Intensive postremission chemotherapy without maintenance therapy in adults with acute lymphoblastic leukemia. Dutch Hemato-Oncology Research Group.

1997 ◽  
Vol 15 (2) ◽  
pp. 476-482 ◽  
Author(s):  
A W Dekker ◽  
M B van't Veer ◽  
W Sizoo ◽  
H L Haak ◽  
J van der Lelie ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Maintenance Therapy ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
Induction Treatment ◽  
High Dose ◽  
Allogeneic Bone ◽  
Cns Prophylaxis ◽  
Oncology Research ◽  
High Dose Cytarabine

PURPOSE To investigate the value of intensive consolidation chemotherapy not followed by maintenance therapy in adult acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS A multicenter phase II trial was conducted in 130 adult patients with ALL between 16 and 60 years of age. After standard induction therapy, postinduction chemotherapy was given: three courses of high-dose cytarabine (2,000 mg/m2 every 12 hours for four doses) in combination with amsacrine (course one), mitoxantrone (course two), and etoposide (course three). CNS prophylaxis consisted of 10 injections of intrathecal methotrexate (IT MTX). Patients younger than 50 years with an HLA-identical sibling were eligible to receive allogeneic bone marrow transplantation (BMT). RESULTS Ninety-five patients (73%) achieved complete remission (CR); 82% were younger than 50 years and 41% were older than 50 years. Seventeen patients (13%) were resistant to chemotherapy, and 18 (14%) died during induction treatment. Only age and performance status were significantly associated with response (P<.001 and .03, respectively). Death during consolidation occurred in four patients. The estimated 5-year overall survival (OS) was 22% for the entire group and 26% for patients younger than 35 years. Disease-free survival (DFS) at 5 years was 28% +/- 6 for patients younger than 35 years, 25% +/- 9 for patients between 35 and 50 years, and 0% for patients older than 50 years. Increasing age (P<.01) and expression of CD34 (P<.01) were adverse factors. Only three patients (3%) developed an isolated CNS relapse. CONCLUSION Intensive consolidation including high-dose cytarabine not followed by maintenance therapy provides an outcome for adult patients with ALL that may be worse or even inferior compared with studies using long-term maintenance therapy. High-dose cytarabine in combination with IT MTX was effective for CNS prophylaxis.

scholarly journals Lineage specific treatment of adult patients with acute lymphoblastic leukemia in first remission with anti-B4-blocked ricin or high-dose cytarabine

Cancer ◽  
2003 ◽  
Vol 97 (6) ◽  
pp. 1471-1480 ◽  
Author(s):  
Ted P. Szatrowski ◽  
Richard K. Dodge ◽  
Carol Reynolds ◽  
Carol A. Westbrook ◽  
Stanley R. Frankel ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Specific Treatment ◽  
Adult Patients ◽  
High Dose ◽  
High Dose Cytarabine ◽  
First Remission

scholarly journals Varying intensity of postremission therapy in acute myeloid leukemia

Blood ◽  
1992 ◽  
Vol 79 (8) ◽  
pp. 1924-1930 ◽  
Author(s):  
PA Cassileth ◽  
E Lynch ◽  
JD Hines ◽  
MM Oken ◽  
JJ Mazza ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mortality Rate ◽  
Maintenance Therapy ◽  
Myeloid Leukemia ◽  
High Dose ◽  
Allogeneic Bone ◽  
Consolidation Therapy ◽  
High Dose Cytarabine ◽  
Postremission Therapy ◽  
Acute Myeloid

The Eastern Cooperative Oncology Group (ECOG) conducted a randomized trial in patients less than or equal to 65 years old (median, 44 years) to determine whether increasing the intensity of postremission therapy in acute myeloid leukemia (AML) would improve the outcome. After uniform induction therapy, patients in complete remission (CR) who were less than 41 years old and who had a histocompatible sibling underwent allogeneic bone marrow transplantation (alloBMT) (54 patients). The remainder of patients in CR were randomized to receive either 2 years of continuous outpatient maintenance therapy with cytarabine and 6- thioguanine (83 patients) or a single course of inpatient consolidation therapy consisting of 6 days of high-dose cytarabine plus 3 days of amsacrine (87 patients). The median duration of follow-up is now 4 years, and patients are included in the analyses of outcome regardless of whether they relapsed before starting the intended treatment. Four- year event-free survival (EFS) was 27% +/- 10% for consolidation therapy versus 16% +/- 8% for maintenance therapy (P = .068) and 28% +/- 11% versus 15% +/- 9% (P = .047) in patients less than 60 years old. The outcome for patients receiving alloBMT was compared with the subset of patients less than 41 years old who received consolidation therapy (N = 29) or maintenance therapy (N = 21). Four-year EFS was 42% +/- 13% for alloBMT, 30% +/- 17% for consolidation therapy, and 14% +/- 15% for maintenance therapy. AlloBMT had a significantly better EFS (P = .013) than maintenance therapy, but was not different from consolidation therapy. In patients less than 41 years old, 4-year survival after alloBMT (42% +/- 14%) did not differ from consolidation therapy (43% +/- 18%), but both were significantly better than maintenance therapy (19% +/- 17%), P = .047 and .043, respectively. The mortality rate for maintenance therapy was 0%, consolidation therapy, 21%; and alloBMT, 36%. Consolidation therapy caused an especially high mortality rate in the patients greater than or equal to 60 years old (8 of 14 or 57%). The toxicity of combined high-dose cytarabine and amsacrine is unacceptable, especially in older patients, and alternative approaches to consolidation therapy such as high-dose cytarabine alone need to be tested. In AML, a single course of consolidation therapy or alloBMT after initial CR produces better results than lengthy maintenance therapy. Although EFS and survival of alloBMT and consolidation therapy do not differ significantly, a larger number of patients need to be studied before concluding that they are equivalent.

Excellent Prognosis of Late Relapses of ETV6/RUNX1 Childhood Acute Lymphoblastic Leukemia: Lessons From the FRALLE 93 Protocol

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1508-1508
Author(s):  
Virginie Gandemer ◽  
Sylvie Chevret ◽  
Arnaud Petit ◽  
Christiane Vermylen ◽  
Thierry Leblanc ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Initial Diagnosis ◽  
Induction Treatment ◽  
High Dose ◽  
Cox Regression Analysis ◽  
Excellent Outcome ◽  
Total Treatment ◽  
First Remission

Abstract Abstract 1508 Background. The long term prognosis of ETV6/RUNX1 -positive acute lymphoblastic leukemia (ALL) remains to be evaluated with regard to the frequency of late relapses and the possible existence of a preleukemic stem cell. We performed a retrospective study based on a long-term follow up of the FRALLE 93 ALL relapses to address the issue of the outcome of ETV6/RUNX1 -positive ones. Methods. 1395 patients aged 0 to 20 years with untreated ALL (except L3) were included between 01-Jan-1993 and 31-Dec-1999. From 1995, children were systematically screened for four fusion transcripts (ETV6-RUNX1, BCR-ABL, E2A-PBX1, MLL-AF4). The FRALLE 93 study population was stratified into three groups (low-risk [LR], intermediate-risk [IR], and high-risk [HR]) based on the following prognostic factors: age, white-cell count at diagnosis, haemoglobin level, immunophenotype, karyotype, and response to steroids. Patients received an initial treatment comprised of a prednisone prophase and a triple-drug intrathecal injection. Induction treatment then included prednisone, vincristine, L-asparaginase, daunorubicin (except for the LR group), and one or two more triple-drug intrathecal injections (TIT). The main treatment features of the SR and IR protocol were induction, consolidation, delayed intensification, and maintenance (total treatment duration of 26 and 38 months for girls and boys respectively). Treatment of the HR patients consisted of induction, consolidation, two delayed intensifications, and maintenance with a total treatment time of 2 years. Depending on subgroups, CNS-directed therapy included intrathecal injections +/− high-dose methotrexate +/− cranial irradiation. Following factors influencing survival after first relapse were analyzed: age, leukocytosis, gender, duration of first remission (CR1), risk groups defined in the REZ-BFM 95/96 study, sites of relapse and post CR2 consolidation treatment (AlloSCT or not). Results. ETV6/RUNX1 status was defined for 724 patients B lineage ALL. Overall, 162 of the 713 children who reached CR1 (45 % of boys) relapsed, including 43 with t(12;21). Cumulative incidence of relapses did not differ between ETV6/RUNX1 -positive and negative ALL (p=0.94), with a 5-year estimate at 19.4% and 19.9%, respectively nor according to gender and type of relapse. Nevertheless, 11 out of 26 relapses in the ETV6/RUNX1 -positive ALL males (43%) were testicular (4 testis isolated) versus 16 out of 70 (23%) in ETV6/RUNX1 -negative ALL cases (p= 0.04). Thirty three (77%) had been stratified as LR (n=6) or IR (n=27) group and 32 displayed good early response at initial diagnosis. Thirty five (81.4%) patients were classified as S1/S2 and 8 (18.6%) as S3/S4. All but three received second line salvage therapy (37/40 were included in the COOPRALL 97) and 16 underwent an AlloSCT (6 S3/S4). Based on univariate analyses, the overall survival of ETV6-RUNX1 -positive ALL after relapse was significantly affected by the duration of the first remission with a OS that was significantly improved when relapse occurred after 36 months (5-year OS: 80.6+/−7.9% versus 34.7+/− 12.3, p=0.002). Female gender was also associated with a poor survival (p= 0.015), whereas the site of relapse (p= 0.13), age at initial diagnosis (p= 0.81), leukocytosis (p=0.42), and consolidation strategy (p=0.18) had no affect on survival. In multivariate Cox-regression analysis, only the duration of first remission remained associated with the outcome (Figure 1). Conclusions. We found a high rate of testicular relapse without any increase of other extramedullary sites and an excellent outcome for ETV6/RUNX1 -positive leukemia relapses occurring over 36 months post-diagnosis. These findings highlight the interest of a primary treatment able to cross the testicular barrier. They also support the hypothesis that ETV6/RUNX1 “late relapses” are due to a novel leukemic clone, sensitive to a novel cycle of ALL chemotherapy. Disclosures: No relevant conflicts of interest to declare.

Nilotinib Combined with Multi-Agents Chemotherapy for Adult Patients with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Results of a Prospective Study from a Single Center

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1301-1301
Author(s):  
Bingcheng Liu ◽  
Ying Wang ◽  
Chunlin Zhou ◽  
Hui Wei ◽  
Dong Lin ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Maintenance Therapy ◽  
Prospective Study ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Grade 3 ◽  
Induction Cycle

Abstract Background: Imatinib combined with conventional chemotherapy has significantly improved the prognosis of adults with Philadelphia-positive acute lymphoblastic leukemia ( Ph+ ALL ). Nilotinib, the second generation TKIs is approximately 30 fold more potent than imatinib and is active in vitro against multiple BCR/ABL mutations. Here, we report the efficacy and safety of nilotinib combined with multiple reagents chemotherapy in newly diagnosed patients with Ph+ ALL. Methods: Newly diagnosed Ph+ ALL patients aged 15 to 59 and with adequate organ function were recruited. The 4weeks induction cycle consist of vincristine, daunorubicin, cyclophosphamide and prednisone. After achieving hematological complete remission (HCR), patients received 2 years of consolidation and maintenance therapy. Consolidation therapy was including 7 courses of multiple drug chemotherapy or allogeneic/autologous hematopoietic cell transplantation (allo/auto HCT). Nilotinib was the only drug for maintenance therapy. Nilotinib 400mg was given orally twice daily along with combination chemotherapy starting from day 15 of induction until the initiation of conditioning for transplantation, hematological relapse or continuing for 2 years since achievement of hematological complete remission (HCR).Central nervous system (CNS) prophylaxis was performed by intrathecally administering triple agents. The data cut-off day was June 1st 2015. HCR and molecular complete remission (MCR), overall survival(OS), hematologic relapse free survival (HRFS), toxicity, nilotinib concentration in serum and cerebrospinal fluid(CSF) were evaluated. MCR was defined as Bcr-Abl fusion gene becomes negative in bone marrow using quantitative RT-PCR. Results: A total of 30 patients (19 males and 11 females) were enrolled from September 2011 to November 2013. The median age was 40 (range 21-57) years old. The type of BCR breakpoint was minor in 24 patients, major in 2 patients and both in 4 patients. All the 30 patients (100%) and 8 patients (26.7%) achieved HCR and MCR respectively after the induction cycle. Cumulative MCR rate was 80%. 17 patients underwent HCT, 14 patients with alloHCT and 2 patients with autoHCT in first HCR, 1 patient received alloHCT after relapse. 9 patients died from leukemia relapse and 4 patients died post-alloHCT without relapse. The median HRFS and OS were 20.7 and 34 months respectively. The 4 year HRFS rate was 41% and the 4 year OS rate was 48%. The molecular response after induction has no impact on HRFS and OS. Patients achieving MCR had better HRFS (32 vs 8.9 months, p=0.006) but not OS(33.3vs 17.2months, p=0.068) than those patient without MCR. During induction, 23 patients experienced infectious fever including 2 patients with septicemia and 6 patients with pneumonia needing antifungal therapy. Intestinal obstruction occurred in 7 patients during induction and relived by interrupting nilotinib treatment. The incidence of non-hematologic adverse events (AE) over grade 3 during the study was 23% jaundice, 10% rash, 6.7% arthralgia and bone pain, 6.7%headache, 3.3% ALT elevation. No QTc prolongation over 500ms happened. Grade 2 tachycardia and premature ventricular contraction occurred in 2 patients and 1 patient respectively. During the high-dose methotrexate treatment cycle, delaying of methotrexate metabolism happened in 20 patients (66.7%), increasing creatine occurred in 8 patients (26.7%, grade 3 in 3 patients), 1 patient received haemodialysis. Nilotinib serum level reached to stable concentration after 15 days of administration. Only traces of nilotinib was detected in CSF. Conclusion: In this prospective study, combination of nilotinib and cytotoxic drug was shown to be effective and tolerable for adult Ph+ALL. Nilotinib could not penetrate the blood brain barrier. (ChiCTR-ONC-12002469) Disclosures Off Label Use: nilotinib,the 2nd generation TKI, was approved for CML. Wang:Novarits and Bristol-Mayers squibb. G.S.: Consultancy.

scholarly journals High-Risk Subtype of Ph-like Acute Lymphoblastic Leukemia (ALL) in Adults: Dismal Outcomes of CRLF2+ ALL Patients Treated with Intensive Chemotherapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1082-1082 ◽  
Author(s):  
Nitin Jain ◽  
Kathryn G. Roberts ◽  
Elias J. Jabbour ◽  
Keyur Patel ◽  
Karina Eterovic ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
Hispanic Ethnicity ◽  
Oncology Research

Abstract Background:Ph-like acute lymphoblastic leukemia (ALL) is a high-risk subtype of ALL in children. There are limited and conflicted data on the incidence and prognosis of Ph-like ALL in adults. Methods:Patients with newly-diagnosed B-ALL who received frontline chemotherapy at MD Anderson Cancer Center underwent gene expression profiling of leukemic cells to identify Ph-like ALL. Gene expression profiling was performed on 148 RNA samples using either U133 Plus 2.0 microarrays, or a customized Taqman low density array (LDA) card to identify patients with the Ph-like ALL gene signature (Roberts et al. NEJM 2014). An additional 7 previously untreated patients were found to have CRLF2 overexpression by multicolor flow-cytometry (MFC), and received induction chemotherapy at MDACC were included in the outcome analysis (but not for subtype frequency calculation). We performed targeted sequencing of 303 recurrently mutated genes (L300 panel, MDACC) in 40 patients with CRFL2 rearrangements (15 with matched germline control). Minimal residual disease (MRD) was assessed by MFC, with a sensitivity of 0.01%. Results:Of 148 patients, 49 (33.1%) were Ph-like, 46 patients (31.1%) were Ph+, and 53 patients (35.8%) were of other B-ALL subtypes (B-other). The median age of Ph-like cohort was 33.5 years (range, 15-71), Ph+ cohort was 49 years (range, 22-84), and B-other was 38 years (range, 15-79). Within the Ph-like ALL cohort, 61% had overexpression of CRLF2. Patients received hyper-CVAD (80%) or an augmented-BFM regimen (20%). The rate of CR/CRp was similar in the 3 disease subgroups (Ph-like ALL 89%, Ph+ ALL 93%, B-other 94%, p = 0.57). However, patients with Ph-like ALL were significantly less likely to achieve MRD-negative remission (30% vs. 56% for Ph+ ALL vs. 87% for B-other, p <0.001). Patients with Ph-like ALL had significantly worse overall survival (OS) and event-free survival (EFS) compared to B-other with a 5-year survival of 23% (vs. 59% for B-other, p=0.006) (Figure 1A). The poor outcomes of Ph-like ALL were also observed when only hyper-CVAD treated patients were considered. Interestingly, 68% of the patients with Ph-like ALL (78% among the CRLF2+ cohort) were of Hispanic ethnicity. This was significantly higher compared to Ph+ ALL (35%) and B-other (30%), p <0.001. Patients with CRLF2 overexpression had significantly inferior OS, EFS, and remission duration when compared to other genomic subgroups, including the Ph-like non-CRLF2 group (Figure 1B). Notably, 5-year survival in the CRLF2+ group was <20%. The following were independently associated with inferior OS on multivariable analysis: age (hazard ratio [HR] 2.474, p<0.001); WBC count (HR 1.183, p=0.007); platelet count (HR 4.283, p<0.001) and Ph-like ALL (HR 1.579, p=0.04) (Table 1). The most common mutations by L300 sequencing of 40 patients with CRLF2 were JAK2 (n=19, 47.5%), KRAS (n=10, 25%), CRLF2 (n=7, 17.5%), NRAS (n=5, 12.5%), PAX5 (n=5, 12.5%), JAK1 (n=4, 10%) (Figure 2). The CRLF2 F232C mutation, noted in 7 (17.5%) patients in this study, appears more frequent than in pediatric patients (3/134, 2.2%, Chen et al. Blood 2012), and in range with a smaller adult series (3/14, 21.4%, Yoda et al. PNAS 2010). CRLF2 F232C mutations were mutually exclusive with JAK2/JAK1 mutations (except in one patient). Conclusions:Our findings show a high frequency of Ph-like ALL in adults; an increased frequency of Ph-like ALL in adults with Hispanic ethnicity; significantly inferior outcomes of adult patients with Ph-like ALL; and significantly worse outcomes in Ph-like ALL patients with CRLF2 overexpression. The frequency of CRLF2 F232C mutation appears to be higher in adult patients with B-ALL than in the children. Ph-like ALL represents a high-risk disease subtype of adult B-ALL. Novel strategies are needed to improve the outcome of these patients. Disclosures Jain: Pharmacyclics: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Incyte: Research Funding; BMS: Research Funding; Abbvie: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Infinity: Research Funding; Novimmune: Consultancy, Honoraria. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Mullighan:Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Loxo Oncology: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding.

scholarly journals Amsacrine with high-dose cytarabine is highly effective therapy for refractory and relapsed acute lymphoblastic leukemia in adults

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 433-435
Author(s):  
ZA Arlin ◽  
E Feldman ◽  
S Kempin ◽  
T Ahmed ◽  
A Mittelman ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Side Effects ◽  
High Risk ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Primary Treatment ◽  
High Dose ◽  
Refractory Disease ◽  
High Dose Cytarabine ◽  
Adults And Children

Abstract Thirty-six patients with relapsed acute lymphoblastic leukemia (ALL) and four with primary refractory ALL were treated with a regimen that included amsacrine, 200 mg/m2, intravenously daily for three days with cytarabine, 3 gm/m2, by infusion over three hours daily for five days. There were 27 remissions in the 36 relapsed patients and two in the four patients with primary refractory disease. Seventeen of the 23 patients with common ALL, four of the six with T-cell ALL, one of the three with B-cell ALL, and seven of eight whose cells were not characterized responded. Toxicity of this regimen was comparable to other reinduction regimens for ALL, but the side effects characteristic of high-dose cytarabine therapy were absent. Since these results compare favorably with conventional induction regimens, its use in the primary treatment of adults and children with high-risk ALL is proposed.

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