Efficacy and Safety of Imatinib on Top of BFM-Like Chemotherapy in Pediatric Patients with Ph+/BCR-ABL+ Acute Lymphoblastic Leukemia (Ph+ALL). the EsPhALL Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 873-873 ◽  
Author(s):  
Andrea Biondi ◽  
Martin Schrappe ◽  
Paola Di Lorenzo ◽  
Anders Castor ◽  
Giovanna Lucchini ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Complete Remission ◽  
Adverse Events ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Early Response ◽  
National Study ◽  
Induction Phase ◽  
Free Survival ◽  
Significant Difference

Abstract Abstract 873 Background. Philadelphia chromosome positive (Ph+) ALL accounts for 3–5% of pediatric ALL. An international survey on 640 children diagnosed between 1995 and 2005 and treated with chemotherapy and stem cell transplantation (SCT) without the use of tyrosin kinase inhibitors (TKI) recently reported an overall 7-year event free survival (EFS) and overall survival (OS) of 31.2% and 44.2%, respectively. In those years, only limited experience was accumulated on the use of Imatinib (IM) for children with Ph+ leukemia. The EsPhALL study was designed as an intergroup, open-label, randomized Phase II/III study, within the I-BFM-SG network, to assess the safety and efficacy of IM in association with chemotherapy. Ten national study groups participated in the study: AIEOP, BFM-G/CH, COALL, FRALLE, NOPHO, MRC, DCOG, CPH, PINDA and HONG KONG. Methods. Patients 1 to 18 years of age diagnosed with Ph+ ALL were eligible to the study. After the induction phase according to national treatment protocol, patients were classified as Good Risk (GR) or Poor Risk (PR) according to their response to treatment. GR patients were those who achieved both the early response (i.e. blast cell count <1000/ml in peripheral blood after 7 days of prednisone and a single dose of intrathecal methotrexate or M1/M2 bone marrow at day 15 or M1 at day 21) and the complete remission after the frontline Induction course (1st complete remission, CR1). They were randomized to receive IM in combination with chemotherapy (GR-IM) or chemotherapy alone (GR-noIM). PR patients (those who did not achieved early response or CR1 or both) received IM in combination with chemotherapy. Due to the availability of external evidence, the randomization in GR was stopped in 2009 and an amended trial started, with all patients receiving IM continuously. The chemotherapy regimen was modeled upon a BFM high risk backbone and IM was delivered at the dose of 300 mg/m2/day. SCT in CR1 was recommended for all PR patients (any donor) and for GR patients if a genotype-matched donor (9/10 or 10/10 alleles) was available. The primary analysis for the randomized question (ITT) was on disease-free survival (DFS) in GR and EFS in PR patients, not censoring for SCT in CR1, with comparison based on the log-rank test. Results. Between 01-Jan-2004 and 31-Dec-2009, 178 patients (age 1.5–17.9 years) were enrolled and stratified as GR (108; 61%) or PR (70; 39%). Ninety GR patients were randomized (18 excluded for parental refusal or clinical decision); of these, 77% underwent SCT in CR1. Out of 35 PR patients who were resistant to Induction, 80% achieved CR1 after consolidation (Phase IB). 84% of PR patients received SCT in CR1. Relapse was the first event in 23 (33%), 12 (27%) and 10 (22%) of PR, GR-noIM and GR-IM patients, respectively. The most common site was the bone marrow (74%, 92% and 60% in PR, GR-noIM and GR-IM patients, respectively). Deaths in CR1 were 8, 4 and 2 in PR, GR-noIM and GR-IM patients respectively, none being related to IM. The 4-year DFS was 73% (95% CI: 56% – 84%) in the GR-IM arm and 62% (95% CI: 45% – 75%) in the GR-noIM arm (p=0.24), with a 4-year OS of 85% (95% CI: 70% – 93%) and 73% (95% CI: 54% – 85%), respectively (p= 0.37). A secondary ‘as treated' analysis was performed accounting for 13 patients who switched from GR-noIM to GR-IM, with 4-year DFS of 56% (95% CI: 36% – 72%) and 75% (95% CI: 61% – 85%), respectively (p=0.06). The EFS in PR patients was 54% (95% CI: 40% – 65%) at 2-years and remained constant through 3 and 4 years, with a 4-year OS of 64% (95% CI: 50% – 74%).The most frequently reported adverse events (AEs) across the treatment arms were decreased leukocytes, platelets and granulocyte counts, decreased hemoglobin, and infections. There was no significant difference in the overall frequency of AEs across all 3 patients' groups. Severe adverse events rate was 28% in GR-IM group, 32% in GR-noIM and 34% in PR group. Conclusions. Results suggest that the addition of IM to intensive BFM-type chemotherapy regimens was associated with an approximate 10% advantage in long-term DFS in GR patients which, however, the study was not powered to detect. The PR group treated with IM had improved EFS and OS as compared to historical controls. IM was generally well tolerated on top of intensive chemotherapy with a reassuring safety profile. Disclosures: Biondi: BMS, Novartis, Micromed: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Pentoxifylline During Steroid Window At Induction To Remission Increases Apoptosis In Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2623-2623
Author(s):  
Oscar Gonzalez-Ramella ◽  
Jimenez-Lopez Xochiquetzatl ◽  
Sergio Gallegos-Castorena ◽  
Pablo Ortiz-Lazareno ◽  
Jose Manuel Lerma-Diaz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Cancer Cells ◽  
Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Control Group ◽  
Induction Phase ◽  
Study Group ◽  
Significant Difference

Abstract Introduction Acute lymphoblastic leukemia (ALL) is the most common cancer diagnostic in children, and it represents the second death cause in this population. Despite advances in the treatment of childhood ALL, there are small portion of patients whom still succumb to this disease. A reduced apoptosis in cells plays an important role in carcinogenesis. This phenomenon is an important component in the cytotoxicity induced by anticancer drugs. A currently challenge is the chemotherapy resistance of tumor cells, inhibiting the apoptosis induced by chemotherapy. Pentoxifylline, (PTX) has been studied for its role on increase of apoptosis on cancer cells by different pathways. Our group has reported its efficacy in vitro and ex vivo in increasing apoptosis induced by chemotherapy drugs such as adriamycin and cisplatin in fresh leukemic human cells, lymphoma murine models and cervical cancer cells. We conducted a phase 1 controlled randomized trial to evaluate the efficacy of adding PTX to the steroid window during the remission induction phase in new diagnosed children with ALL. Methods We included all children from both sexes from 9 months to 17 years old during October 2011 to December 2012. Patients were divided into 3 groups, the first one as a non-malignant control group (NL group) included children with a non-hematology disease in which bone marrow aspiration (BMA) was mandatory in order to reach the diagnosis. The second one, the ALL control group whom received prednisone (PRD group) for the steroid window at 40mg/m2/day PO from day -7 to day 0; and then the third one (PTX group), the study group which included children receiving the steroid phase with PRD as early described, plus PTX at 10mg/kg/day IV divided in 3 doses, at the same days as recommended in our treatment protocol (Total Therapy XV). For all 3 groups a BMA was performed at diagnosis, for PRD group as well as PTX group, a second BMA was also collected at day 0. Apoptosis was evaluated by means of Annexin V Apoptosis Detection Kit FITC/PI (eBioscience¨, San Diego, CA, USA) in 1×106 bone marrow mononuclear cells. We measured minimal residual disease (MRD) by flow cytometry at day 14 to demonstrate complete remission in leukemic patients. Statically analysis was performed by U Man Whitney. Results We enrolled 32 patients: 10 in NL group; 11 in PRD group; and 11 in PTX group. The median age of all groups was 6 years (range 9 months-17 years). In PRD group, patient 1 abandoned treatment after administration of day 0, nevertheless the second BMA sample was collected. Patient number 7 died at day 4 due to complications from tumor lysis syndrome. Consequently, in these patients we were not able to measure MRD and BM aspiration at day 14. Except one patient in PRD group, all achieved complete remission at day 14. We did not find any significant difference between NL group and PRD and PTX groups before intervention (U=32 p=0.7; U=28.5 p=0.48 respectively). There was no significant difference between treatment groups before intervention (U= 37 p=0.79). However, after treatment we found an important difference between PRD and PTX groups, we observed an increase in apoptosis in PTX group in comparison with PRD group (U=17.5 p=0.04). There were no adverse effects during treatment. Conclusions The present study is the first one that shows the efficacy of PTX in increasing apoptosis induced by PRD in new ALL diagnosed children, whom have not received any treatment yet. This might be helpful, not only in patients with relapse, but to increase the overall cure rate in ALL. Further studies are needed to prove this hypothesis. With this objective, our study group is already planning a second trial were PTX will be given during all remission induction phase. Experimental reports strongly suggest that PTX induces inhibition of the transcription factor NF-ĸB, by inhibiting survival gens and facilitating apoptosis. To prove it, we are currently processing these patients' samples to know their genetic expression. Disclosures: No relevant conflicts of interest to declare.

Paediatric-Inspired Acute Lymphoblastic Leukemia Protocols, Are They Too Toxic for Young Adults?

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5162-5162
Author(s):  
Melissa G. Ooi ◽  
Wee J Chng ◽  
Chin-Hin Ng ◽  
Yi Ching Yuen ◽  
Allen Eng Juh Yeoh ◽  
...  
Keyword(s):  
Young Adults ◽  
Acute Lymphoblastic Leukemia ◽  
Young Adult ◽  
Complete Remission ◽  
Adverse Events ◽  
Lymphoblastic Leukemia ◽  
Main Concern ◽  
Induction Phase ◽  
Free Survival ◽  
Paediatric Patients

Abstract BACKGROUND In children with acute lymphoblastic leukemia, (ALL), current therapies yield complete remission (CR) rates of 98% and event-free survival (EFS) rates of 70% to 80% at 5 years[1]. In adults, even if the CR rate reaches 85% to 90%, therapeutic results remain less satisfactory, with a disease-free survival (DFS) rates of only 30% to 40% at 5 years. The largest adult trial conducted by the British Medical Research Council (MRC) and Eastern Cooperative Oncology Group (ECOG) has recently reported a 90% CR rate with a 5-year overall survival (OS) rate of 43% in patients with Philadelphia chromosome (Ph)-negative ALL [2]. In a study that retrospectively compared two trials, one designed for children and the other for adults, adolescents and young adults age 15 to 20 years old markedly benefited from a pediatric approach[3]. Whether pediatric or pediatric-inspired treatments might also improve the outcome of adults older than age 20 years remained unresolved. The main concern was the perceived worse tolerance of higher cumulative doses of chemotherapy. MASPORE, a BFM based paediatric ALL protocol, has been used successfully in Singapore and Malaysia's paediatric cohort. In this single centre study, we wanted to investigate if the young adults with ALL (<30 years age) will also benefit from MASPORE and to investigate if they can tolerate a paediatric type regiment. METHODS We looked at our young adult patients (18-30 years old inclusive) over a period of 8 years. There was a total of 15 patients who was diagnosed with ALL (either T or B cell). Patients who were Philadelphia positive were excluded from this trial. The grading for the adverse events was done according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. RESULTS Our patients appeared to have a number of adverse events on this paediatric protocol. The grade 3/4 adverse events were 50% of all events collected. Table 1 demonstrated the type and incidence of events. As our serious adverse events appear to be L-asparaginase related, we focused in on those events associated with L-asparaginase and compared our data with our paediatric counterpart. Our patients had a high incidence of pancreatitis (13.3%) and thrombosis (40%), compared to the paediatric patients, who reported an incidence of 2.05% pancreatitis and 2.6% thrombosis. If line related thrombosis was removed from the equation, our thrombosis risk was still 13.3% which is 6.5 times the paediatric rate. Interestingly, the pancreatitis that our patients experienced was a biochemical pancreatitis with no clinical symptoms. Although fewer paediatric patients suffer from pancreatitis, there appear to be sicker with pancreatitis needing intervention. CONCLUSION The young adult cohort appears to have a much higher incidence of adverse events when compared to the paediatric patients. The thrombosis and pancreatitis incidence rate appear to be 6.5 times more frequent compared to the paediatric patients. The limitation of this study is the small number of young adult ALL. Our department has instituted a policy change since this data was analysed. To reduce the incidence of line related thrombosis, the use of a peripherally inserted central catheter is discouraged during induction phase. We are also minimising the days off thromboprophylaxis; the low molecular weight heparin is only withheld on the day of the intrathecal chemotherapy. Since this protocol change, there has been no more line related thrombosis and other thrombosis noted. Our future work would be to reanalyse our thrombosis data after this protocol change and to investigate further as to why the young adults suffer more with pancreatitis compared to the children. References 1. Pui, C.H. and W.E. Evans, Treatment of acute lymphoblastic leukemia. N Engl J Med, 2006. 354(2): p. 166-78. 2. Goldstone, A.H., et al., In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood, 2008. 111(4): p. 1827-33. 3. Boissel, N., et al., Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials. J Clin Oncol, 2003. 21(5): p. 774-80 Disclosures Chng: Celgene: Honoraria, Research Funding.

Outcome of Allogeneic Hematopoietic Stem-Cell Transplantation in Adult Patients With Acute Lymphoblastic Leukemia: No Difference in Related Compared With Unrelated Transplant in First Complete Remission

2004 ◽  
Vol 22 (14) ◽  
pp. 2816-2825 ◽  
Author(s):  
Michael G. Kiehl ◽  
Ludwig Kraut ◽  
Rainer Schwerdtfeger ◽  
Bernd Hertenstein ◽  
Mats Remberger ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Hematopoietic Stem ◽  
First Complete Remission

Purpose The role of unrelated allogeneic stem-cell transplantation in acute lymphoblastic leukemia (ALL) patients is still not clear, and only limited data are available from the literature. We analyzed factors affecting clinical outcome of ALL patients receiving a related or unrelated stem-cell graft from matched donors. Patients and Methods The total study population was 264 adult patients receiving a myeloablative allogeneic stem-cell transplant for ALL at nine bone marrow transplantation centers between 1990 and 2002. Of these, 221 patients receiving a matched related or unrelated graft were analyzed. One hundred forty-eight patients received transplantation in complete remission; 62 patients were in relapse; and 11 patients were refractory to chemotherapy before transplant. Fifty percent of patients received bone marrow, and 50% received peripheral blood stem cell from a human leukocyte antigen–identical related (n = 103), or matched unrelated (n = 118) donor. Results Disease-free survival (DFS) at 5 years was 28%, with 76 patients (34%) still alive (2.2 to 103 months post-transplantation), and 145 deceased (65 relapses, transplant-related mortality, 45%). We observed an advantage regarding DFS in favor of patients receiving transplantation during their first complete remission (CR) in comparison with patients receiving transplantation in or after second CR (P = .014) or who relapsed (P < .001). We observed a clear trend toward improved survival in favor of B-lineage ALL patients compared with T-lineage ALL patients (P = .052), and Philadelphia chromosome–positive patients had no poorer outcome than Philadelphia chromosome–negative patients. Total-body irradiation–based conditioning improved DFS in comparison with busulfan (P = .041). Conclusion Myeloablative matched related or matched unrelated allogeneic hematopoietic stem-cell transplantation in ALL patients should be performed in first CR.

Overexpression of HIF1 Alpha Predicts Worse Overall and Event-Free Survival in Patients with Philadelphia Chromosome-Negative Precursor B-Lymphoblastic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2508-2508 ◽  
Author(s):  
S. Konoplev ◽  
S.M. Kornblau ◽  
E. Schlette ◽  
H Lu ◽  
D. A Thomas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Akt Signaling ◽  
Leukemic Cells ◽  
Newly Diagnosed ◽  
Event Free Survival ◽  
Data Set ◽  
Free Survival ◽  
Survival Signaling

Abstract Background: Low oxygen levels are a defining characteristic of solid tumors, but the role of hypoxia in leukemogenesis remains unclear. Recent reports indicate that the endosteum at the murine bone-bone marrow (BM) interface is hypoxic, and data in a rat model demonstrate that leukemic cells infiltrating bone marrow were markedly hypoxic compared with cells in the BM of healthy rats. Hypoxia triggers a complex cellular and systemic adaptation mediated primarily through transcription by hypoxia inducible factors (HIFs) including HIF-1a. Although hypoxia is the best-characterized mechanism of HIF activation in tumors, HIF activity also can be induced in tumor cells through activation of the PI3K/Akt-signaling pathway. In this study, we assessed AKT and HIF-1a expression in newly diagnosed precursor B-cell acute lymphoblastic leukemia (pre-B ALL) and correlated the results with overall and progression-free patient survival. Methods: We analyzed expression of phosphorylated AKT (pAKT) and HIF-1a in leukemic cells by immunohistochemical methods using archival fixed, paraffin-embedded BM biopsy specimens of newly diagnosed pre-B ALL and antibodies specific for pAKT (Cell Signaling Technology, Beverly, MA) and HIF-1a (BD Biosciences, San Jose, CA). The initial observations were confirmed by a Reverse Phase Protein Array (RPPA) data set generated from protein lysates prepared from fresh blood and BM aspirate samples from patients with newly diagnosed pre-B ALL. Results: There were 26 men and 27 women with a median age of 39 years (range, 17–77). The median follow-up was 17 months (range, 1–71). The median WBC was 5.7 × 109/L (range, 0.8–369 × 109/L), the median percentage of blasts in bone marrow was 88% (range, 21–97%). Conventional cytogenetic studies detected a normal karyotype in 13 patients and abnormal karyotype in 37 patients including the Philadelphia chromosome (Ph) in 15 patients; no analyzable metaphases were recovered in 5 patients. Fluorescence in situ hybridization for BCR/ABL rearrangement was performed in all patients and was positive in all 15 patients with Ph and in 1 patient with normal conventional cytogenetics. 50 patients received HYPER-CVAD therapy, 3 patients received augmented BFM therapy. 49 (92%) patients achieved complete remission with a median time to response of 3 weeks (range, 2–8 weeks), 12 of them relapsed. 17 patients died, including 6 patients in complete remission. 3 year overall survival was 56% (CI, 46–66%). HIF-1a expression was detected in 37 (70%) patients, including 10 patients with Ph-positive ALL. HIF-1a expression was associated with expression of pAKT (R=0.4479, p&lt;0.01), and was not associated with age, sex, WBC, percentage of blasts in blood or BM, platelet count, serum levels of albumin, beta-2-microglobulin, bilirubin, creatinine, LDH, or presence of the Ph. HIF-1a expression was associated with worse overall survival for the entire patient population (p=0.023). The negative prognostic impact of HIF-1a expression remained when only Ph-negative patients were analyzed (p=0.004), Fig 1. Patients with HIF-1a expression appear to have worse progression-free survival, but the difference did not reach statistical significance, p=0.39. These results were confirmed by RPPA data set generated from 104 patients with newly diagnosed Ph-negative ALL. HIF-1a overexpression was strongly associated with worse overall (p=0.026) and event-free (p=0.0178). No association of HIF-1a overexpression with other clinical or laboratory parameters was detected. Conclusions: This is the first report demonstrating that HIF-1a expression is associated with worse overall and event-free survival in Ph-negative pre-B ALL. These findings implicate that inhibition of AKT signaling or blockade of HIF-1α-mediated pro-survival signaling events may improve clinical outcomes in pre-B ALL. Analysis of the key pro-survival signaling pathways activated by hypoxia and HIF-1a is ongoing (Frolova et al., ASH 2008). Figure Figure

scholarly journals Chemotherapy with the Use of TKIs Based on MRD Has the Potential to Avoid Hematopoietic Stem Cell Transplantation in Treatment for Children with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL). Results of the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) Study ALL-Ph13

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3394-3394
Author(s):  
Atsushi Sato ◽  
Hirohide Kawasaki ◽  
Takao Deguchi ◽  
Yoshiko Hashii ◽  
Yuka Iijima-Yamashita ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Hematopoietic Stem Cell Transplantation ◽  
Complete Remission ◽  
Adverse Events ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Hematopoietic Stem ◽  
Fatal Adverse Events ◽  
First Complete Remission

Abstract Aims: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) patients generally have a poor prognosis when treated with chemotherapy alone. In adults, allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission is still the standard strategy for Ph+ALL. However, in children, HSCT should be avoided as much as possible to eliminate late complications. There are some reports showing that the combination of tyrosine kinase inhibitors (TKIs) with chemotherapy may avoid HSCT in childhood Ph+ALL. Thus, we planned this clinical trial (JPLSG ALL-Ph13) with the aim of improving outcomes with as few HSCT by chemotherapy with TKIs based on Ig/TCR minimal residual disease (MRD). Methods: Patients aged 1 to 19 with Ph+ALL were enrolled in JPLSG ALL-Ph13 Study. The diagnosis of Ph+ALL was performed using reverse-transcription PCR for BCR-ABL1. Chemotherapy follows the BFM ALL high-risk regimen (IA, IB, HR3, HR2, HR1, III, IM, III, IM, III, and maintenance). Imatinib was started on day 15 of induction therapy and continued until the final day of maintenance therapy (Ima group). If Ig/TCR MRD was positive (≥10 -4) at the end of IB, imatinib was changed to dasatinib and chemotherapy was continued (Dasa group). If MRD was positive at the end of the HR blocks, HSCT was performed (HSCT group). Results: During the period 2013-17, 43 patients were registered in this study, and 2 patients were excluded by not meeting inclusion criteria. Thirty-three, 7, and 1 patient were stratified into Ima, Dasa, and HSCT groups, respectively. Induction rate was 52.6% at the end of IA and 89.2% at the end of IB. MRD-negative rate was 61.3% at the end of IB and 87% at the end of HR. Although 51.2% of patients eventually received HSCT, only 13.9% received HSCT at the first complete remission. In all patients, the 3-year event-free survival (EFS) rate was 65.1%, and the 3-year overall survival (OS) rate was 85.1%. Four patients died of serious infections during treatment (2 in IA, 2 in 1st III). Interpretation: In our previous study for children with Ph+ALL (the JPLSG Ph+ALL04 study), all patients underwent HSCT, with the 3-year EFS rate of 57% and the OS rate of 80%. In this ALL-Ph13 study, the EFS and OS are almost the same as those in the Ph+ALL04. These are also almost the same as those in the EsPhALL2010 study, which aimed at avoiding HSCT. However, as in the EsPhALL2010 study, the comparatively high incidence of fatal adverse events was a problem with this study. Conclusion: Chemotherapy with the use of TKIs based on MRD has the potential to avoid HSCT in treatment for children with Ph+ALL. Reducing the occurrence of fatal adverse events is a future challenge to overcome. Disclosures No relevant conflicts of interest to declare.

Philadelphia-Like Signature In Childhood Acute Lymphoblastic Leukemia: The AIEOP Experience

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 353-353 ◽  
Author(s):  
Geertruy te Kronnie ◽  
Daniela Silvestri ◽  
Elena Vendramini ◽  
Grazia Fazio ◽  
Franco Locatelli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Gene Expression Signature ◽  
Induction Phase ◽  
Dna Index ◽  
Study Gene Expression ◽  
Significant Difference

Abstract Background Despite the current risk-based stratification and therapies, up to 20% of pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) experience relapse. A major research effort is dedicated to identifying poor prognostic subgroups in the larger subset of patients with intermediate-risk disease, where most relapses occur. Recently, two groups in the US and the Netherlands independently identified a novel BCP-ALL subtype negative for the BCR/ABL fusion gene but with a gene-expression profile similar to Philadelphia chromosome-positive (Ph+) ALL. This ‘Ph-like’ (or ‘BCR/ABL-like') subtype encompasses 10-15% of BCP-ALL patients, predicts high incidence of relapses and defines a candidate subgroup for targeted treatment with tyrosine kinase inhibitors and alternative drugs. Aim Aim of this project was to identify BCP-ALL Ph-like cases and their prognosis in patients treated in Study Protocols of the Italian Association of Pediatric Hematology and Oncology (AIEOP) Methods In the context of the Microarray Innovations in LEukemia (MILE) study, gene expression profiling was successfully performed on 400 Italian childhood BCP-ALL cases enrolled in AIEOP-BFM ALL2000/R2006 protocols, from whom material was available. The MILE classifier recognized the most common genetic subgroups, namely t(4;11), t(12;21), t(1;19) or t(9;22) positive, or high hyperdiploid (DNA index≥1.16). Out of 400 BCP-ALL cases, 143 negative for common fusion transcripts, non-high hyperdiploid (DNA index<1.16) and non-Down Syndrome, were defined as ‘B-others’. Results Using signatures of known ALL subgroups, the likelihood to be close to one of the ‘known’ classes was defined for each of the B-others samples. Specifically, 43 B-other cases (43/143=30.1%, about 10% of total BCP-ALL cohort) presented as a cluster with a gene expression signature close to the BCR/ABL signature, therefore referred to as ‘Ph-like’. Among B-others, Ph-like cases had a significantly increased proportion of males, age>10 years and WBC>20x109/L. The 5y event-free survival (EFS) of Ph-like patients was 54.8% (SE 8.2) vs 83.1% (3.9) in the remaining B-others patients (p<0.001), mostly due to an increased cumulative incidence of relapse (CIR: 33.9% (7.4) vs 14.9% (3.7); p=0.009). Notably, Ph-like patients did not differ for prednisone (PDN) and minimal residual disease (MRD) response or final risk stratification. Indeed, out of 36/43 stratified by MRD, only 7 patients had high-risk MRD, while 20 were MRD intermediate and 9 even MRD standard risk. Only 3 non-HR cases by MRD were then classified as HR based on PDN response. Of relevance, the significant difference in 5y EFS was confirmed in the 33 Ph-like patients with no HR features (59.8% (9.2) vs 88.5% (3.9) in the remaining B-others patients with similar features (p<0.001), with a significantly increased CIR (32.1% (8.4) vs 10.2% (3.7); p=0.005). Among 43 Ph-like cases, 1 was resistant and 1 died during the induction phase. Out of the 14 relapses, 10 were isolated medullary, and 4 combined with an extramedullary site (no CNS relapses). Two patients died in remission and no secondary malignancies occurred during the observation period. Overall, 25/43 (58.1%) Ph-like patients are alive in complete remission versus 84/100 (84.0%) in B-others, non Ph-like patients. Conclusions and perspectives We identified a ‘Ph-like’ subgroup in the Italian cohort of children with BCP-ALL, associated to a poor outcome. Ph-like patients, independently of the other known risk features, could be considered eligible for alternative treatments. The genetic characterization of this subgroup is ongoing within the AIEOP-BFM research trial cooperative group, which is aimed at further defining the pathogenetic mechanisms and identifying the therapeutic translation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Molecular remission after combination therapy with blinatumomab and ponatinib with relapsed/refractory Philadelphia chromosome-positive acute lymphocytic leukemia: two case reports

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Junichiro Yuda ◽  
Nobuhiko Yamauchi ◽  
Ayumi Kuzume ◽  
Yong-Mei Guo ◽  
Nobue Sato ◽  
...  
Keyword(s):  
Complete Remission ◽  
Combination Therapy ◽  
Adverse Events ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Molecular Response ◽  
Hematopoietic Stem ◽  
Safety And Efficacy ◽  
Old Japanese ◽  
Philadelphia Chromosome Positive

Abstract Background The outcomes of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) can improve with allogeneic hematopoietic stem cell transplantation (HSCT) during the first complete remission after treatment with a tyrosine kinase inhibitor (TKI) combined with chemotherapy. However, frail patients who are not eligible for allogeneic HSCT or those with TKI-resistant mutations within the BCR–ABL kinase domain have a poor clinical course. Blinatumomab (BLIN) is a bispecific T-cell engager antibody construct that directs cytotoxic T cells to CD19-expressing B-ALL cells. To date, only a few studies have shown the safety and efficacy of Blinatumomab (BLIN) + TKI combination therapy for relapsed/refractory (R/R) Ph+ ALL. Here we report the case of two patients with R/R Ph+ ALL who were treated with BLIN + TKI with durable molecular response. Case presentation Patient 1: A 69-year-old Japanese male with R/R Ph+ ALL was treated with conventional chemotherapy and dasatinib in April 2016. In May 2018, he developed molecular relapse due to the acquisition of T315I during dasatinib maintenance therapy. Thereafter, he achieved molecular complete remission (mCR) after switching from dasatinib to ponatinib. However, he developed a second relapse after the emergence of triple compound mutations (G250E/D276G/T315I) in November 2018. He subsequently received a total of nine cycles of BLIN and ponatinib combination therapy, which resulted in sustained mCR without any adverse events. Patient 2: A 69-year-old Japanese female with R/R Ph+ ALL was treated with chemotherapy and imatinib in April 2008. She developed molecular relapse due to the emergence of the T315I mutation in October 2017. She achieved mCR after switching from imatinib to ponatinib. However, she developed a second relapse after acquiring ABL exon4 skipping in addition to T315I. She subsequently received a total of seven cycles of BLIN and ponatinib combination therapy, which resulted in sustained mCR. Conclusion In our two cases, BLIN + ponatinib combination therapy was highly effective for R/R Ph+ ALL without any incidence of severe adverse events. Further studies with larger cohorts are warranted to validate the safety and efficacy of this potent combination therapy.

scholarly journals Combination Chemotherapy Plus Dasatinib Leads to Comparable Rates of Overall Survival and Relapse-Free Survival As Allogeneic Hematopoietic Stem Cell Transplantation in Philadelphia Positive Acute Lymphoblastic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4629-4629
Author(s):  
Jeremy Chang ◽  
Golnaz Vahdani ◽  
George Yaghmour ◽  
Kum-Ja Lee ◽  
Ashley Weissman ◽  
...  
Keyword(s):  
Combination Chemotherapy ◽  
Survival Benefit ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Relapse Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Allogeneic Hsct ◽  
Transplant Patients ◽  
Significant Difference

Abstract Introduction: The presence of the Philadelphia chromosome has historically been associated with a poor prognosis in patients with acute lymphoblastic leukemia (ALL). Prior studies had demonstrated that the 5-year overall survival (OS) rate among adult patients with Philadelphia-chromosome positive (Ph+) ALL was 25% compared to 41% in Philadelphia-chromosome negative (Ph-) ALL (Moorman et. al. Blood 2007). While hematopoietic stem cell transplantation (HSCT) has long been regarded as the standard of care for adult Ph+ ALL patients despite its significant transplant-related morbidity and mortality, its benefit is less clear in the era of newer-generation tyrosine kinase inhibitors (TKI) such as dasatinib. Methods: We conducted a retrospective study at a single urban transplant center with academic affiliation to analyze the outcomes of adult patients diagnosed with Ph+ ALL between 2005-2018. Patients were treated with either combination chemotherapy plus dasatinib or combination chemotherapy plus dasatinib and allogeneic HSCT. Chemotherapy regimens included hyper-CVAD, Berlin-Frankfurt-Munster-like (BFM-like) protocol, and a regimen developed at the University of Southern California (USC ALL regimen) using pegaspargase (Douer et. al. Journal of Clinical Oncology 2014). All patients in both the transplant group and the non-transplant group received TKI therapy with dasatinib throughout their treatment courses; in the former, patients received dasatinib both prior to and following their transplants. Statistical analysis was performed using the Fisher Exact Probability Test with p-values <0.05 deemed significant. Results: A total of 71 Ph+ ALL patients were included in this study. Forty-three patients (60.5%) were male and the median age at the time of diagnosis was 44 years (range 20-69). Median follow-up time was 15 months (range 1-131). Chemotherapy regimens included the USC ALL regimen in 69.8% of patients, hyper-CVAD in 25.6%, and BFM-like protocol in 7%. While in remission, 31 (43.6%) patients underwent allogeneic HSCT with subsequent post-transplant dasatinib therapy. Median time of dasatinib initiation following transplant was at day 102. Matched related donor transplants were performed in 48% of patients, matched unrelated donor transplants in 24%, and haploidentical donor transplants in 29% of patients. In comparing OS rates, 1-year OS was 92.9% vs. 100% (p = 0.49), 2-year OS was 90.1% vs. 83.3% (p = 0.60), and 3-year OS was 75% vs. 62.5% (p = 0.64) in the allogeneic HSCT group compared to the non-transplant group, respectively (Figure 1). The 3-year relapse-free survival (RFS) rates also proved to be similar at 70.5% in the allogeneic HSCT group and 80.1% in the non-transplant group (p = 0.94, Figure 2). In addition, 37% of patients had a poor prognostic factor of a white blood count (WBC) >30 x 109/L at the time of diagnosis. When comparing rates of OS and RFS between transplant vs. non-transplant patients in this group, there was also no significant difference. Conclusion: This study showed that in the management of adult Ph+ ALL patients, there was no significant difference in OS or RFS between patients who underwent allogeneic HSCT compared to those who received only combination chemotherapy with dasatinib. In addition, prior studies of Ph+ ALL patients treated with either chemotherapy alone or chemotherapy followed by HSCT concluded that the OS rates were approximately 50%, 35%, and 30% at the 1-year, 2-year, and 3-year marks, respectively (Rowe et. al. Blood 2005). Our analysis, however, demonstrated improved rates of survival at all time points for this patient population with the addition of dasatinib. Subgroup analysis of patients with a WBC >30 x 109/L at the time of diagnosis also showed no significant difference in OS between transplant and non-transplant patients despite previous reports showing a survival benefit from HSCT (Huang et. al. Blood 2016). This may be attributed to the fact that our patients received the newer and more potent agent dasatinib compared to imatinib in these prior studies. Since allogeneic HSCT demonstrated no survival benefit in our study and can also introduce risks of serious infectious complications, venoocculsive disease (VOD), and graft-versus-host disease (GVHD) that contribute to patient morbidity and mortality, it may serve a less beneficial role for the Ph+ ALL population in the era of newer-generation TKIs. Disclosures No relevant conflicts of interest to declare.

Blast Percentage of Bone Marrow Aspirate on Day 14 of Induction Chemotherapy Predicts Adult Acute Lymphoblastic Leukemia Treatment Outcomes

2018 ◽  
Vol 139 (4) ◽  
pp. 220-227 ◽  
Author(s):  
Han-Seung Park ◽  
Dae-Young Kim ◽  
Eun-Ji Choi ◽  
Jung-Hee Lee ◽  
Je-Hwan Lee ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Treatment Outcomes ◽  
Induction Chemotherapy ◽  
Lymphoblastic Leukemia ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Adult Acute Lymphoblastic Leukemia

The prognosis of adult acute lymphoblastic leukemia is much worse than that of pediatric acute lymphoblastic leukemia, even when patients achieve complete remission. Early response to treatment can be an important alternative indicator of treatment outcomes. The purpose of our current study was to identify the prognostic value of the blast percentage of the induction interim bone marrow, which might predict relapse-free survival and overall survival in patients with adult acute lymphoblastic leukemia. A retrospective analysis was performed on 80 adult patients diagnosed with Philadelphia chromosome-negative acute lymphoblastic leukemia from 1994 to 2011. Complete remission was observed in 75 (93.8%) patients after induction chemotherapy. On multivariate analysis, a reduction of blasts to a level of 5% or less in the induction interim bone marrow and CD20 positivity were significant prognostic predictors of relapse-free survival (hazard ratio, HR = 2.88, p = 0.006, and HR = 2.67, p = 0.010) and overall survival (HR = 2.10, p = 0.033, and HR = 2.39, p = 0.013). The blast percentage of the induction interim bone marrow may be a useful prognostic factor to predict outcome.

Early Response Characteristics and Blast Cytogenetic FEatures In 5,377 Children with Standard Risk Acute Lymphoblastic Leukemia (SR-ALL): A Children's Oncology Group (COG) Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 414-414
Author(s):  
Kelly W. Maloney ◽  
Mignon L. Loh ◽  
Elizabeth Raetz ◽  
Michael J. Borowitz ◽  
Meenakshi Devidas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Induction Therapy ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Early Response ◽  
Response To Therapy ◽  
Intrathecal Therapy ◽  
Post Induction

Abstract Abstract 414 The COG uses clinical characteristics, blast cytogenetic features and early response to therapy, as measured by bone marrow (BM) morphology on days 8, 15 and 29 and BM minimal residual disease (MRD) measured by flow cytometry in one of two central COG reference laboratories on day 29 of induction in order to modulate the intensity of post-induction therapy for children with ALL. A slow early response (SER) to therapy was defined by M2/M3 BM on day 15 or MRD ≥ 0.1% on day 29. The COG AALL0331 trial accrued 5377 children with NCI SR- ALL (age 1–10 years with an initial white blood cell count of <50,000/microliter) between 4/11/2005 and 5/28/2010. Induction therapy consisted of dexamethasone (6mg/m2/day × 28 days), PEG asparaginase (2500 units/m2 × 1), vincristine (1.5 mg/m2 weekly × 4) and intrathecal therapy (cytarabine on day 0 and methotrexate on days 8 and 29) according to age based dosing. Those patients with a day 29 M2 BM (5–25% blasts) or MRD ≥1% received two additional weeks of induction therapy using the same agents with one added dose of daunorubicin (25 mg/m2). Children with an M3 marrow (>25% blasts) on day 29, or an M2 marrow or MRD ≥1% on day 43 after 2 weeks of extended induction therapy were classified as induction failures. Following the first month of therapy, patients were assigned to different risk groups for post-induction therapy. We examined the correlations between clinical features, leukemic blast cytogenetic features (favorable: ETV6-RUNX1 and trisomies 4, 10, and 17 or unfavorable: MLL rearrangements, BCR-ABL1 and hypodiploidy), and response to induction therapy. MRD at end induction was ≥ 0.1% more frequently in patients with the absence of either ETV6-RUNX1 (10.4% vs. 3.5%, P<0.0001) or trisomies 4, 10, and 17 (TT) (9.5% vs 5.9%, p=0.0001) or among those who harbored MLL rearrangements (26.1% vs. 8.5%, p=0.0004). MRD > 0.1% at end induction was seen in 23.3% of hypodiploid patients and 32.4% of Philadelphia chromosome + or BCR-ABL1 + patients. In addition, those who had an M2/M3 marrow at day 15 (36.7% vs. 5.9%, p <0.0001) were more likely to have MRD ≥ 0.1% at end induction. There was no difference in the proportion of boys and girls with MRD ≥0.1% (8.5% vs. 8.1%). Only 114/5082 (2.2%) children received extended induction. Induction failures were rare, occurring in only 37/5075 (0.7%) of patients. Induction failures defined by an M3 marrow on day 29 occurred in 6/5123 patients, while induction failures at day 43 after extended induction, occurred in 31/5067 (0.61%) patients (day 43 M2 marrow: 2, day 43 MRD ≥1%: 29). (see Table 1). Conclusions: Inferior MRD responses were associated with the absence of favorable blast cytogenetics and slow initial responses (M2/3 marrow) on day 15 of induction consistent with the known prognostic significance of these variables. Overall, NCI SR patients on AALL0331 had a very low incidence of induction failures, as measured either by bone marrow morphology or by MRD≥1% at day 43. However, the use of MRD identified additional patients who had a suboptimal response to induction, allowing for early augmentation of therapy. Disclosures: Borowitz: genzyme: Research Funding; becton-dickinson: Research Funding; Alexion: Consultancy; beckman-coulter: Research Funding. Mattano:pfizer: Employment.

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