Adult Lymphoblastic Leukemia Research Articles

Peripheral blood haploidentical hematopoietic stem cell transplantation for treatment of acute lymphoblastic leukemia in adults: monitoring minimal residual diseases to intervene recurrence

Peripheral blood haploidentical hematopoietic stem cell transplantation for treatment of acute lymphoblastic leukemia in adults: monitoring minimal residual diseases to intervene recurrence

Second primary acute lymphoblastic leukemia in adults: a SEER analysis of incidence and outcomes.

We conducted a surveillance epidemiology and end results (SEER)‐based analysis to describe the incidence and characteristics of second primary acute lymphoblastic leukemia (sALL) among adults (≥18 years) with a history of primary malignancies (1M). Standardized incidence ratios (SIRs) of sALL cases were calculated by site and 1M stage. We also evaluated the differences in 5‐year sALL survival by age, site, and extent of 1M, latency of sALL after 1M, and evidence of underlying racial/ethnic disparity. We identified 10,956 patients with de‐novo/primary acute lymphoblastic leukemia (1ALL) and 772 with sALL. Women (49.1% vs. 42.9%), white patients (72.0% vs. 59.5%), older patients (58.8% vs. 25.2%; age ≥65 years), and patients diagnosed between 2003 and 2012 (66.8% vs. 53.9%) had a higher proportion of sALL compared with 1ALL. There was a significantly inferior median 5‐year survival for sALL patients compared to 1ALL (6 vs. 15 months; HR 1.20, 95% CI 1.10–1.31, P < 0.001). The median latency period was 60.0 months; the most common 1M among sALL patients were breast (17.9%) and prostate (17.4%). Patients with any 1M were at increased risk of developing sALL (SIR 1.76, 95% CI 1.58–1.95, P < 0.001). Hematological‐1M sites had significantly higher SIRs (hematological‐SIR 7.35; solid‐SIR 1.33; P < 0.001). We observed a significant increase in sALL incidence after a 1M and a significantly worse 5‐year survival with different demographic characteristics from 1ALL. There is a need to define appropriate screening methods for patients surviving their primary cancer.

BRD4 Proteolysis Targeting Chimera (PROTAC) ARV-825 Targets Both NOTCH1-MYC Regulatory Circuit and Leukemia-Microenvironment in T-ALL

Background:Salvage options for patients with relapsed T cell acute lymphoblastic leukemia (T-ALL) are limited, with less than 25% of these patients achieving second remission 1, 2. 70% of T-ALL cases have activating mutations of the NOTCH1 pathway, which transcriptionally activates MYC by binding to its ‘superenhancer’ region 3, 4. Other deregulated oncogenic pathways in T-ALL include PI3K/Akt, the anti-apoptotic Bcl-2 family, and CDKN2A/2B cell cycle regulators 5, 6. The NOTCH1-MYC regulatory circuit is an attractive therapeutic target, but clinical development of gamma-secretase inhibitors (GSI) to target NOTCH1 has been limited by ‘on target’ toxicities. A better target may be BRD4, a critical component of superenhancer complexes that binds to acetylated histone (3 and 4) and drives NOTCH1 mediated MYC transcription7.ARV-825 is a hetero-bifunctional PROteolysis TArgeting Chimera (PROTAC) that has 3 components: a thienodiazepine-based BRD4 ligand, a linker arm, and a cereblon-binding ligand. ARV-825 recruits BRD4 to the E3 ubiquitin ligase cereblon and leads to efficient and sustained degradation of BRD4, resulting in down-regulation of MYC.Methods: We investigated the effectiveness of ARV-825 against T-ALL cell lines, including GSI-resistant lines. Since microenvironmental signals are critical for the survival of T-ALL, we specifically tested the impact of BRD4 degradation on CD44/CD44v, which integrates cell-extrinsic microenvironmental signals and is part of cysteine transporter that maintains low intra-cellular reactive oxygen species (ROS), necessary for T-ALL survival and the persistence of disease. We also examined the anti-leukemic effect of ARV-825 in a T-ALL patient-derived xenograft (PDX) mouse model of disseminated leukemia with a constitutively active NOTCH1 mutation.Results: The IC50s for all tested T-ALL cell lines at 72 hours were in the low nanomolar range (< 50 nM). ARV-825 leads to sustained degradation of BRD4 and down-regulation of its transcriptional targets MYC, Bcl-2 and Bcl-XL and inhibits cell proliferation and induces apoptosis in GSI-sensitive (HPB-ALL, KOPT1) and GSI-resistant (MOLT4, SUPT1) cell lines.Mass cytometry based proteomic analysis (CyTOF) and immunoblotting showed that ARV-825 down-regulated cell intrinsic oncogenic molecules: transcription factors Myc and NFkB, cell cycle regulator CDK6, activated PI3K/Akt, and anti-apoptotic Bcl2 family proteins. In addition ARV-825 down regulated two key molecules involved in leukemia-stroma interaction; CD44 (Fig. 1), and CD98, a component of amino acid transporters xCT, LAT1 and 2, both essential in regulation of oxidative stress. Quantitative PCR and immunoblotting analysis confirmed the transcriptional down regulation of total CD44 and CD44 variants 8-10 (2-fold change treated vs . untreated). As a functional correlate of down-regulation of CD98/CD44/CD44v, flow cytometry confirmed increased intracellular ROS generation (Fig. 2).Finally, in a PDX mouse model of human T-ALL, ARV-825 treatment resulted in lower leukemia burden (confirmed by flow cytometry for human CD45+ cells in bone marrow) and better survival compared to vehicle-treated control mice (p=0.002) (Fig.3).Reference:1. Marks DI, Rowntree C. Management of adults with T-cell lymphoblastic leukemia. Blood 2017; 129(9): 1134-1142.2. Litzow MR, Ferrando AA. How I treat T-cell acute lymphoblastic leukemia in adults. Blood 2015; 126(7): 833-41.3. Sanchez-Martin M, Ferrando A. The NOTCH1-MYC highway toward T-cell acute lymphoblastic leukemia. Blood 2017; 129(9): 1124-1133.4. Demarest RM, Ratti F, Capobianco AJ. It's T-ALL about Notch. Oncogene 2008; 27(38): 5082-91.5. Girardi T, Vicente C, Cools J, De Keersmaecker K. The genetics and molecular biology of T-ALL. Blood 2017; 129(9): 1113-1123.6. Joshi I, Minter LM, Telfer J, Demarest RM, Capobianco AJ, Aster JC et al. Notch signaling mediates G1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases. Blood 2009; 113(8): 1689-98.7. Loven J, Hoke HA, Lin CY, Lau A, Orlando DA, Vakoc CR et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 2013; 153(2): 320-34. [Display omitted] DisclosuresQian:4Arvinas, LLC. New Haven, CT: Employment. Raina:4Arvinas, LLC. New Haven, CT: Employment. McKay:6 ImmunoGen, Inc.Waltham, MA: Employment. Kantarjian:Novartis: Research Funding; Amgen: Research Funding; Delta-Fly Pharma: Research Funding; Bristol-Meyers Squibb: Research Funding; Pfizer: Research Funding; ARIAD: Research Funding. Andreeff:Daiichi Sankyo: Consultancy.

Current paradigms in the management of Philadelphia chromosome positive acute lymphoblastic leukemia in adults.

Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) is a biologically, clinically, and genetically distinct subtype of precursor-B ALL. The Ph chromosome, results from a reciprocal translocation of the ABL1 kinase gene on chromosome 9 to the breakpoint cluster region (BCR) gene on chromosome 22. Depending on the translocation breakpoint, typically a p210 BCR-ABL1 or a p190 BCR-ABL onc protein are generated; both are constitutively active tyrosine kinases that play a central role to alter signaling pathways of cell proliferation, survival, and self-renewal, leading to leukemogenesis. In Ph-positive ALL, the p190-BCR-ABL (minor [m]-bcr) subtype is more frequent than the p210-BCR-ABL (major [M]-bcr) subtype, commonly found in chronic myeloid leukemia. The Philadelphia chromosome is the most frequent recurrent cytogenetic abnormality in elderly patients with ALL. Its incidence increases with age, reaching ∼50% in patients with ALL aged 60 years and over. Patients traditionally had a very poor outcome with chemotherapy, particularly if they do not undergo allogeneic hematopoietic cell transplantation (allo-HCT) in first complete remission (CR1). With the availability of multiple tyrosine kinase inhibitors (TKI), the therapeutic armamentarium is expanding quickly. However, there is no consensus on how to best treat Ph-positive ALL. With modern therapy, improved outcomes have led to the emergence of a number of controversies, including the need for intensive chemotherapy, the ideal TKI, and whether all eligible patients should receive an allo-HSCT, and if so, what type. Here, we discuss these controversies in light of the available literature.

Our Experience in the Treatment of Adult Lymphoblastic Leukemia (including Adult T-Cell Leukemia/Lymphoma) with German Multicenter ALL (GMALL) Protocol

acute lymphoblastic leukemia, chemotherapy, minimal residual disease.

Acute lymphoblastic leukemia in adults: Steps ahead

Acute lymphoblastic leukemia in adults: Steps ahead

The evolving role of chemotherapy and hematopoietic cell transplants in Ph-positive acute lymphoblastic leukemia in adults.

The introduction of the tyrosine kinase inhibitors (TKI) into the treatment of patients with Ph or BCR-ABL1-positive acute lymphoblastic leukemia has revolutionized the treatment of this poor prognosis acute leukemia. The combination of TKI with chemotherapy has improved response rates and allowed more patients to proceed to allogeneic hematopoietic cell transplant (alloHCT). Older patients have excellent responses to TKI and corticosteroids or in combination with minimal chemotherapy. This raises the question as to whether patients require full-intensity chemotherapy with TKI to achieve molecular remissions. The pediatricians have proposed that cure is achievable without alloHCT in children. These results have suggested that many patients may not require traditional chemotherapy in addition to TKI to achieve remission, and that patients who achieve a negative minimal residual disease state may not require alloHCT. The data in support of these questions is presented here and a suggested future clinical trial design based on these data is proposed.

A Pediatric-Inspired Regimen Containing Multiple Doses of Intravenous Pegylated Asparaginase Appears Safe and Effective in Newly Diagnosed Adult Patients with Ph-Negative Acute Lymphoblastic Leukemia in Adults up to Age 60: Results of a Multi-Center Phase II Clinical Trial

▪Background: The U.S. Intergroup C10403 trial has demonstrated that treating acute lymphoblastic leukemia (ALL) in adolescents and young adults up to age 39 using a pediatric regimen improves event-free and overall survival compared with adult regimens (Stock W et al. ASH 2014). However, the safety and efficacy in implementing pediatric regimens in older adults above age 40 have not been well studied. Herein, we report the results from a phase II multicenter study of pediatric-inspired regimen in newly diagnosed adult patients (pts) with ALL up to age 60 (NCT01920737).Methods: Newly diagnosed adult pts aged 18 to 60 with ALL were eligible. Burkitt type and Ph+ ALL were excluded. The treatment regimen consisted of induction 1 (I1), induction 2 (I2) followed by several cycles of intensifications and re-inductions and 3 years of maintenance therapy. The treatment contained a total of 6 doses of 2,000 IU/m2 pegylated asparaginase (Peg-ASP), administered IV at various intervals of ³4 weeks based on our previous pharmacokinetics (PK) data (Douer D et al. Blood 2007). Minimal residual disease (MRD) was assessed after I1 and I2 by multiparameter flow cytometry. Serum asparaginase enzymatic activity and presence of anti-asparaginase antibody (Ab) were assessed on day 7 after each Peg-ASP dose.Results: 27 pts were enrolled between 4/2014 and 4/2016. The median age at diagnosis was 43.6 (range, 20-60) years: 52% were 40-60 years. The majority had precursor B-ALL (70%) and rest T-ALL. Four pts (15%) had extramedullary disease only (mediastinal mass, lymph nodes, bone). Of the 27 pts, 26 pts (96%) achieved complete remission (CR) after I1. MRD was assessed in 20 pts; 8 (40%) and 15 (75%) pts achieved MRD neg CR after I1 and after I2, respectively. Six pts proceed to allogeneic HSCT. With a median follow-up of 7.8 months (range, 0.9-22.5), 3 patients (12%) relapsed: 2 occurred among the 12 MRD+CR group (17%) after I1 at 4.5 and 8.8 months, and 1 occurred among the 8 MRD negative CR group (13%) after I1 at 7 months from I1 completion. No relapses occurred among the 6 MRD unknown pts. No pt died on study. Grade 3-4 Peg-ASP-related toxicities (Table 1) included hypertriglyceridemia (59%), transaminitis (52%), hyperglycemia (41%), hyperbilirubinemia (30%), and pancreatitis (4%). Notably, all cases of hyperbilirubinemia occurred during I1 but despite continued use of Peg-ASP, grade 3-4 hyperbilirubinemia did not recur. Four pts (15%) developed hypersensitivity reactions to Peg-ASP and subsequently received Erwinia asparaginase without reaction and completed the full intended doses of Peg-Asp treatments. Three pts (11%) discontinued Peg-ASP due to toxicity (n=2; hyperbilirubinemia, transaminitis) and physician preference (n=1). Asparaginase PK and anti-ASP Ab data were available in 16 pts. In pts without hypersensitivity to Peg-ASP, a median asparaginase enzymatic activity was 0.58 IU/ml (range, 0.30-0.88) and 0.73 IU/ml (range, 0.53-0.88) on day 7 of Peg-ASP during I1 and I2, respectively. One pt developed silent inactivation after I1 with the activity level <0.01 IU/ml during I2 but without detectable anti-ASP Ab; 3 pts with hypersensitivity reactions had no or lowest activity levels, ranging from <0.01-0.1 IU/ml. Four pts (15%) had pre-existing anti-ASP Ab at pre-treatment; none of these was neutralizing and all 4 pts had adequate enzymatic activity.Conclusions: This phase 2 study suggests that a pediatric-inspired regimen containing rationally synchronized 6 doses of 2,000 IU/m2 IV Peg-ASP is safe and effective in older adults with newly diagnosed Ph-negative ALL up to age 60. Although follow-up remains short, we have observed high CR rates and few relapses. Hypertriglyceridemia, hyperglycemia, transaminitis and hyperbilirubinemia occurred frequently but few discontinued treatment due to toxicities. The rate of silent inactivation of asparaginase was low (6%), and almost all pts without hypersensitivity had adequate activity on day 7. Further results of asparaginase PK analysis and silent inactivation will inform the appropriate dosing of Peg-ASP and utility of PK/Ab tests in future adult ALL trials. [Display omitted] DisclosuresPark:Amgen: Consultancy; Genentech/Roche: Research Funding; Juno Therapeutics: Consultancy, Research Funding. Ritchie:Arian: Speakers Bureau; Novartis: Honoraria; Pfizer: Honoraria; Celgene: Speakers Bureau; Incyte: Speakers Bureau. Rao:Gilead Sciences: Employment, Equity Ownership. Douer:Jazz Pharmaceuticals: Honoraria; Gilled Sciences, Inc: Consultancy; Shire: Consultancy, Speakers Bureau; Pfizer: Consultancy; Spectrum: Consultancy.

High Frequency and Poor Outcome of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia in Adults.

Purpose Philadelphia chromosome (Ph) -like acute lymphoblastic leukemia (ALL) is a high-risk subtype of childhood ALL characterized by kinase-activating alterations that are amenable to treatment with tyrosine kinase inhibitors. We sought to define the prevalence and genomic landscape of Ph-like ALL in adults and assess response to conventional chemotherapy. Patients and Methods The frequency of Ph-like ALL was assessed by gene expression profiling of 798 patients with B-cell ALL age 21 to 86 years. Event-free survival and overall survival were determined for Ph-like ALL versus non-Ph-like ALL patients. Detailed genomic analysis was performed on 180 of 194 patients with Ph-like ALL. Results Patients with Ph-like ALL accounted for more than 20% of adults with ALL, including 27.9% of young adults (age 21 to 39 years), 20.4% of adults (age 40 to 59 years), and 24.0% of older adults (age 60 to 86 years). Overall, patients with Ph-like ALL had an inferior 5-year event-free survival compared with patients with non-Ph-like ALL (22.5% [95% CI, 14.9% to 29.3%; n = 155] v 49.3% [95% CI, 42.8% to 56.2%; n = 247], respectively; P < .001). We identified kinase-activating alterations in 88% of patients with Ph-like ALL, including CRLF2 rearrangements (51%), ABL class fusions (9.8%), JAK2 or EPOR rearrangements (12.4%), other JAK-STAT sequence mutations (7.2%), other kinase alterations (4.1%), and Ras pathway mutations (3.6%). Eleven new kinase rearrangements were identified, including four involving new kinase or cytokine receptor genes and seven involving new partners for previously identified genes. Conclusion Ph-like ALL is a highly prevalent subtype of ALL in adults and is associated with poor outcome. The diverse range of kinase-activating alterations in Ph-like ALL has important therapeutic implications. Trials comparing the addition of tyrosine kinase inhibitors to conventional therapy are required to evaluate the clinical utility of these agents in the treatment of Ph-like ALL.

High-dose cytarabine added to CY/TBI improves the prognosis of cord blood transplantation for acute lymphoblastic leukemia in adults: a retrospective cohort study.

High-dose cytarabine added to CY/TBI improves the prognosis of cord blood transplantation for acute lymphoblastic leukemia in adults: a retrospective cohort study

Clinical use of blinatumomab for B-cell acute lymphoblastic leukemia in adults.

Adults with relapsed or refractory B-cell acute lymphoblastic leukemia have a dismal prognosis with a short median overall survival that can be measured in months. Because most patients will have chemotherapy-resistant disease, allogeneic hematopoietic stem cell transplantation remains the only potentially curative treatment. Despite advances in current management, patients continue to have poor outcomes and lack of durable responses. Thus, new therapies with alternative modes of actions are currently being investigated. Blinatumomab is a novel bispecific T-cell engager that simultaneously binds CD3-positive cytotoxic T-cells and CD19-positive B-cells, resulting in selective lysis of tumor cells. It has shown promising results in patients with relapsed or refractory acute lymphoblastic leukemia or those achieving hematologic response with persistent minimum residual disease. Future clinical trials will answer questions regarding its optimal place in the treatment paradigm. Dose-limiting toxicities include immunological toxicities and cytokine release syndrome. However, most patients tolerate the therapy relatively well. This review will focus on the pharmacology, clinical efficacy, and safety of blinatumomab in the treatment of adult B-cell acute lymphoblastic leukemia while highlighting its unique drug warnings and toxicity management.

Acute Lymphoblastic Leukemia in Adults - an Analysis of 51 Cases from a Tertiary Care Center in Pakistan.

Acute lymphoblastic leukemia (ALL) is a malignant disease in which early lymphoid precursors proliferate and replace the normal hematopoiesis. It has distinctive clinical and biological features. In respect to adult ALL, available data from Pakistan are limited. Therefore we reviewed the demographical and clinico- hematological profiles along with FAB stratification of adult patients with ALL presented at our hospital. In this cross sectional study, 51 adults (≥15 years) patients with ALL were enrolled from January 2010 to December 2014. The mean age was 23.8±12.9 years with the median age of 18.0 years. The male to female ratio was 2:1. The major complaints were fever (60.7%), generalized weakness (47.0%), overt bleeding (19.6%) and weight loss (13.7%). Physical examination revealed lymphodenopathy as a predominant finding detected in 43.1% followed by splenomegaly and hepatomegaly in 23.5% and 21.5%, respectively. The mean hemoglobin level was 9.0±2.75g/dl with a mean MCV of 82.2±15.4 fl, a mean total leukocyte count of 31.1±64.0x109/l, a mean ANC of 2.1±3.0 x109/l and a mean platelet count of 71.7±85.7x109/l. According to FAB classification, 47.1% were L1 type, 45.1% L2 and 7.8% L3 variant. Clinico-pathological features appeared comparable to published data. Febrile illness associated with lymphodenopathy was the commonest presentation. FAB classification revealed a predominance of ALL-L1 variant in Pakistani adult patients with ALL.

Treatment of Relapsed/Refractory Acute Lymphoblastic Leukemia in Adults.

Patients with relapsed and refractory acute lymphoblastic leukemia (ALL) have a dismal prognosis with less than 10% of patients surviving 5years. Most such patients cannot be rescued with currently available therapies, whatever the initial treatment they receive. Therefore, there is an urgent need for novel treatment options. Fortunately, over the past several years, an improved understanding of the biology of the disease has allowed the identification of rational molecular targets for therapeutic endeavors and the emergence of novel therapies has sparked great interest. This review will discuss the current treatment landscape for adult patients with relapsed and/or refractory ALL.

Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia in Adults.

The majority of adults with acute lymphoblastic leukemia will achieve a first complete remission (CR). However relapse is the most common cause of treatment failure. Outcomes after relapse remain poor, with long-term survival in the order of 10%. Treatment decisions made at the time of first complete remission are thus critical to ensuring long-term survival. Allogeneic hematopoietic cell transplant (HCT) is effective at preventing relapse in many transplant recipients but is also associated with significant treatment related morbidity and mortality. Alternatively, ongoing systemic chemotherapy offers lower toxicity at the expense of increased relapse rates. Over the past decades, both the safety of transplant and the efficacy of non-transplant chemotherapy have improved. Emerging data show substantially improved outcomes for young adults treated with pediatric-inspired chemotherapy regimens that question the role of HCT in the upfront setting. In this review, we review the data supporting the role of allogeneic transplantation in adult acute lymphoblastic leukemia (ALL), and we propose a therapeutic algorithm for upfront therapy of adults with ALL.

Outcomes of Down-Syndrome Associated Acute Lymphoblastic Leukemia in Adults: A Single Center Retrospective Review

Background:Children and adults with Down Syndrome (DS) have an approximately 20-fold increased risk of developing acute lymphoblastic leukemia, which in the majority of cases is of the B-cell precursor (BCP) type, and have significantly inferior outcomes due to both higher relapse rates and increased treatment-related mortality.During treatment for ALL, children with DS are at a higher risk of complications such as prolonged neutropenia, severe mucositis and longer hospitalizations. In view of the significant barriers to successful treatment for pediatric DS-ALL and the absence of outcome data for DS-ALL in adults, we retrospectively reviewed the outcomes of adult patients with DS-ALL treated at our center.Methods:All patients greater than 18 years of age diagnosed with DS-ALL who were followed at Princess Margaret Cancer Center/University Health Network (PMH/UHN) between January 1, 2000 and June 30, 2014 were identified using the institutional leukemia database.Diagnosis of ALL was established by standard FAB WHO Criteria using multiparameter flow cytometry for immunophenotyping according to ISCN guidelines. Treatment of adult DS patients with de novo ALL and those with relapsed ALL who had not previously received intensive asaparaginas therapy, were treated according to a modified Dana Farber Cancer Institute (DFCI) ALL regimen; reduced doses of methotrexate were used due to the increased risk of mucositis reported in children with DS. This regimen includes an at least four fold higher total dose of E. coli derived asparaginase compared to other adult regimens.Results:Seven adult patients with DS-ALL were treated at our center from 2000 to 2014. Four of these were diagnosed with de novo DS-ALL (after age of 18 years) and three patients developed a late isolated bone marrow relapse of DS-ALL as adults after previous treatment for childhood DS-ALL. Approximately half of our patients had favourable cytogenetics and half had intermediate risk cytogenetics . Treatment was not altered based on cytogenetics.The median age of 4 patients, with de novo adult DS-ALL, was 26 years (range 21-42 years). 75% achieved a CR after initial induction; one patient died during induction from sepsis. Two of the four de novo adult DS-ALL patients relapsed after CR1 durations of 11 and 35 mon.. One patient received palliative chemotherapy. At the time of last follow up, 3 of these patients have died. The one remaining patient is alive in continuous CR at 41 mos.The three adult DS patients with relapsed ALL had a median age of 14 years (7-15 years) at diagnosis of primary DS-ALL and 29 years (21-36) at the diagnosis of relapse. Two of these received DFCI as re-induction while the third received Hyper-CVAD. Despite achieving an initial remission all patients with relapsed DS-ALL died , two from subsequent relapsed and one from an invasive aspergillosis. One patient relapsed while on therapy at 4.7 months. The other patient relapsed while off therapy at 15.2 months.The overall and relapsed-free survival of adult patients with DS and de novo ALL at 3 years was 50% and 33.3%, respectively, and thus markedly inferior to results of a similarly treated population of adults (aged 18-35 years) without DS ( 3-year OS 83%, 3-year RFS 77%) at our center.Conclusions:The results of our series of adult patients with DS and ALL suggest that the barriers to successful treatment of ALL in adults with DS are similar to those observed in children. Although the rarity of adult ALL in general, and that of adult DS-ALL in particular, limits sample size and conclusions, this report is to our knowledge the first describing survival outcomes of adults with DS and ALL and highlights that treatment of primary adult DS-ALL is feasible but significantly less successful compared to adults without DS. As in children, subsequent relapse and treatment-related mortality impacting outcome are equally problematic. DisclosuresGupta:Incyte: Honoraria, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.

High Frequency and Poor Outcome of Ph-like Acute Lymphoblastic Leukemia in Adults

▪Introduction: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype characterized by kinase-activating alterations that are amenable to treatment with tyrosine kinase inhibitors. The prevalence of Ph-like ALL increases with age and accounts for over 25% of patients with B-progenitor ALL between the ages of 21-39 years. However, the frequency, outcome and genetic basis of Ph-like ALL in adults over the age of 39 is unknown. The goals of this study were to define the prevalence of Ph-like ALL across the adult age spectrum, assess response to conventional chemotherapy, and define the genetic landscape of Ph-like ALL in adults.Methods: We studied 692 adults with B-ALL obtained from multiple groups including the Alliance (Cancer and Leukemia Group B), ECOG-ACRIN, MD Anderson Cancer Center, Northern Italy Leukemia Group, Princess Margaret Cancer Centre, SWOG and UK NCRI. The cohort was divided into three age groups: 21-39 years (median age 28±6 years, n=333), 40-59 years (median age 47±6 years, n=246) and 60-79 years (median age 67±7 years, n=101). RNA samples were screened using a Taqman low density array (LDA) card that identifies patients with the Ph-like ALL gene signature, in addition to BCR-ABL1, ETV6-RUNX1, TCF3-PBX1, MLL-rearranged and ERG altered ALL. Cytogenetic data was also available for the majority of cases. High expression of CRLF2 was determined by the LDA card, and CRLF2 rearrangement (IGH-CRLF2 or P2RY8-CFRLF2) was confirmed using fluorescence in situ hybridization. Total stranded transcriptome sequencing (RNA-seq) using the Illumina platform was performed on 99 cases and sequencing data was analyzed using FusionCatcher and CICERO.Results: The overall prevalence of ETV6-RUNX1, TCF3-PBX1 and ERG ALL in adults was low (1.3%, 3.6% and 3.1%, respectively), whilst the prevalence of patients with BCR-ABL1, Ph-like and MLL-rearranged ALL was 20%, 24% and 14%, respectively. Ph-like ALL comprised 26% of patients between 21-39 years of age and 20% of patients aged 40-79. Patients with BCR-ABL1 and Ph-like ALL presented with higher white blood counts at diagnosis compared to non Ph-like ALL patients (57.7 and 65.0 vs 28.5 x 109/L). Patients with Ph-like ALL were also more likely to be male compared to patients with BCR-ABL1 and non Ph-like ALL, with 66% vs 50% and 50%, respectively(p<0.0001; Fisher's exact test). The outcome of patients with Ph-like ALL was markedly inferior to other ALL subtypes (excluding patients with BCR-ABL1 and MLL rearrangement), with 5-year event free survival rates of 23.2±5.4 vs 51.2±4.7 (p<0.0001) and overall survival rates of 26.5±5.5 vs 56.3±4.6 (p<0.0001).We then characterized the kinase-activating alterations in adult Ph-like ALL. Similar to previous reports, 99 of 186 (53%) of patients with Ph-like ALL had high expression of CRLF2. Of 75 cases tested, 56 harbored IGH-CRLF2 and 19 P2RY8-CRLF2. Of the 87 Ph-like ALL patients with low CRLF2 expression, we identified rearrangements involving tyrosine kinase or cytokine receptor genes in 45 patients: ABL1 (n=5 patients), ABL2 (n=7), CSF1R (n=1), EPOR (n=8), JAK2 (n=18), PDGFRA (n=1), PDGFRB (n=2), PTK2B (n=1) and TYK2 (n=2). Nine of these 45 fusions have not previously been identified in Ph-like ALL including MEF2D-CSF1R, HMBOX1-JAK2, SMU1-JAK2, SNX29-JAK2 (n=2 patients), ZNF340-JAK2, FIP1L1-PDGFRA, TMEM2-PTK2B and ZNF340-TYK2. Exome sequencing is being performed on cases that do not harbor a kinase fusion by RNA-seq analysis.Conclusion: Ph-like ALL is common across the age spectrum of adult ALL, comprising over 20% of patients from ages 21-79 years, with a notably high prevalence of fusions involving JAK2. These findings warrant the development of clinical trials that assess the efficacy of tyrosine kinase inhibitors to improve the treatment outcome, similar to those that are being established for pediatric ALL. DisclosuresFielding:Amgen: Consultancy, Honoraria. Rowe:Amgen: Consultancy; BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx Ltd.: Consultancy. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. Mullighan:Amgen: Honoraria; Incyte: Consultancy.

A review of blinatumomab, a novel immunotherapy.

Blinatumomab is a novel bispecific CD19-directed CD3 T-cell engager recently approved for the treatment of relapsed or refractory Ph-negative acute lymphoblastic leukemia in adults. The drug was approved after a phase II trial in adults with relapsed/refractory disease demonstrated complete remission or hematologic complete remission in 43% of patients within two treatment cycles, of which 40% went on to receive an allogeneic hematopoietic stem cell transplant. In a long-term survival analysis of patients with minimal residual disease after chemotherapy, hematologic relapse-free survival was estimated at 61% at a median of 33 months after blinatumomab. Nine patients underwent hematopoietic stem cell transplant, and six patients remained in complete remission without hematopoietic stem cell transplant or further therapy. Limited data in relapsed pediatric acute lymphoblastic leukemia are reviewed. Blinatumomab carries boxed warnings for neurotoxicity and cytokine release syndrome, which may be serious and lead to treatment interruption and discontinuation. Clinical controversies with blinatumomab include use in patients with Ph-positive acute lymphoblastic leukemia, dosing in underweight adults, and the optimal management of cytokine release syndrome. Oncology pharmacists must be aware of detailed preparation and administration procedures required for safe use of blinatumomab. Clinical trials are ongoing in the first-line setting for patients with Ph-negative acute lymphoblastic leukemia, in Ph-positive acute lymphoblastic leukemia, and other B-cell malignancies.

How I treat T-cell acute lymphoblastic leukemia in adults

AbstractT-cell immunophenotype of acute lymphoblastic leukemia (T-ALL) is an uncommon aggressive leukemia that can present with leukemic and/or lymphomatous manifestations. Molecular studies are enhancing our understanding of the pathogenesis of T-ALL, and the discovery of activating mutations of NOTCH1 and FBXW7 in a majority of patients has been a seminal observation. The use of pediatric intensive combination chemotherapy regimens in adolescents and young adults has significantly improved the outcome of patients with T-ALL. The use of nelarabine for relapsed and refractory T-ALL results in responses in a substantial minority of patients. Allogeneic hematopoietic cell transplantation (HCT) still plays a key role in patients with high-risk or relapsed/refractory disease. γ-Secretase inhibitors hold promise for the treatment of patients with NOTCH1 mutations, and the results of clinical trials with these agents are eagerly awaited. It is recommended that younger patients receive a pediatric-intensive regimen. Older and unfit patients can receive suitable multiagent chemotherapy and be allocated to HCT based on their response, risk factors, and comorbidities. Although advances in the treatment of T-ALL have lagged behind those of B-cell ALL, it is hoped that the molecular revolution will enhance our understanding of the pathogenesis and treatment of this aggressive lymphoid malignancy.

Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia in adults: a broader range of options, improved outcomes, and more therapeutic dilemmas.

The article addresses selected key areas of flux in the management of Philadelphia chromosome-positive acute lymphoblastic leukemia. There is no doubt that tyrosine kinase inhibitors (TKIs) have made a major contribution to higher rates of complete remission and that more patients are now surviving long term. Many patients tolerate TKIs well, and remission can be achieved with minimal toxicity. Because remissions can include a proportion of patients who become BCR-ABL1 transcript negative, the question of whether allogeneic hematopoietic stem cell transplantation can be avoided requires discussion. Despite the major progress that has been made and the relative profusion of therapeutic choice compared with 10 years ago, evidence is still lacking for many of the major possible interventions, and how to combine them is unclear. Because of the rarity of the condition and the enticing possibility of increasing traction to therapy, clinical trials and international cooperation remain paramount.

A Novel Approach to Acute Lymphoblastic Leukemia in Adults: Association Analysis of Polymorphisms in Vascular Endothelial Growth Factor (VEGF) Gene and Clinical Outcome

A Novel Approach to Acute Lymphoblastic Leukemia in Adults: Association Analysis of Polymorphisms in Vascular Endothelial Growth Factor (VEGF) Gene and Clinical Outcome