression reactivation. Results: Seven patients have been treated (median age 25, range 8–44). All had refractory disease and had previously completed at least 8 courses of hyperCVAD therapy and 2 years of maintenance therapy or similar. Four patients have been treated at dose level 1 of single agent decitabine, and 3 at dose level 2 (20 mg/m2). Three of these patients have also been treated at dose level 1 of the combination of hyperCVAD and decitabine. No severe drug related toxicites have been observed. Four patients had achieved a response: 1 CR after decitabine and hyperCVAD, and 3 PR (normalization of peripheral blood with bone marrow blasts reduction of more than 50% but above 5%). One PR was achieved after decitabine and hyperCVAD, but two with only decitabine. Two of these patients did not qualify for CR because bone marrow blasts were 6%. Of these four responding patients, 1 in CR received successful alloSCT, 1 progressed after 2 courses of single agent decitabine, and 2 pediatric patients continue on therapy. The study continues. Molecular studies are ongoing. Conclusions: In summary, frequent administration of low dose decitabine, alone or in combination with hyperCVAD, may be clinically safe and active in advanced relapsed/refractory ALL. No significant financial relationships to disclose.

scholarly journals Low-dose versus high-dose methotrexate during remission induction in childhood acute lymphoblastic leukemia (Protocol 81-01 update)

Blood ◽  
1991 ◽  
Vol 78 (10) ◽  
pp. 2514-2519 ◽  
Author(s):  
CM Niemeyer ◽  
RD Gelber ◽  
NJ Tarbell ◽  
M Donnelly ◽  
LA Clavell ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Low Dose ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Remission Induction ◽  
High Dose ◽  
Childhood All ◽  
To Receive

Abstract We evaluated event-free survival (EFS) and leukemia-free interval (LFI) of children treated for acute lymphoblastic leukemia (ALL). Patients were randomized to receive either a low dose or high dose of methotrexate (MTX) as a single agent at the time of diagnosis. Five days later, multidrug therapy was begun. We assessed the early antileukemic efficacy of the two doses of MTX, as well as toxicity and long-term efficacy. An increase in cell kill, as indicated by a larger decrease in the percentage of viable cells in the bone marrow between days 0 and 5, was observed for the high-dose MTX group when compared with the low-dose MTX group (P = .04). At 7.1 years of median follow- up, the 38 children randomized to receive high-dose MTX had a better EFS and LFI compared with the 39 patients randomized to receive low- dose MTX. The 7-year percentages (+/- SE) for EFS were 82% +/- 6% for high-dose MTX and 69% +/- 7% for low-dose MTX (P = .13). The 7-year percentages for LFI were 91% +/- 5% and 69% +/- 7%, respectively (P = .01). We recommend that high-dose MTX be considered as an effective addition to induction therapy in childhood ALL.

Short Survival, Despite Promising Response Rates, after Bortezomib Treatment of Multiple Myeloma Patients with a 13q-Deletion.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 509-509 ◽  
Author(s):  
Johannes Drach ◽  
E. Kuenburg ◽  
Verena Sagaster ◽  
Niklas Zojer ◽  
Hannes Kaufmann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Prognostic Factors ◽  
Serum Albumin ◽  
Single Agent ◽  
Remission Induction ◽  
High Dose ◽  
Minor Response ◽  
Bone Marrow Plasma ◽  
13Q Deletion

Abstract Presence of a chromosome 13q-deletion confers a poor prognosis to patients with multiple myeloma (MM) irrespective of the treatment modality (standard-dose chemotherapy, high-dose melphalan with autologous transplantation, allogeneic transplantation, thalidomide), which underlines the need for effective therapy in this high-risk MM patient population. Bortezomib (B) is the first compound of a new class of agents - the proteasome inhibitors - showing activitiy in relapsed and chemotherapy-refractory MM. Preliminary evidence suggests that B may also be active in MM with unfavorable standard prognostic factors. Therefore, the aim of our investigation was to study the activity of B in relapsed MM in the context of chromosomal aberrations (in particular deletion of chromosome 13q14 [del(13q14)] and 14q-translocations [t(14q32)]) as detected by interphase fluorescence in situ hybridization (FISH). Up to now, 52 patients with relapsed/refractory MM (47 after ≥2 lines of prior therapy) were treated with B (1.3 mg/m2 on days 1, 4, 8, 11; q21 days). Patients not achieving at least a minor response to single-agent B were treated with B plus dexamethasone (DEX; 8–20mg); subsequently, melphalan (10 mg/m2) or doxorubicin (9 mg/m2) was added to B/DEX treatment. To date 44 patients are evaluable for response, time to treatment failure (TTF), overall survival (OS), and association with prognostic factors. 23 evaluable patients (52%) experienced an objective response, with 8 patients (18%) achieving a CR/near-CR (&gt;90% paraprotein reduction), 12 patients (27%) achieving a PR (50 – 90% paraprotein reduction), and 3 patients (75) showing a MR (25 – 50% paraprotein reduction). Median time to response was 3 weeks (range, 3 – 9 weeks). According to FISH, 22 patients (50%) had a del(13q14). B was effective for remission induction in both del(13q14) MM patients (18% CR/nearCR, 18% PR, 5% MR) and 13q-normal patients (18% CR/nearCR, 36% PR); however, median TTF (2.6 versus 6.7 months) and median OS (6.1 months versus not yet reached; P = .047) were shorter for del(13q14) patients compared to 13q-normal patients. Of note, failure to respond to B and short OS was observed in 2 patients with del(13q14) and concomitant amplification of CKS1B (1q21). Additional studies regarding 1q21 are in progress. Remission rates, TTF, and OS were similar in patients with and without a t(14q32). One patient with a t(4;14)(p16;q32) responded not only to single agent B with a remission lasting for 7 months, but later also responded to B/DEX and the B/DEX/chemotherapy combination with remissions lasting for several months each. On the other hand, only one of 5 patients with a t(11;14)(q13;q32) achieved a response (MR) to B. Beta-2-microglobulin did not influence treatment outcome after B. Significantly shortened OS following B treatment was noted in MM patients with serum albumin &lt;3.5 g/dl (4.7 months versus median not yet reached) and bone marrow plasma cells &gt;50% (6.4 months versus not yet reached). In conclusion, B is an effective salvage treatment for MM patients with relapsed/refractory MM, even in those with prognostically adverse cytogenetic features such as del(13q14). Due to the still short TTF and OS, MM patients with adverse prognostic indicators (unfavorable cytogenetics, low serum albumin, high bone marrow plasma cell infiltration) may derive a particular benefit from combining B with other anti-MM agents.

scholarly journals Phase I Trial of Intra-arterial Administration of Autologous Bone Marrow-Derived Mesenchymal Stem Cells in Patients with Multiple System Atrophy

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Seok Jong Chung ◽  
Tae Yong Lee ◽  
Yang Hyun Lee ◽  
KyoungWon Baik ◽  
Jin Ho Jung ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Multiple System Atrophy ◽  
Phase I ◽  
Dose Group ◽  
Low Dose ◽  
Autologous Bone Marrow ◽  
High Dose ◽  
Autologous Bone

Background. This study is aimed at investigating the safety and tolerability of the intra-arterial administration of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in patients with multiple system atrophy- (MSA-) cerebellar type (MSA-C). Methods. This was a single-center, open-label phase I clinical trial in patients with MSA-C. A three-stage dose escalation scheme (low-dose, 3.0 × 10 5 cells/kg; medium-dose, 6.0 × 10 5 cells/kg; high-dose, 9.0 × 10 5 cells/kg) was applied to determine the maximum tolerated dose of intra-arterial administration of BM-MSCs based on the no-observed-adverse-effect level derived from the toxicity study. The occurrence of adverse events was evaluated 1 day before and 1, 14, and 28 days after BM-MSC therapy. Additionally, we assessed changes in the Unified MSA Rating Scale (UMSARS) score 3 months after BM-MSC treatment. Results. One serious adverse drug reaction (ADR) of leptomeningeal enhancement following the intra-arterial BM-MSC administration occurred in one patient in the low-dose group. The safety review of the Internal Monitoring Committee interpreted this as radiological evidence of the blood-brain barrier permeability for MSCs. No other ADRs were observed in the medium- or high-dose groups. In particular, no ischemic lesions on diffusion-weighted images were observed in any of the study participants. Additionally, the medium- and high-dose groups tended to show a slower increase in UMSARS scores than the low-dose group during the 3-month follow-up. Conclusion. The present study confirmed that a single intra-arterial administration of autologous BM-MSCs is a safe and promising neuroprotective strategy in patients with MSA-C.

scholarly journals P179 Glucocorticoid exposure and link to serious adverse events in patients with ANCA-associated vasculitis

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
Philip Spearpoint ◽  
Cormac Sammon ◽  
Antonio Ramirez de ◽  
Arellano Serna ◽  
Peter Rutherford
Keyword(s):  
Cardiovascular Disease ◽  
Adverse Events ◽  
Renal Disease ◽  
Real World ◽  
Low Dose ◽  
Remission Induction ◽  
High Dose ◽  
Anca Associated Vasculitis ◽  
Increased Risk ◽  
New Onset

Abstract Background Remission induction in ANCA-associated vasculitis (AAV) is with high dose glucocorticoids (GC) and immunosuppressants. Patients are exposed to high GC dose and/or prolonged low dose. EULAR/EDTA guidelines target 7.5-10mg at 3 months but acknowledge this is often achieved later. This study used UK real world practice data to examine the scale of GC exposure and associated clinical risks in AAV. Methods The study utilised the Clinical Practice Research Datalink (CPRD) - Hospital Episode Statistics (HES) linked database. AAV patients were identified using specific READ and ICD codes and followed between 01/01/1997 and 01/01/2018. GP prescriptions were used to describe periods of continuous GC use, stop and restart and when high dose (&gt; 30mg/day) and low dose (&lt;30mg/day) was prescribed. Diagnostic codes indicative of infections and adverse events linked to GCs were used to estimate rates in the AAV population using a generalized linear model with a Poisson distribution. Results 450 AAV patients with at least one GC prescription were analysed. The median dose decreased to 9.3 mg (IQR 5.0 - 17.0) at 6 months and 5.1 mg (0.00 - 10.0) at 12 months,50% patients were taking &gt; 10mg at 5 months and 25% were still &gt; 10mg at 12 months. However, within 6 months of achieving 10mg/day, 50% relapse to needing dose &gt;10mg, 75% within 2 years and 90% within 6 years. In adjusted Poisson model (age, gender, year of diagnosis before/after 2013) the rate of infection in AAV patients taking high dose was 2.59 times (CI95 1.95, 3.45) that of those on low dose and lower in those not taking GCs (IRR 0.27 (0.22-0.34)). Increased risk of new onset cardiovascular disease (IRR 2.55 (0.92, 7.04)) and new onset renal disease (IRR 3.4 (1.29-8.96)) were higher in patients receiving high dose. Conclusion AAV patients have significant exposure to high dose GCs and in real world practice, GC dose remains higher than recommended in current clinical guidelines. High dose GCs are associated with high risk of infection and new cardiovascular disease and renal disease. This creates a significant patient burden and has implications for healthcare resource use. Disclosures P. Spearpoint: Corporate appointments; Employee of Vifor Pharma. C. Sammon: Corporate appointments; Employee of PHMR. A. Ramirez de Arellano Serna: Corporate appointments; Employee of Vifor Pharma. P. Rutherford: Corporate appointments; Employee of Vifor Pharma. Shareholder/stock ownership; Vifor Pharma.

Phase II Evaluation of the Tyrosine Kinase Inhibitor MLN518 in Patients with Acute Myeloid Leukemia (AML) Bearing a FLT3 Internal Tandem Duplication (ITD) Mutation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1792-1792 ◽  
Author(s):  
Daniel J. De Angelo ◽  
Richard M. Stone ◽  
Mark L. Heaney ◽  
Stephen D. Nimer ◽  
Ronald Paquette ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Steady State ◽  
Phase Ii ◽  
Plasma Concentrations ◽  
Remission Induction ◽  
Western Blots ◽  
Adequate Treatment ◽  
The Mean ◽  
Trough Plasma ◽  
Bone Marrow Blasts

Abstract MLN518 is a small molecule inhibitor of FLT3, PDGFR and c-Kit that is currently being evaluated as a therapy for AML. Previous phase I evaluation of MLN518 showed that it inhibits the phosphorylation of both wild-type and ITD-mutated FLT3 in patients’ leukemic blasts with an IC90 in the range of 100–175 ng/mL. Anti-leukemic activity was also observed, with decreases in both peripheral and bone marrow blasts. Dose-limiting toxicity, consisting of reversible general muscular weakness and/or fatigue was associated with trough plasma MLN518 concentrations > 1000 ng/mL. We are now conducting a phase II study of MLN518 in patients with relapsed or refractory AML and in untreated patients with AML considered unfit for standard AML therapies. Eligibility requires demonstration of the FLT3 ITD mutation in the patient’s blasts. All patients are treated with MLN518 at an initial dose of 525 mg po bid, with provision for dose reduction if MLN518-associated weakness occurs. Twenty patients have been treated with MLN518 in this study, eighteen of whom are currently evaluable (2 patients have recently started therapy). Toxicities associated with MLN518 therapy have included weakness/fatigue, QTc prolongation (relationship to MLN518 uncertain), and nausea and vomiting. MLN518 plasma concentration-time data for the first fourteen patients demonstrates that all patients achieved steady-state trough plasma concentrations > 150 ng/mL. Both inter- and intra-subject variability (%CV) in trough steady-state concentrations were < 30%. Assessment of total and phosphorylated FLT3 in leukemic blasts isolated from peripheral blood was possible in 4 patients. Western blots from blasts obtained before and after MLN518 dosing demonstrated either partial or complete inhibition of FLT3 phosphorylation with MLN518 plasma concentrations > 130 ng/mL. Of the eighteen evaluable patients, response could not be assessed in three because intercurrent illness and/or MLN518-associated toxicity precluded adequate treatment with MLN518 (≥ 14 days). Seven patients experienced progressive AML without evidence of any anti-leukemic effect. Two patients had stable disease for ≥ 50 days and subsequently underwent bone marrow transplantation. Although no complete or partial remissions have been observed, 6 patients have demonstrated evidence of an anti-leukemic effect with decreases in both peripheral and bone marrow blasts of 1-3 months duration. In these 6 patients the mean decrease in the absolute peripheral blast count was 92%, with a range of 85–100%. The mean decrease in the bone marrow blast percentage was 62%, with a range of 44–94%. We conclude that MLN518 has anti-leukemic activity in FLT3 ITD-mutated AML and should be further evaluated as a component of remission-induction and/or maintenance therapy in this disease.

High Dose Methotrexate (HD MTX at 2 gr/sqm x 4) Associated to Extended Intrathecal (IT) Chemotherapy Is Effective for Prevention of Central Nervous System (CNS) Relapse in Childhood ALL Treated with BFM Systemic Therapy.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 10-10 ◽  
Author(s):  
Valentino Conter ◽  
Carmelo Rizari ◽  
Maria Grazia Valsecchi ◽  
Daniela Silvestri ◽  
Maurizio Aricò ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Relapse Rate ◽  
Preventive Therapy ◽  
High Dose ◽  
Cranial Radiotherapy ◽  
Eligibility Criteria ◽  
Secondary Neoplasms ◽  
Childhood All ◽  
Continuation Phase ◽  
Cns Relapse

Abstract Introduction: In the last two decades, treatment to prevent CNS relapses in childhood ALL has been characterized by a progressive replacement of cranial radiotherapy (CRT) with HD-MTX and/or protracted IT chemotherapy. AIEOP has already reported that HD-MTX (5 g/sqm x 4), associated with protracted use of IT MTX led to a 6-year isolated CNS relapse rate of 0.8% in a relatively small fraction of intermediate risk (IR) ALL children (30% of the total) treated in the BFM-oriented AIEOP ALL 88 study (J Clin Oncol, 13; 10: 2497–2502, 1995). Aim: To evaluate if adequate CNS relapse prevention is obtained also by using HD-MTX at lower doses (2 gr/sqm x 4 instead of 5 gr/sqm x 4) and in a larger proportion of patients (up to 80% of the overall population) when associated to protracted IT chemotherapy. Patients and methods: Eligibility: children with newly diagnosed non-T ALL with no HR features [i.e. no poor-prednisone response and/or no t(9;22) or t(4;11) clonal translocations and/or no CR after protocol IA] and no CNS or testicular involvement at the onset. Chemotherapy was based on a traditional BFM back-bone (protocols IA+B, M, II, continuation phase). CNS relapse preventive therapy consisted of one IT MTX at diagnosis; TIT x 4 in protocol IA+IB; HD-MTX (2 g/sqm x 4) + TIT x 4 in protocol M; TIT x 2 in protocol II; during the continuation phase, TIT x 6 in the IR group and TIT x 8 in the standard risk (SR) group. Results: From 4/95 to 8/2000 1745 patients were recruited in the study AIEOP ALL 95; of these, 1441 (82.6 % of the overall ALL population) were SR (n=115) or IR (n=1326) and fulfilled the eligibility criteria for the present study. Among these 1441 patients, the following events have been observed: 264 relapses, 8 deaths in induction, 13 deaths in complete remission and 3 secondary neoplasms. Among relapses, 198 were isolated in the bone marrow, 15 isolated in the CNS, 15 isolated in the testes, 12 in the CNS+bone marrow, 10 in the testis+bone marrow, 9 in other sites +bone marrow, 5 in other isolated extramedullary sites. With a median follow-up of 5.5 years, the 6-year event-free survival (EFS) of the 1441 patients was 78.6% (SE 1.2) with an isolated CNS relapse rate of 1% (SE 0.3); when also the combined relapses involving the CNS were counted, the CNS relapse rate was 2%. Conclusions: These data confirm and extend our previous findings, suggesting that, in the context of an intensive chemotherapy program, prevention of CNS relapse may be effectively obtained in non-HR ALL children using HD-MTX at 2 gr/sqm x 4, associated with protracted IT chemotherapy, thus permitting to avoid the use of CRT.

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