Prognosis of Acute Myeloid Leukemia with Translocation (8;21): A Survey of 142 Cases Investigated in the JALSG AML97 Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4511-4511
Author(s):  
Nahoko Hatsumi ◽  
Shuichi Miyawaki ◽  
Hisashi Sakamaki ◽  
Shigeki Ohtake ◽  
Fumiharu Yagaski ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Maintenance Therapy ◽  
Induction Therapy ◽  
Risk Group ◽  
Standard Dose ◽  
Significant Prognostic Factor ◽  
Female Ratio ◽  
Poor Risk ◽  
Two Factors ◽  
Wbc Count

Abstract Background: Translocation (8;21) is one of the most common structural aberrations found in AMLand good response rates and a better DFS have been described in pts possessing it. Especially, the DFS rate may exceed 60–70% in younger pts given repetitive courses of HDAra-C. However, it was recently reported that a subtype of AML with t(8;21) showed a poor prognosis and this case also had the KIT mutation. As a result, we retrospectively analyzed the prognosis of AML pts with t(8;21) prospectively enrolled in the JALSG AML97 study. Patients and Methods: Between 1997 and 2001, JALSG AML97 enrolled 809 pts previously untreated for AML and pts with M3 were excluded. From the 789 eligible pts, we selected the subjects with t(8;21) for this study. Induction therapy consisted of cytarabine and idarubicin. All CR pts were randomized to receive either four courses of standard dose consolidation therapy without maintenance therapy or three courses of standard dose consolidation with 6 courses of maintenance therapy. HDAra-C was not administered in the JALSG AML97 study. Peripheral blood and bone marrow smears and karyotypes were reevaluated by the central review committees. Any patients who underwent SCT were censored at the date of SCT. The Kaplan-Meier method was used to estimate OS and DFS. For comparisons of OS or DFS, the log rank test was used. Result: Cytogenetic studies were performed in 783 patients (99.2%) and only 15 studies resulted in failure. One hundred forty-two (18.5%) of those pts showed t(8;21). The median age was 43 yrs (15–64). The male: female ratio was 95: 47. The distribution of FAB types was as follows: AMLM2, 130; M4, 6; M1, 5; and M5, 1. A total of 69 (48.6%) pts had a sole t(8;21), 46 (32.4%) had a loss of a sex chromosome, and 27 (19.0%) had other cytogenetic abnormalities. The CR rate was 90.0%. Thirty-two pts underwent two courses of induction therapy. The early death (< one month) rate was 1.4% (2/142). Only a high WBC count (>=10x109/L) was found to be a marginally significant prognostic factor (p=0.0517). The estimated OS rate at 5yrs was 53.6%, and the DFS of the CR pts was 41.2%. We found no relationship between OS or DFS and the following factors: age, gender, karyotypic abnormality, performance status, the percentage of MPO positive blasts, the presence or absence of Auer rods, the platelet count, the number of induction therapies for CR and the type of postremisson therapy. However, two factors, the WBC count and the percentage of blasts in bone marrow were found to be strongly predictive factors for the outcome. For the pts with a WBC count >=10x109/L, the DFS rate at 5yrs was 30.8%, while for the pts with less than 10x109/L, it was 48.8% (p=0.0215). For the pts with blast >=50% and less than 50%, the DFS rates at 5yrs were 32.2% and 56.7% (p=0.0087), respectively. According to these two factors, a poor risk group (N=30, 21.0%) was thus identified. They had a WBC count >=10x109/L and blast >=50%. The DFS rate at 5yrs was only 22.3 % in the poor risk group while that of the other pts was 48.9% (P=0.0003). Conclusion: This study confirmed that all AML pts with t(8;21) shows a high response rate and a good prognosis, thus indicating that this favorable AML group includes a poor risk group which can be identified based on the WBC count and the blast percent in the bone marrow.

Postremission Therapy in Adult Acute Myeloid Leukemia (AML): A Randomized Comparison of Intensified Consolidation Therapy without Maintenance Therapy Against Conventional Consolidation with Maintenance Therapy -JALSG AML-97 Trial-.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 868-868 ◽  
Author(s):  
Shuichi Miyawaki ◽  
Hisashi Sakamaki ◽  
Shigeki Ohtake ◽  
Fumiharu Yagasaki ◽  
Kinuko Mitani ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Induction Therapy ◽  
Risk Group ◽  
Randomized Study ◽  
Risk Groups ◽  
Consolidation Therapy ◽  
Poor Risk ◽  
Short Course ◽  
To Receive ◽  
Good Risk

Abstract Between 1997 and 2001, JALSG conducted a randomized study to assess the optimal post remission therapy for adult AML in the first CR. The JALSG AML97 enrolled 809 previously untreated AML patients (pts) aged 15–64 yrs. Induction therapy consisted of cytarabine (100mg/m2 day1–7) and idarubicin (IDR 12mg/m2 day1– 3). If the patients did not achieve remission after the first induction therapy, the same therapy was given once more. Pts were categorized into good, intermediate or poor risk groups by risk factors based on the previous JALSG AML studies. All CR pts were randomized to receive either the intensified short course post remission regimen (arm A) or the conventional JALSG’s post remission regimen for AML including maintenance therapy (arm B). Arm A: 1) AraC 200mg/m2 day1–5+ Mitoxantrone (MTZ) 7mg/m2 day1–3, 2) AraC 200mg/m2 day1–5+Daunorubicin (DNR) 50mg/m2 day1–3, 3) AraC 200mg/ m2 day1–5+ Aclacinomycin (ACR) 20mg/m2 day1–5, 4) AraC 200mg/m2 day1–5+ Etoposide (ETP) 100mg/m2 day1–5 + Vincristine (VCR) 0.8mg/m2 day 8 + Vindesine (VDS) 2 mg/m2 day10. Arm B: 1) AraC 200mg/m2 day1–5 + MTZ 7mg/m2 day1–3, 2) Behenoyl AraC (BHAC) 200mg/m2 day1–7 + ETP 100mg/m2 day1–5 + DNR 50mg/m2 day1–3 + 6 mercptopurine (6MP) day1–7, 3) BHAC 200mg/m2 day1–7 + ACR 14mg/m2 day1–7, and then 6 courses maintenance therapy: 1) BHAC 170mg/m2 day1–5 + DNR 50mg/m2 day1,4+6MP day1–7, 2) BHAC 170mg/m2 day1–5 + MTZ 5mg/m2 day1–3, 3) BHAC 170mg/m2day1–5 + ETP 80mg/m2 day1,5,7 + VDS 2mg/m2 day1,8, 4) BHAC 170mg/m2 day1–5 + ACR 14mg/m2 day1–4 + 6MP day1–7, 5) BHAC 170mg/m2 day1–5 + DNR 50mg/m2 day1–4 + 6MP day1–7, 6) BHAC 170mg/m2 day1–5 + ETP 80mg/m2 day1,5,7 + VDS 2mg/m2 day1,8. Result: Of the 809 pts registered, 789 pts (median age: 45 years) were evaluable. 621 pts (78.7%) achieved CR after one or two courses of induction therapy. The 5-year OS rate of arm A was 45.6% and of arm B 53.2% (p=0.3259). The 5-year DFS rate of CR patients was 34.8% in arm A and 28.9% in arm B (p=0.4978). Among the good risk group, the 5-year OS rate of arm A was 62.1% and of arm B 70.2% (p=0.5068), and the 5-year DFS rate of arm A was 53.4% and of arm B 42.0% (p=0.3719). Among the intermediate risk group, the 5-year OS rate of arm A was 35.6% and of arm B 45.5% (p=0.4776), and the 5-year DFS rate of arm A was 26.0% and of arm B 26.1% (p=0.9653). Among the poor risk group, the 5-year OS rate of arm A was 29.7% and of arm B was 33.4% (p=0.6523), and the 5-year DFS rate of arm A was 20.4% and of arm B was 13.5% (p=0.6339). In conclusion: JALSG’s conventional post remission therapy consisting of 3 courses of consolidation and 6 courses of maintenance therapy could be replaced by a shorter duration of intensified consolidation therapy.

Long-Term Follow-up of the Randomized JALSG AML 201 Study Comparing High Dose Ara-C Therapy with Conventional Consolidation Therapy in Adult Acute Myeloid Leukemia (AML)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 135-135
Author(s):  
Shuichi Miyawaki ◽  
Shigeki Ohtake ◽  
Shin Fujisawa ◽  
Hitoshi Kiyoi ◽  
Katsuji Shinagawa ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Risk Group ◽  
Randomized Study ◽  
Risk Groups ◽  
Young Group ◽  
High Dose ◽  
Poor Risk ◽  
Wbc Count ◽  
Leukemia Group

Abstract A randomized study had been performed between December 2001 and December 2005 to assess the optimal post remission therapy for adult AML in the first CR. The updated results are here presented, after a median follow-up of 48 months. JALSG AML201 enrolled 1064 previously untreated AML patients (pts) aged 15–64 yrs. The induction therapy consisted of cytarabine (Ara-C 100 mg/m2 day1–7) and idarubicin (IDR 12 mg/m2 day1–3) (arm A) or cytarabine (100 mg/m2 day1–7) and daunorubicin (DNR 50 mg/m2 day1–5) (arm B). If the patients did not achieve remission after the first induction therapy, then the same therapy was given once more. Pts were categorized into good, intermediate or poor risk groups by risk factors based on the criteria established in previous JALSG AML studies (Miyawaki et al. Cancer 2005). All CR pts were stratified according to the induction, the number of courses of induction, age and karyotype and were randomly assigned to the high dose Ara-C (HDAC) post remission regimen (arm C) or the conventional JALSG post remission regimen (arm D). Arm C: the three courses of HDAC which consisted of Ara-C 2.0 g/m2 q12h day1–5, arm D: the first course consisted of Ara-C 200 mg/m2 day1–5+ mitoxantrone (MIT) 7 mg/m2 day1–3, 2) Ara-C 200 mg/m2 day1–5+ DNR 50 mg/m2 day1–3, 3) Ara-C 200 mg/m2 day1–5+ aclarubicin (ACR) 20 mg/m2 day15, 4) Ara-C 200 mg/m2 day1–5+ etoposide (ETP) 100 mg/m2 day1–5 + vincristine (VCR) 0.8 mg/m2 day 8 + vindesine (VDS) 2 mg/m2 day10. Results: Of the 1064 pts registered, 1057 pts (median age: 47 years) were evaluable. 823 pts (78%) achieved CR after one or two courses of induction therapy. Of the 823 pts in CR, 781 pts were assigned to arm C (n=389) or arm D (n=392). The 5-year OS rate of arm C was 57.8% while that of arm D was 55.9% (p=0.96). The 5-year RFS rate of the CR pts was 42.7% in arm C and 38.9% in arm D (p=0.73). Among the good risk group (n=155), the 5-year OS rate of arm C was 69.9% while that of arm D was 80.5 % (p=0.11), and the 5-year RFS rate of arm C was 54.5% while that of arm D was 55.7% (p=0.53). Among the intermediate risk group (n=439), the 5-year OS rate of arm C was 50.9% while that of arm D was 48.5% (p=0.59), and the 5-year RFS rate of arm C was 41.5% while that of arm D was 36.5% (p=0.50). Among the poor risk group (n=49), the 5-year OS rate of arm C was 12.9% while that of arm D was 17.2% (p=0.58), and the 5-year RFS rate of arm C was 14.3% while that of arm D was 15.5% (p=0.78). In the CBF leukemia group (n=218), the 5-year OS rate of arm C was 75.0% while that of arm D was 65.8% (p=0.17), and the 5-year RFS rate of arm C was 56.5% while that of arm D was 38.7% (p=0.05). Among the young group (&lt;50yrs) (n=467), the 5-year OS rate of arm C was 62.1% while that of arm D was 66.4% (p=0.23), and the 5-year RFS rate of arm C was 44.6% while that of arm D was 45.6% (p=0.59). Among the old group (&gt;=50 yrs) (n=314), the 5-year OS rate of arm C was 51.3% while that of arm D was 40.1% (p=0.16), and the 5-year RFS rate of arm C was 40.0% while that of arm D was 28.1% (p=0.23). After all of consolidation, the lowest WBC count and the duration of neutropenia in arm C were significantly lower and longer than those in arm D. There was a higher rate of documented infection in arm C (20.9%) than in arm D (14.5%) (p&lt; 0.001). Conclusion: The conventional post remission therapeutic regimen established by JALSG consisting of 4 courses of consolidation was found to be as effective as the three courses of HDAC therapy. HDAC therapy produced a slightly positive effect on RFS in only the CBF leukemia group.

scholarly journals Optimizing Response to Enasidenib with Dose Escalation: Case Series

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-5
Author(s):  
Amany R. Keruakous ◽  
Sarah A. Schmidt ◽  
Marcus T. Autry ◽  
Pragathi Balakrishna ◽  
Julia Ye ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dose Escalation ◽  
Karyotype Analysis ◽  
Standard Dose ◽  
Case Series ◽  
Bone Marrow Evaluation ◽  
Poor Risk ◽  
Daily Dose ◽  
Variant Frequency ◽  
Idh2 Mutation

Background: Isocitrate dehydrogenase enzymes catalyze the conversion of isocitrate to alpha-ketoglutarate. Mutated IDH enzymes generate the "oncometabolite" 2-hydroxyglutarate (2-HG), which inhibits TET2 function. IDH2 mutations have been reported in 9% to 19% of acute myeloid leukemia (AML) cases. Inhibition of the mutant IDH2 enzyme led to decreased 2-HG levels and induced myeloid differentiation in IDH2 mutant AML. Enasidenib, a small-molecule inhibitor of mutant IDH2, was approved in 2017, after a successful phase I/II trial showing an overall response rate (ORR) of 40.3% in relapsed/refractory (R/R) disease, with 19.3% of patients achieving complete remission (CR). A Phase III trial is currently ongoing. It targets the mutant IDH2 variants R140Q, R172S, and R172K; at an approved dose of 100 mg oral daily dose. At higher doses the drug was less tolerated, however, few subjects received dose modification at the 650 mg daily dose group; these events did not qualify as a dose-limiting toxicity (DLT). In this descriptive study, we are reporting a case series of R/R AML, with an IDH2 mutation, that are treated with escalated dose enasidenib. Method: This case series is based on retrospective observations of patients with R/R IDH2 mutant AML since January 2017, who are treated with enasidenib. We are reporting two cases treated with an escalated dose of 200 mg daily. We included patients with intermediate to poor-risk AML, who received at least one prior line of therapy, started on standard dose enasidenib (100 mg daily) for a minimum of 6 months and followed until disease relapse or death. We excluded patients who are primarily resistant to enasidenib (AML risk stratification and response evaluation by ELN-Leukemia NET. IDH2 mutations were identified by a local diagnostic laboratory that is regulated under CLIA through PCR which is validated to detect 10% or more mutant allele frequency. To quantify IDH2 variant frequency, confirmatory testing was performed via ARUP next-generation sequencing panel (NGS). Results: Here we report the descriptive outcomes of 2 cases from a single institution, who were treated with escalated dose enasidenib (200 mg oral daily) for R/R AML with an IDH2 mutation. The first case describes a 65-year-old female diagnosed with poor-risk AML in the setting of pancytopenia with bone marrow evaluation consistent with the background of erythroid and granulocytic dysplasia, with normal karyotype analysis. The patient has treated with induction chemotherapy and 2 cycles consolidation that was complicated with bacterial infections, prolonged hospitalization, and profound deconditioning led to stopping treatment. After 18 months of surveillance, repeat bone marrow evaluation for new-onset pancytopenia revealed relapsed AML with evidence of IDH2 mutation at codon 140, with a variant frequency of 36.9% by NGS. The case was started on enasidenib at 100 mg oral daily dose. After 6 months of therapy, the patient continued to be cytopenic, repeated bone marrow evaluation showed residual AML with IDH2 variant frequency of 27.6%. The decision was made to increase the enasidenib dose to 200 mg daily. With follow up for another 5 months on the escalated dose, the patient achieved hematologic complete response (hCR) with normalization of peripheral platelet count and ANC. [Figures 1-2] The patient maintained hCR for another 5 months on 200 mg enasidenib daily until she died from COVID-19 infection. The second case describes a 59-year-old female with poor-risk AML in the setting of leukocytosis, with bone marrow evaluation consistent with the background of megakaryocytic dysplasia and karyotype analysis positive for monosomy 7. The patient was treated with induction chemotherapy and failed to respond. Repeat bone marrow evaluation showed primary refractory disease with positive IDH2 mutation at codon 140 with a variant frequency of 40.7%. Treatment with 100 mg enasidenib was started. The patient maintained a partial response for 6 months, then peripheral blasts counts started to gradually increase. The decision was made to increase enasidenib dose to 200 mg daily, which improved peripheral blasts within one month of escalated dose therapy. [Figure 3] The patient maintained a response to therapy for another 3 months before she relapsed. Conclusion: Our limited data showed that initial response to standard dose enasidenib could potentially be optimized by dose escalation to 200 mg daily. Disclosures No relevant conflicts of interest to declare.

Should Adolescents With Acute Lymphoblastic Leukemia Be Treated as Old Children or Young Adults? Comparison of the French FRALLE-93 and LALA-94 Trials

2003 ◽  
Vol 21 (5) ◽  
pp. 774-780 ◽  
Author(s):  
Nicolas Boissel ◽  
Marie-Françoise Auclerc ◽  
Véronique Lhéritier ◽  
Yves Perel ◽  
Xavier Thomas ◽  
...  
Keyword(s):  
Young Adults ◽  
Prognostic Factors ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Univariate Analysis ◽  
Significant Prognostic Factor ◽  
Free Survival ◽  
Poor Risk ◽  
B Lineage ◽  
Wbc Count

Purpose: To compare pediatric and adult therapeutic practices in the treatment of acute lymphoblastic leukemia (ALL) in adolescents. Patients and Methods: From June 1993 to September 1994, 77 and 100 adolescents (15 to 20 years of age) were enrolled in the pediatric FRALLE-93 and adult LALA-94 protocols, respectively. Among the different prognostic factors, we retrospectively analyzed the effect of the trial on achieving complete remission (CR) and event-free survival (EFS). Results: Patients were younger in the FRALLE-93 than in the LALA-94 protocol (median age, 15.9 v 17.9 years, respectively), but other characteristics were similar, including median WBC count (18 × 109 cells/L v 16 × 109 cells/L), B/T-lineage (54 of 23 v 72 of 28 patients), CD10-negative ALL (13% v 15%), and poor-risk cytogenetics (t(9;22), t(4;11), or hypodiploidy less than 45 chromosomes: 6% v 5%). The CR rate depended on WBC count (P = .005) and trial (94% v 83% in FRALLE-93 and LALA-94, respectively; P = .04). Univariate analysis showed that unfavorable prognostic factors for EFS were as follows: the trial (estimated 5-year EFS, 67% v 41% for FRALLE-93 and LALA-94, respectively; P < .0001), an increasing WBC count (P < .0001), poor-risk cytogenetics (P = .005), and T-lineage (P = .01). The trial and WBC count remained significant parameters for EFS in multivariate analysis (P < .0001 and P = .0004). Lineage subgroup analysis showed an advantage for the FRALLE-93 trial for CR achievement (98% v 81%; P = .002) and EFS (P = .0002) in B-lineage ALL and for EFS (P = .05) in T-lineage ALL. Age was not a significant prognostic factor in this population of adolescents. Conclusion: This study’s findings indicate that adolescents should be included in intensive pediatric protocols and that new trials should be designed, inspired by pediatric protocols, for the treatment of young adults with ALL.

scholarly journals the Poorer-Risk AML, the Weaker Immunologic Surveillance? --Higher PD-L1 Expression on Non-APL AML Cells Is Associated with Poorer Risk Status According to Cytogenetics and Molecular Abnormailties

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1619-1619 ◽  
Author(s):  
Shenmiao Yang ◽  
Xiao Jun Huang
Keyword(s):  
Bone Marrow ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
Immune Surveillance ◽  
Leukemic Cells ◽  
Intermediate Risk ◽  
Risk Status ◽  
Molecular Abnormalities ◽  
Poor Risk

Abstract Backgroud The specific recurrent cytogenetic and molecular abnormalities are significantly associated with prognosis and have been used to establish risk stratification which directs the therapeutic strategy in AML. Whether the immune surveillance contributes to the prognosis according to the cytogenetic and molecular risk status is unknown. The checkpoint PD-1/PD-L1 pathway is involved in the tumor surveillance. Down-regulation of PD-1/PD-L1 pathway caused a slower AML progression in mouse models through anergy of CD8+ CTL cells. Clinical trials of PD-1/PD-L1 inhibitor-based regimens in patients with AML are ongoing and seem to have promising results. But few studies investigated clinical significance of PD-L1 expression on leukemic cells in AML patients. Method We prospectively observed 120 consecutive adult patients with non-APL AML. PD-L1 mRNA of bone marrow mononuclear cells at diagnosis was detected by RT-PCR and the specific fluorescence indices (SFI) of PD-L1 expression on bone marrow blast cells was determined by flow cytometry. Cytogenetic and molecular genetic risks were assessed according to NCCN AML guideline (2016 version 2). Patients with age >60 years or failure of karyotype analysis were excluded. All remaining 95 patients were treated with "3+7" idarubicine and cytarabine induction regimen. Patients with response of ≥PR were administered the same regimen as the initial chemotherapy, and then consolidated with intermediate-dose cytarabine for four cycles followed by MA, AA, HA and AE regimens subsequently. Patients at poor risk or with unsatisfied controlled minimal residual disease were recommended allogeneic transplantation (allo-HCT). Among the patients with indication of allo-HCT, those who had both donor and desire received allo-HCT after 3 cycles of consolidation in their first CR (CR1). Result The diagnoses according to morphology included AML-M0 (n=1), AML-M1 (n=5), AML-M2 (n=55), AML-M4 (n=19), AML-M5 (n=13) and AML-M6 (n=2). Twenty patients were at favorable risk, 43 were at intermediate risk and 32 were at poor risk. We found a correlation between SFIs of PD-L1 and PD-L1 mRNA (r=0.413, P<0.001). After the base 10 logarithm transformation, quantity of PD-L1 mRNA in mononuclear cells of bone marrow were different among all risk groups (P=0.025). Post Hoc multiple comparisons showed PD-L1 mRNA of poor-risk group was higher than that of favorable-risk group (P=0.008). PD-L1 mRNA of the intermediate-risk group was also higher when compared to that of favorable-risk group (P=0.029). SFIs of PD-L1 on leukemic cells was higher in poor-risk group than in either intermediate-risk (P=0.040) or favorable-risk group (P=0.042), although no statistic difference was found among three groups (P=0.057). With ROC curves, we found PD-L1 mRNA could well predict both the early CR defined as the CR achieved after the initial chemotherapy (AUC=0.736, P=0.050) and the final CR defined as CR1 achieved after any cycles of induction chemotherapy (AUC=0.911, P=0.006). SFI of PD-L1 on leukemic cells could only predict the final CR (AUC=0.889, P=0.009). With both the best specificity of 0.833 and sensitivity of 1.000 for predicting final CR and specificity of 0.667 and sensitivity of 0.917 for predicting early CR, the cutoff value of PD-L1 mRNA was identified as 0.0681. SFI of PD-L1 less than 1.852 was a good predictor for achieving final CR with the sensitivity of 0.800 and specificity of 1.000. PD-L1 mRNA≥0.0681 was the only independent poor-risk factor for the early CR (HR=12.697, 95%CI 2.710-59.481, P<0.001). Conclusion AML cells with poorer-risk cytogenetic and molecular abnormalities seemed to have a higher PD-L1 expression which may compromise the leukemic immune surveillance by CTL suppression. Higher PD-L1 expression on AML cells was associated with poorer response to IA-based induction regimens. Disclosures No relevant conflicts of interest to declare.

Chimerism and clinical outcomes of 110 recipients of unrelated donor bone marrow transplants who underwent conditioning with low-dose, single-exposure total body irradiation and cyclophosphamide

Blood ◽  
2005 ◽  
Vol 105 (8) ◽  
pp. 3035-3041 ◽  
Author(s):  
Mark Girgis ◽  
Chris Hallemeier ◽  
William Blum ◽  
Randy Brown ◽  
Hsiu-san Lin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Low Dose ◽  
Risk Group ◽  
Unrelated Donor ◽  
Single Exposure ◽  
Organ Toxicity ◽  
Poor Risk ◽  
Total Body ◽  
Good Risk

AbstractWe hypothesized that low-dose (550-cGy), single-exposure, high dose rate (30 cGy/min) total body irradiation (TBI) with cyclophosphamide as conditioning for HLA-compatible unrelated donor (URD) bone marrow transplantation (BMT) would result in donor chimerism (DC) with a low risk for serious organ toxicity and treatment-related mortality (TRM). Twenty-six patients with good risk diagnoses (acute leukemia in first complete remission [CR] and chronic-phase chronic myelogenous leukemia [CML]) and 84 with poor risk diagnoses underwent this regimen and URD BMT. Unsorted marrow nucleated cells were assessed for chimerism using VNTR probes. All DC occurred in 78 (86%) of 91 evaluable patients at 1 or more follow-up points. Graft failure occurred in 7 (7.7%) patients. Fatal organ toxicity occurred in only 2% of patients. TRM rates through 2 years of follow-up were 19% and 42% in those with good and poor risk diagnoses, respectively. Overall and disease-free survival rates in the good risk group were 47% and 40%, respectively, and in the poor risk group they were 25% and 21%, respectively, at a median follow-up for living patients of 850 days (range, 354-1588 days). This regimen resulted in 100% DC in most patients undergoing URD BMT with a relatively low risk for fatal organ toxicity and TRM.

Time To Complete Remission Is Not a Significant Prognostic Factor in AML: A Report on 1,959 Consecutive Patients Registered to 6 Studies of the Eastern Cooperative Oncology Group (ECOG).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 862-862 ◽  
Author(s):  
Jacob M. Rowe ◽  
Haesook T. Kim ◽  
Peter A. Cassileth ◽  
Mark R. Litzow ◽  
Peter H. Wiernik ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Prognostic Factor ◽  
Complete Remission ◽  
Induction Therapy ◽  
Cox Model ◽  
Autologous Bone Marrow Transplantation ◽  
Eastern Cooperative Oncology Group ◽  
Prognostic Significance ◽  
Significant Prognostic Factor ◽  
Number Of Cycles

Abstract Prognostic factors for AML at diagnosis include cytogenetics, FLT3 ITD, age, MDR status and white cell count at presentation. Several groups (Blood2000; 95:72; BJH1999; 107:69; Haematologica2004; 89:528) have reported that time to achievement of complete remission (CR) is an independent post-induction prognostic factor in AML. Furthermore, some investigators have classified patients who do not achieve CR with one cycle as primary induction failure. Between 1983 and 1993 1,959 patients were registered to 6 consecutive ECOG studies (E3483, PC486, E1490, E2491/INT0129, E3489 and E3993). These studies were for patients age 18–55 years (E3483, PC486 and E3489); age 56–70 years (E1490); age >56 years (E3993) and with no age limit (E2491/ INT0129). Of these 1,959 patients, 1261 achieved CR (64%) and were available for analysis. All patients received standard induction therapy, consisting of daunorubicin 60 mg/m2 (E3483, PC486 and E1490), or 45 mg/m2 (E2491/ INT0129) or idarubicin 12 mg/m2 (E3489), or a randomization between daunorubicin 45 mg/m2, idarubicin 12 mg/m2 or mitoxantrone 12 mg/m2 (E3993) - all for 3 days - together with cytarabine 100–200 mg/m2 by continuous infusion for 7 days. It should be noted that in the North American Intergroup APL study (E2491/ INT0129) patients who received ATRA in induction are excluded from this analysis. All patients were to receive a second cycle of identical induction therapy if the day 10–14 bone marrow demonstrated unequivocal residual leukemia. Identical study-specific post-remission therapy, including consolidation therapy and/or allogeneic or autologous bone marrow transplantation, was given to all patients who went into CR - irrespective if this was achieved after 1 or 2 cycles. This retrospective analysis compared patients who achieved CR after 1 cycle versus 2 cycles of induction therapy. The data were obtained from the ECOG database that recorded the number of days that patients received induction therapy (≤8 days vs >8 days). The table presents the data for disease-free survival (DFS) and overall survival (OS). These data are based on the Cox model, adjusting for other variables. Total Failed Median DFS/OS (mo) 5-year DFS/OS p-value DFS 1 cycle 406 321 10.2 24.4% 2 cycles 855 629 11.9 28.6% 0.07 OS 1 cycle 406 287 23.7 36.1% 2 cycles 855 583 24.1 35.7% 0.7 In this large cohort of patients, by multivariate analysis, age, WBC at diagnosis were significant factors for DFS and OS. However, the number of cycles given for induction or the time to achieve a CR in AML patients could not be demonstrated to have any independent prognostic significance. These data suggest that post-remission strategies in AML should not be influenced by the number of cycles required to achieve CR.

Bortezomib-Based Therapy without Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma Patients with t(4;14): A Canadian National Trial,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3982-3982
Author(s):  
Donna E. Reece ◽  
Giovanni Piza Rodriguez ◽  
David Szwajcer ◽  
Leonard A Minuk ◽  
Mariela Pantoja ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Maintenance Therapy ◽  
Disease Progression ◽  
Induction Therapy ◽  
Research Funding ◽  
Pegylated Liposomal Doxorubicin ◽  
Progression Free Survival ◽  
Newly Diagnosed

Abstract Abstract 3982 Newly diagnosed multiple myeloma (MM) patients (pts) with t(4;14) identified by FISH who undergo a single ASCT after older induction regimens have a median progression-free survival (PFS) of only 8–9 months (mos) and median overall survival (OS) of 18 mos (Chang H, et al. Bone Marrow Transplan t 2005; 36: 793; Gertz M, et al. Blood 2005; 106: 2837). Given the efficacy of bortezomib in t(4;14) disease, we designed a phase II study based on this agent in which ASCT was not performed as part of first-line therapy. Pts received induction therapy with four 21-day cycles of pegylated liposomal doxorubicin 30 mg/m2on day 4, bortezomib 1.3 mg/m2on days 1, 4, 8, 11 and dexamethasone 40 mg on days 1–4, 8–11, 15–18 of cycle 1 and on days 1–4 and 11–14 of cycles 2–4 (DBD), followed by post-induction therapy with eight 28-day cycles of oral cyclophosphamide 300 mg/m2on days 1, 8, 15, 22, bortezomib 1.5 mg/m2 on days 1,8,15 and prednisone 100 mg q 2 days (CyBor-P). Maintenance therapy with dexamethasone 40 mg/weekly was then administered until disease progression. Although elective stem cell collection was recommended after induction therapy, routine ASCT was not performed in the absence of disease progression. Between February 2008-May 2011, 383 newly diagnosed MM pts were screened for t(4;14) in 8 Canadian centers, and 43 (11.2%) were found to be positive by FISH. Five did not meet the CRAB criteria for symptomatic MM, 7 were ineligible, 3 declined participation and 28 were entered onto study. One of these was later determined to have a variant abnormality of chromosome 4, but not t(4;14), and underwent ASCT after induction therapy; this pt is included in the safety analysis only. The median age was 60 years (range 42–69) and 63% were male. The median percent of nuclei positive for t(4;14) by FISH in the initial bone marrow (unpurified) was 26% (range 2–62), serum β2-microglobulin 239 nmol/L (range 43–1695) and albumin 36 g/L (range 28–48); ten pts had ISS stage 1,10 had stage 2 and 7 had stage 3 MM. Immunoglobulin subtype included IgGκ in 7, IgAκ in 6, IgAλ in 6, IgGλ in 5 and IgMλ in 1. Using modified uniform criteria, the best response in 23 evaluable pts includes: sCR in 6 (26%), CR in 4 (17%), VGPR in 9 (39%), PR in 2 (9%) and SD in 2 (9%). Median F/U is 13.5 mos (range 1.2–35); 6 have progressed at median of 3 mos on study (range 1–11). Four pts have died (due to progression in 3 and complex medical problems/consent withdrawal in 1 in VGPR). SAEs were reported in 7 pts; only 6 pts (21%) developed grade 2 peripheral neuropathy, which necessitated dose reductions of bortezomib in 4. The actuarial 2-yr PFS is 47.7% (95%CI 25.9–87.9%), median PFS is 23. 2 months and 2-yr OS is 76.8% (95%CI 58.3–100%); the median OS has not yet been reached. We conclude: 1) the incidence of t(4;14) by FISH in newly-diagnosed MM pts is 11.2%; which appears to be lower than the 15% anticipated 2) 11.6% of these are asymptomatic; 3) this bortezomib-based regimen is well-tolerated; 4) the overall response rate (sCR + CR + VGPR + PR) is 91% with 82% achieving ≥ VGPR and 43% ≥ CR; 5) the PFS and OS with this approach compare favorably with those seen with older studies of single or double ASCT, and even with some recently reported trials using more modern induction regimens before ASCT, in pts with t(4;14); and 6) the use of more effective maintenance therapy, including agents targeting the aberrations associated with t(4;14), would be of interest in future trials. Disclosures: Reece: Millennium: Research Funding; Otsuka: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Johnson&Johnson: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bristol, Meyers, Squibb: Honoraria, Research Funding; Amgen: Honoraria. Off Label Use: Bortezomib regimens other than VMP (boretzomib, melphalan and prednisone)for initial therapy of myeloma. Piza Rodriguez:Celgene: Unrestricted educational grant; Otsuka: Honoraria. Belch:Ortho/Janssen: Honoraria; Celgene: Honoraria. White:Celgene: Consultancy, Honoraria, Research Funding; Ortho/Janssen: Honoraria, Research Funding. Chen:Celgene: Research Funding. Kukreti:Celgene: Honoraria.

Pharmacotherapy of Disseminated Histoplasmosis in Patients with AIDS

1993 ◽  
Vol 27 (12) ◽  
pp. 1510-1518 ◽  
Author(s):  
S. Diane Goodwin ◽  
Courtney V. Fletcher ◽  
Richard H. Drew
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Maintenance Therapy ◽  
Amphotericin B ◽  
Induction Therapy ◽  
Antifungal Agent ◽  
Clinical Presentation ◽  
Biomedical Literature ◽  
Aids Patients ◽  
Disseminated Histoplasmosis

OBJECTIVE: To review the pharmacotherapy of disseminated histoplasmosis (DH) in patients with AIDS. The article provides an overview of the pathophysiology, epidemiology, clinical presentation and diagnosis of this disease. Clinical trials reporting intervention with antifungal therapy are reviewed, with an emphasis on efficacy and toxicity of these agents. DATA SOURCES: A MEDLINE search from 1976 to the present was performed to identify pertinent biomedical literature, including reviews. STUDY SELECTION: All available reviews and clinical trials in AIDS patients were evaluated, as were all available case series and interventional clinical trials. DATA SYNTHESIS: DH in patients with HIV infection is an AIDS-defining opportunistic infection caused by Histoplasma capsulatum. It is most frequently observed in HIV-infected patients living in or traveling to endemic regions. The clinical presentation most often includes fever and weight loss, but may be complicated by comorbid illness such as other opportunistic infections. Diagnosis is best established by histologic examination of peripheral blood smear or bone marrow aspirate, or isolation of the organism in cultures of blood, bone marrow, and respiratory secretions. Serologic examinations may provide supportive diagnostic information. Detection of histoplasma polysaccharide antigen (HPA) in serum or urine may prove to be a promising approach for the rapid diagnosis and therapeutic monitoring of DH in AIDS patients. In contrast to immunocompetent hosts, high relapse rates are reported after therapy in AIDS patients. Therefore, initial (induction) therapy is routinely followed by long-term (maintenance) therapy to prevent relapse. Issues regarding the selection, dosage, and duration of therapy, as well as prophylaxis of patients at highest risk, still need to be addressed by controlled clinical trials. CONCLUSIONS: Amphotericin B is presently the drug of choice for induction therapy. Maintenance therapy with either amphotericin B or an oral azole antifungal agent active against H. capsulatum is necessary to prevent relapse. Itraconazole, a triazole antifungal agent, may provide effective alternative therapy for both induction and maintenance treatment of DH.

scholarly journals Low-Dose Everolimus Maintenance Therapy for Renal Angiomyolipoma Associated With Tuberous Sclerosis Complex

2021 ◽  
Vol 8 ◽  
Author(s):  
Cong Luo ◽  
Wen-Rui Ye ◽  
Xiong-Bin Zu ◽  
Min-Feng Chen ◽  
Lin Qi ◽  
...  
Keyword(s):  
Adverse Events ◽  
Maintenance Therapy ◽  
Tuberous Sclerosis ◽  
Induction Therapy ◽  
Tuberous Sclerosis Complex ◽  
Low Dose ◽  
Standard Dose ◽  
Gene Mutations ◽  
Renal Angiomyolipoma ◽  
Significance Level

Objective: To assess the safety and efficacy of low-dose everolimus maintenance therapy for tuberous sclerosis complex-related renal angiomyolipoma (TSC-RAML) patients that had previously undergone standard-dose treatment for a minimum of 6 months.Materials and Methods: In total, 24 patients with a definitive TSC diagnosis were enrolled from April 2018 – April 2019 at Xiangya Hospital, Central South University. All patients underwent low-dose everolimus maintenance therapy following standard-dose everolimus induction therapy for a minimum of 6 months. Patients additionally underwent TSC1/TSC2 genetic testing, And they were followed-up at 3, 6, 12, 18, and 24 months. The Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) criteria were used to monitor patient RAML responses, while adverse events (AEs) were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). P &lt; 0.05 was the significance level for all analyses, which were performed using SPSS 19.0.Results: TSC1/TSC2 gene mutations were present in all 24 patients, all of whom achieved a significant reduction in TSC-RAML volume within the initial 6-month induction therapy period, and exhibited volume stabilization during the low-dose maintenance therapy treatment period without any instances of TSC-RAML regrowth. Adverse events (AEs) were significantly less severe and less frequent over the course of maintenance therapy relative to standard therapy.Conclusions: Low-dose everolimus maintenance therapy represents an effective approach to achieving TSC-RAML control following a minimum of 6 months of full-dose induction therapy, and may be associated with decreases in everolimus-related AE frequency and severity.

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