Augmented Berlin-Frankfurt-Muenster Based Therapy For Young Adults With Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1400-1400 ◽  
Author(s):  
Michael E. Rytting ◽  
Deborah A. Thomas ◽  
Susan O'Brien ◽  
Kurt Schroeder ◽  
Rebecca Garris ◽  
...  
Keyword(s):  
Young Adults ◽  
Acute Lymphoblastic Leukemia ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Univariate Analysis ◽  
Philadelphia Chromosome ◽  
Significant Difference ◽  
Grade Iii

Abstract Pediatric-based therapy of acute lymphoblastic leukemia (ALL) has been proposed as superior treatment for teen-agers and young adults with ALL. Several trials report improved survival rates in young adult ALL patients (pts) when treated with pediatric-based regimens. Augmented Berlin-Frankfurt-Muenster (ABFM) treatment is effective treatment for ALL in adolescents up to age 21. In an attempt to improve cure rates in AYA pts with ALL, we administered ABFM therapy to pts age 12 to 40 in a prospective, single institution trial. Results were then retrospectively compared to the HYPER CVAD regimen, the historical adult ALL regimen used at our institution. 85 pts with de novo Philadelphia chromosome negative ALL have completed at least 6 months of therapy. There are 69 (81%) pts with pre-B ALL and 16 (18%) pts with T-cell ALL/lymphoma. The age range is 13-39 with a median of 21. The median WBC at diagnosis is WBC=14 thousand/microliter (range 0.4-494). 80/85 (94%) pts entered remission (<5% blasts on day 29 marrow morphology). 1 patient died during induction. 61(72%) pts attained remission at day 15 of induction. 29 (22%) did not have morphological remission by day 15 of induction. At the end of induction, 46(58%) pts were minimal residual disease (MRD) negative by flow cytometry (<0.01% blasts). 25(31%) were positive for MRD and 6(7%) were not available or equivocal. By approximately day 84 of treatment, 55(69%) pts were negative for MRD and 13(16%) were positive or suspicious. Toxicities encountered include severe allergy to PEG-asparaginase in 17 (20%) pts, thrombosis in 18 (21%), hyperbilirubinemia grade III-IV in 31 (36%), elevated ALT grade III-IV in 28 (33%), hypofibrinogen grade III-IV in 30 (35%), pancreatitis in 9(11%), and avascular necrosis in 9 (11%). Grade III-IV hepatic toxicity is frequent but resolves within two weeks in almost all pts. For the entire cohort, the estimated 3 year overall survival (OS) is 75% and 3 year complete remission duration (CRD) is 71%. In univariate analysis, negative MRD at day 29 was associated with improved OS and day 84 negative MRD was associated with improved CRD. The presenting WBC was associated with OS and CRD. On multivariate analysis, only WBC over 50k/microliter maintained significance for OS and CRD. In comparing ABFM to HYPER CVAD, there is no significant difference in OS or CRD between the two regimens (fig. 1 and 2). This lack of difference in OS and CRD persists when patients are stratified for age > or </= 21 years, for presenting WBC over 50 thousand, and for MRD at the end of induction. In our hands, pediatric based therapy has significant though tolerable toxicity. Outcomes in AYA pts are similar but not superior to results obtained with historical ALL therapy. Disclosures: No relevant conflicts of interest to declare.

Pediatric-Based Therapy for Young Adults with Newly Diagnosed Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2037-2037 ◽  
Author(s):  
Michael Rytting ◽  
Deborah A. Thomas ◽  
Anna R Franklin ◽  
Elias Jabbour ◽  
William Wierda ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Young Adults ◽  
De Novo ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Unknown Origin ◽  
High Dose ◽  
Days Of Therapy ◽  
Grade Iii

Abstract Abstract 2037 Poster Board II-14 Adolescents 14 to 21 years of age with de novo acute lymphoblastic leukemia (ALL) have improved outcomes if treated on pediatric chemotherapy regimens as opposed to adult regimens. Young adults with ALL may also benefit from chemotherapy modeled after pediatric regimens, though toxicities may be limiting. We report on 48 young adult patients between the ages of 12 to 40 years with de novo Philadelphia chromosome negative ALL treated with the augmented Berlin-Frankfurt-Munster (BFM) chemotherapy regimen. All patients have completed at least the initial 28 days of therapy (induction) consisting of high dose prednisone, pegylated asparaginase (PEG-asp), vincristine, daunorubicin and intrathecal treatments. The median age of the group was 20 yrs (14-36); 40 patients had pre-B ALL and 8 T-ALL, No infectious deaths were observed during induction. 45 (95%) patients achieved a remission by 29 days and 2 achieved remission after a 2 week extension of induction. One patient was refractory to therapy. 39 (81%) patients achieved a morphological marrow remission (<5% blasts) by day 15 of treatment (rapid early responders). Minimal residual disease (MRD) assessed by flow cytometry was negative at the end of induction for 30 (62%), positive in 10 (21%), suspicious in 6 (12%) and not available for 2 patients. In the 41 patients who completed 12 weeks of therapy, MRD was negative in 35 (85%) and positive in 6 (15%). 7 (15%) patients have relapsed or have refractory disease; 1 patient died in CR. Admission for fever of unknown origin with neutropenia occurred in 10 (21%) patients, an additional 10 (21%) patients had documented infections. Grade III-IV hepatic toxicity has been prominent: 22 (45%) increased transaminase, 14 (29%) hyperbilirubinemia. 9 (19%) patients had allergic reactions to PEG-asp, and 10 (21%) had thrombotic events. The majority of grade III-IV adverse events have been reversible. The median complete remission duration is 57 weeks (range 5-143). The overall survival at two years is 82%. In summary, this pediatric-based regimen for young adults with ALL effectively induces remission, both by morphology and by flow cytometry. Toxicity has been significant, but mostly transient and tolerable. Longer follow-up is needed to determine the long-term efficacy of this regimen in young adults with ALL. Disclosures: Rytting: Enzon: Speakers Bureau. Jabbour:Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau.

Adolescent and Young Adult Patients with Acute Lymphoblastic Leukemia (ALL) Treated with Modified Augmented Berlin-Frankfurt-Muenster (ABFM) Therapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1527-1527
Author(s):  
Michael E. Rytting ◽  
Deborah A. Thomas ◽  
Elias Jabbour ◽  
Anna R.K. Franklin ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Young Adults ◽  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Disease Free Survival ◽  
Adolescent And Young Adult ◽  
Days Of Therapy ◽  
Grade Iii

Abstract Abstract 1527 Several pediatric-based protocols for treatment of acute lymphoblastic leukemia (ALL) in adolescents and young adults have been completed or are ongoing. Some studies have enrolled patients (pts) up to age 55 years, and, so far, results have been satisfactory. Augmented Berlin-Frankfurt-Muenster (ABFM) has been shown to be an effective and tolerable treatment for ALL in adolescents. To evaluate the efficacy and toxicity of this therapy in young adults, we designed a protocol of modified ABFM therapy for pts with ALL from age 12 to 40 years old. 83 pts have been enrolled on protocol and are evaluable for toxicity. 68 pts with de novo Philadelphia chromosome negative ALL have completed at least 29 days of therapy (induction) on protocol. They have the following characteristics: 56 (82%) pts have pre-B ALL and 12 (18%) have T-ALL. The median age is 21 (mean=23; range=13–39). The median presenting WBC=5.3 (mean=32; range= 0.4–494). 65/68 (96%) pts have achieved a remission. One patient died during induction. 50 (74%) pts have attained remission by 15 days of induction, while 15 (22%) have been slow responders. 5/68 (7%) pts have required an extension of induction by 2 weeks. At day 29 of therapy, 38 (56%) pts had negative minimal residual disease (MRD) by flow cytometry, 20 (29%) patients were positive for MRD, 10 were suspicious or not available. By day 84 of therapy, 49 (72%) pts were negative for MRD and 9 (13%) were positive. Currently, there have been 17 relapses and 10 deaths. Toxicities in the entire group include severe asparaginase allergy in 15 (18%) pts, thrombus formation in 16 (19%) pts, hyperbilirubinemia grade III-IV in 19 (23%) pts, ALT/AST grade III-IV in 23 (28%) pts, CNS stroke-like symptoms in 6 (7%) pts, hypofibrinogen grade III-IV in 26 (31%), pancreatitis in 6 (7%), and avascular necrosis in 6 (7%) pts. Hepatic toxicity has resolved completely within two weeks in almost all pts as has the CNS toxicity. In summary, induction success, by morphology and flow cytometry, has been satisfactory with this regimen. CRD and OS have not been significantly better than with HyperCVAD therapy for this age group. Expected toxicities have been prominent, but mostly transient. Hypofibrinogenemia is frequent, but bleeding is rare. Thrombosis and severe allergic reactions are more frequent than in pediatric trials. For pts 25 years of age and younger, the overall survival (OS) and disease free survival (DFS) at 2 years are 88% and 84% respectively. For pts > 25 years of age, the OS and DFS at two years are 65% and 50% respectively. This difference in OS between the groups is statistically significant. Continued enrollment is anticipated to further evaluate the survival differences between these two patient groups. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Allogeneic transplantation for Ph+ acute lymphoblastic leukemia with posttransplantation cyclophosphamide

2020 ◽  
Vol 4 (20) ◽  
pp. 5078-5088
Author(s):  
Jonathan A. Webster ◽  
Leo Luznik ◽  
Hua-Ling Tsai ◽  
Philip H. Imus ◽  
Amy E. DeZern ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Kinase Inhibitors ◽  
De Novo ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Philadelphia Chromosome ◽  
Allogeneic Transplantation ◽  
Donor Type

Abstract Allogeneic blood or marrow transplantation (alloBMT) is standard of care for adults with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) in first complete remission (CR1). The routine pretransplant and posttransplant use of tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes, but the optimal conditioning regimen, donor type, and TKI remain undefined. The bone marrow transplant database at Johns Hopkins was queried for adult patients with de novo Ph+ ALL who received alloBMT using posttransplantation cyclophosphamide (PTCy) as a component of graft-versus-host disease (GVHD) prophylaxis from 2008 to 2018. Among transplants for Ph+ ALL, 69 (85%) were performed in CR1, and 12 (15%) were performed in second or greater remission (CR2+). The majority of transplants (58%) were HLA haploidentical. Nearly all patients (91.4%) initiated TKI posttransplant. For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%. Nonmyeloablative alloBMT with PTCy for Ph+ ALL in an MRD-negative CR1 after initial treatment with dasatinib yields favorable outcomes.

scholarly journals Clinical Significance of Ck2 (CSNK2) and C-Myc Expression in Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5269-5269
Author(s):  
Paola Bonaccorso ◽  
Manuela La Rosa ◽  
Nellina Andriano ◽  
Valeria Iachelli ◽  
Emanuela Cannata ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Flow Analysis ◽  
State Level ◽  
Potential Candidate ◽  
Wild Type ◽  
Significant Difference ◽  
Pediatric All

Abstract Background. Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood and a major cause of childhood cancer-related mortality. Although the cure rate now approaches 90%, certain pediatric ALL subgroups present subsequent relapse. For this reason, analyses of cell signaling pathways will help to identify new markers and/or targets for tailored therapy. PI3K/AKT/mTOR activation is frequently found in both B-ALL and T-ALL. Protein kinase Ck2 (CSNK2) activity in pediatric ALL was increased and its inhibition restored PTEN phosphatase activity with subsequent inactivation of AKT. Moreover, Ck2 may serve the activity of oncogenes such as BCR-ABL and c-MYC, control the activation of other critical signaling cascades (JAK-STAT), and sustain multiple cellular stress-elicited pathway such as the proteotoxic stress, unfolded protein and DNA-damage responses. Ck2 has also been shown to have an essential role in tuning signals derived from the stromal tumor microenvironment (Piazza F et al, Oncogene2016). Material and Methods. We analyzed cDNA collected from 46 patients with B-ALL [19 High Risk (HR) for Minimal Residual Disease (MRD) and 27 NON-HR] and 25 with T-ALL (8 HR and 17 NON-HR), respectively, diagnosed in our Center from 2000 to 2012. The latter subgroup was screened fro PTEN-Exon7 mutations and TXL3 rearrangements. We evaluated the gene expression of Ck2 and c-Myc genes using RQ-PCR with Sybr-Green and a relative quantification method (ΔΔCt method), comparing gene's expression from patients with samples from 6 healty donors (HDs). In order to demonstrate the correlation between genetic alteration and signaling transduction, specifically in HR patients , we analyzed some phosphoproteins by Phospho-flow approach. We profiled 5 proteins (STAT3, STAT5, CREB, PTEN and pS6) in 4 T-ALL cases (3 with PTEN-Exon 7 mutation). Results. We observed a significant difference of Ck2 expression in T-ALL NON-HR patients vs HDs (Mean Ck2 Fold-Changes 3.494 vs 1.17, p=0.0315) and in T-ALL HR patients (6.384 vs 1.17, p=0.0219) vs HDs (Fig 1A and B). Comparing NON-HR vs HR cases, we found a statistically significant difference (p<0.0001) (Fig 1C). c-Myc mean expression was very similar between the two T-ALL subgroups. Moreover, among T-ALL cases, we identified 5 patients with PTEN-Exon7 mutations and 6 with TLX3 rearrangements. We observed that cases with PTEN-Exon7 mutation showed lower c-Myc expression than cases with PTEN-Exon7 wild-type (mean c-Myc 8.550 vs 1.920) whereas patients with TLX3 rearrangements showed higher c-Myc expression than TLX3 negative (mean c-Myc 18.260 vs 5.502) (p<0.005) (Fig 2A and B). We did not observe any correlation between these rearrangements and Ck2 expression. We also performed Ck2 and c-Myc expression analysis in B-ALL (NON-HR and HR) subgroups. We surprisingly observed a Ck2 overexpression in both NON-HR and HR B-ALLs compared to HDs. On the other side, we did not observed significant difference about c-Myc expression in cases with B-ALL vs HDs; whilst we observed an overexpression of c-Myc in HR vs NON-HR patients with B-ALL (mean 7.075 vs 2.095, respectively)(p<0.0004). Phospho-Flow analysis, in 3 cases with PTEN-Exon7 mutation (1 Ck2+/normal Myc, 1 normal Ck2/normal Myc, 1 Ck2-/normal Myc) showed PTEN null, very lower pS6 basal level and higher CREB basal level than in case with PTEN-Exon7 wild-type. Moreover, we observed that the latter patient, presented with a TLX3 rearrangements (Ck2+/Myc+) with higher c-Myc expression, showed higher STAT3 basal state level confirming that STAT3 induces the expression of c-Myc. Conclusions. Based on our preliminary findings, Ck2 could be considered as a marker and /or a potential candidate for targeted therapy, specifically in HR-ALL, as confirmed by the use of CK2 inhibitor (CX-4945) in ongoing clinical trials. c-Myc overexpression confirmed its association with HR features. The potential role as markers of both genes needs to be demonstrated in a larger population study. Combined application of genomic and phosphoproteomic strategies will lead us to better profile diagnostic samples of HR-ALL, addressing future tailored treatments. Disclosures No relevant conflicts of interest to declare.

Thrombotic Events in Adults with Acute Lymphoblastic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2734-2734
Author(s):  
Christine M. Cserti ◽  
Joseph Brandwein ◽  
Jeffrey H. Lipton ◽  
Anne G. McLeod ◽  
Hans Messner ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Median Time ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Treatment Protocol ◽  
High Dose ◽  
Cell Subtype ◽  
Significant Difference ◽  
History Of

Abstract A strong link between asparaginase-containing (ase +) chemotherapy regimens and venous thrombotic events (VTE) has been established for pediatric acute lymphoblastic leukemia (ALL), but this association has not been studied in adult ALL. We recently adopted as our first-line therapy for adult ALL a treatment protocol (DFCI 00–01) that employs weekly high-dose ase throughout a 27 week intensification phase. We reviewed the records of 92 adult patients consecutively accrued at Princess Margaret Hospital (from Jan 2000 to Dec 2003) for venous thrombotic events (VTE). Median age at diagnosis of ALL was 41±17 y, or 19±3 y for those who presented after a history of pediatric ALL (n=6), and 42±16 y for adults who presented with de novo ALL (n=86). Thirty-five (37%) were female, 59 (63%) male. Twenty-four (26%) were Philadelphia-chromosome positive; 71% of these received regimens containing imatinib. At least 1 symptomatic, radiologically confirmed VTE was seen in 19 patients (21%), with 3 (3%) diagnosed prior to any antileukemic therapy. Overall survival (OS) versus thrombosis-free survival (TFS) is illustrated in the Kaplan-Meier curve below. Median time to VTE was 94±92 d [95% CI]. Average age of patients with VTE was 44 ±15y; no events were observed in patients with a prior pediatric history of ALL. The sites of VTE were: 10/22 (46%) in the lower extremities, 5/22 (23%) propagating from central venous access catheters (CVAC), 4/22 (18%) as pulmonary emboli (2 in isolation), and 3/22 (14%) CNS (2 cerebral venous sinus and 1 retinal venous thrombus). The first antileukemic regimen administered was DFCI 00–01 ± imatinib in 79/92 (86%), HyperCVAD ± imatinib in 7 (8%), an unclassified ase+ regimen in 1 (1%), or an unclassified asparaginase-excluding (ase−) regimen in 5 (5%). A significant difference in the rate of ase-dependent VTE was observed when all regimens (1° or subsequent) were counted, with 18 VTE during 103 ase+ regimens (17.5%), versus only 1 VTE in 32 ase− regimens (3.1%), [p=0.04]. Median time to VTE in DFCI 00-01was 109±98d, most often occurring during the intensification phase. The odds ratio for VTE with any T-cell subtype of ALL compared to any B-cell subtype was 4.6 [p=0.0043]. Conclusions : A high, significant VTE rate (~18%) was observed in adults with ALL undergoing ase+ antileukemic therapy, nearly 6X the rate observed either prior to treatment or during ase− regimens (~3%). Ase is thus strongly associated with VTE, warranting improved surveillance and antithrombotic prophylaxis. Risk factors (underlying thrombophilias, leukemic subtypes) similarly deserve further study. Figure Figure

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 T-Cell Acute Lymphoblastic Leukemia—Current Concepts in Molecular Biology and Management

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1621
Author(s):  
Parveen Shiraz ◽  
Waqas Jehangir ◽  
Vaibhav Agrawal
Keyword(s):  
Young Adults ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
De Novo ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cell Transplant ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Children And Young Adults

T-cell acute lymphoblastic leukemia (T-ALL) is an uncommon, yet aggressive leukemia that accounts for approximately one-fourth of acute lymphoblastic leukemia (ALL) cases. CDKN2A/CDKN2B and NOTCH1 are the most common mutated genes in T-ALL. Children and young adults are treated with pediatric intensive regimens and have superior outcomes compared to older adults. In children and young adults, Nelarabine added to frontline chemotherapy improves outcomes and end of consolidation measurable residual disease has emerged as the most valuable prognostic marker. While outcomes for de-novo disease are steadily improving, patients with relapsed and refractory T-ALL fare poorly. Newer targeted therapies are being studied in large clinical trials and have the potential to further improve outcomes. The role of allogeneic stem cell transplant (HSCT) is evolving due to the increased use of pediatric-inspired regimens and MRD monitoring. In this review we will discuss the biology, treatment, and outcomes in pediatric and adult T-ALL.

Philadelphia Chromosome–Negative B-Cell Acute Lymphoblastic Leukemia in Adolescents and Young Adults

2020 ◽  
Vol 16 (5) ◽  
pp. 231-238 ◽  
Author(s):  
Amy Y. Wang ◽  
Lori S. Muffly ◽  
Wendy Stock
Keyword(s):  
Clinical Trials ◽  
Young Adults ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Clinical Decision Making ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Adolescents And Young Adults ◽  
Genetic Characteristics

Adolescents and young adults (AYAs) with Philadelphia chromosome–negative acute lymphoblastic leukemia (ALL) represent a unique patient population with a disproportionate survival disadvantage compared with younger children. Substantial progress has been made as we began to understand and address the multifaceted drivers behind this outcome disparity. New insights into the biology of B-cell ALL have uncovered distinct genetic characteristics more commonly found in AYAs that affect prognosis. Dramatic improvements in survival have been achieved with the use of pediatric-inspired protocols in the front-line setting, as well as antibody-based and chimeric antigen receptor T-cell therapies in the relapsed and refractory setting. Guided by the incorporation of minimal residual disease testing to inform clinical decision making, these represent major paradigm shifts in management. Efforts to design clinical trials geared toward AYAs and to enroll AYAs in available clinical trials will ensure ongoing progress. Holistic care of AYAs with ALL further involves recognition of psychosocial issues arising as a consequence of their diagnosis and the delivery of age-appropriate supportive care.

IGH@ Translocations Are Prevalent in Teenagers and Young Adults With Acute Lymphoblastic Leukemia and Are Associated With a Poor Outcome

2014 ◽  
Vol 32 (14) ◽  
pp. 1453-1462 ◽  
Author(s):  
Lisa J. Russell ◽  
Amir Enshaei ◽  
Lisa Jones ◽  
Amy Erhorn ◽  
Dino Masic ◽  
...  
Keyword(s):  
Young Adults ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Children And Adolescents ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Hazard Ratio ◽  
Old Patients ◽  
Increased Risk

Purpose To determine the prevalence and prognostic association of immunoglobulin heavy chain (IGH@) translocations in acute lymphoblastic leukemia (ALL). Patients and Methods The cohort comprised 3,269 patients treated on either the UKALL2003 trial for children and adolescents (1 to 24 years old) or the UKALLXII trial for adolescents and adults (15 to 59 years old). High-throughput fluorescent in situ hybridization was used to detect IGH@ translocations. Results We identified IGH@ translocations in 5% of patients with ALL (159 of 3,269 patients), in patients with both B-cell (148 of 2,863 patients) and T-cell (11 of 408 patients) disease. Multiple partner genes were identified including CRLF2 (n = 35), five members of the CEPB gene family (n = 17), and ID4 (n = 11). The level of the IGH@-positive clone varied and indicated that some IGH@ translocations were primary events, whereas others were secondary aberrations often associated with other established aberrations. The age profile of patients with IGH@ translocations was distinctive, with a median age of 16 years and peak incidence of 11% among 20- to 24-year-old patients. Among patients with B-cell precursor ALL who were Philadelphia chromosome negative, those with an IGH@ translocation had an inferior overall survival compared with other patients (UKALL2003: hazard ratio, 2.37; 95% CI, 1.34 to 4.18; P = .003; UKALLXII: hazard ratio, 1.73; 95% CI, 1.22 to 2.47; P = .002). However, this adverse effect was not independent of age or minimal residual disease status and did not seem to be driven by an increased risk of relapse. Conclusion IGH@ translocations define a genetic feature that is frequent among adolescents and young adults with ALL. Although associated with an adverse outcome in adults, it is not an independent prognostic factor in children and adolescents.

Adolescent and Young Adult Patients Treated with Modified Augmented Berlin-Frankfurt-Muenster Therapy

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3250-3250
Author(s):  
Michael E. Rytting ◽  
Hagop M. Kantarjian ◽  
Deborah A Thomas ◽  
Elias Jabbour ◽  
Anna Franklin ◽  
...  
Keyword(s):  
Young Adults ◽  
Young Adult ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Disease Free Survival ◽  
Adult Patients ◽  
Hepatic Toxicity ◽  
Days Of Therapy ◽  
Grade Iii

Abstract Abstract 3250 Pediatric protocols for acute lymphoblastic leukemia (ALL) are currently employed by many groups to treat adolescents and young adults (AYA) with ALL. Adults up to age 55 are presently enrolled in such treatment regimens, and investigators have reported excellent results in these young adult patients (pts). Augmented Berlin-Frankfurt-Muenster therapy has been shown to be effective therapy for adolescents with ALL. To evaluate the efficacy and toxicity of this therapy in young adults, we designed a protocol of modified augmented Berlin-Frankfurt-Muenster (ABFM) therapy for patients with ALL from age 12 to 40. 70 pts have been enrolled on protocol and are evaluable for toxicity. 60 pts with de novo Philadelphia chromosome negative ALL have completed at least 29 days of therapy (induction) on protocol. They have the following characteristics: 52 (87%) pts have pre-B ALL and 8 (13%) have T-ALL. The median age is 20 (mean=22; range=13-39). The median presenting WBC=5.2 (mean=32; range= 0.4–494). 58/60 (97%) pts have achieved a remission. There have been no induction deaths. 49(82%) pts have attained remission by 15 days of induction, while 11 (18%) have been slow responders. 5/60 (8%) pts have required an extension of induction by 2 weeks. At day 29 of therapy, 38 (63%) pts had negative minimal residual disease (MRD) by flow cytometry, 15 (25%) patients were positive for MRD, 7 were suspicious or not available. By day 84 of therapy, 46 (77%) pts were negative for MRD and 9 (15%) were positive. Currently, there have been 10 relapses and 9 deaths. Toxicities in the entire group include severe asparaginase allergy in 15 (21%) pts, thrombus formation in 15 (21%) pts, hyperbilirubinemia grade III-IV in 19 (27%) pts, ALT/AST grade III-IV in 20 (28%) pts, CNS stroke-like symptoms in 6 (8%) pts, and avascular necrosis in 6 (8%) pts. Hepatic toxicity has resolved completely within two weeks in almost all pts as has the CNS toxicity. Grade III-IV hepatic toxicity have been transient. For pts 25 years of age and younger (n=25), the overall survival (OS) and disease free survival (DFS) at 2 years are 91% and 85% respectively. For pts > 25 years of age (n=15), the OS and DFS at 2 years are 55% and 61% respectively. This difference is statistically significant for the two groups; p=0.04 for DFS and p=0.004 for OS. Continued enrollment is anticipated to further evaluate the survival differences between these two patient groups. Disclosures: No relevant conflicts of interest to declare.

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