Treatment Of Adult Acute Lymphoblastic Leukemia Research Articles

Expert recommendations for pancreatitis/pancreatic necrosis treatment after L-asparaginase in children with acute lymphoblastic leukemia

L-asparaginase is one of the most effective drugs in pediatric and adult acute lymphoblastic leukemia treatment. But drug side effects are an important problem. pancreatitis and pancreatic necrosis are not common (2–18 %) complication, but high chance of severe disease with fatal outcome make to bring in careful attention of pediatric oncologists-hematologists, surgeons, intensivists, radiologists. Recognizing multidisciplinary importance of this problem, at June 21st, 2023 at Morozov Children’s Clinical hospital a Round table on pancreatitis/pancreatic necrosis after L-asparaginase use was organized. This article presents expert recommendations from federal and regional clinics in diagnosis and treatment of such severe complication.

Prognostic Factors and Outcome of Patients with Adult Acute Lymphoblastic Leukemia Treated with the Hyper-CVAD Regimen: A Retrospective Study.

The Hyper-CVAD regimen has shown promising results for adult patients with acute lymphoblastic leukemia (ALL), as designed by the MD Anderson Cancer Center (MDACC). This treatment has resulted in a complete remission rate of 92% and a 5-year overall survival of 38%. However, given the diversity of patient demographics and institutional methods, outcomes may differ between various institutions. This study will compare the outcome of adult ALL patients treated with the Hyper-CVAD regimen in Iran with those obtained in the original series presented at the MDACC. Patients and Method. In this retrospective study, we evaluated the 2-year leukemia-free survival (LFS) and the 2-year overall survival (OS) of 70 ALL patients treated between 2014 and 2019 in the Seyed Al-Shohada Hospital in Isfahan, Iran. In total, 59 ALL patients (84.28%) achieved complete remission (CR). The CR rate had statistical differences by bone marrow transplantation (BMT) and WBC count. The 2-year LFS and OS were 40% and 42%, respectively. There were significant differences in LFS and OS by BMT, myeloid marker, and WBC count. The outcome of the traditional Hyper-CVAD regimen in treating adult ALL was not satisfying. More efficient therapies should be applied for the treatment of adult ALL.

Pediatric-Inspired Protocol Improved Overall Survival in Young Adult Aged 18-30 Years Old with Philadelphia-Negative Acute Lymphoblastic Leukemia Compared to the Standard Adult Hypercvad Protocol

Background:Pediatric acute lymphoblastic leukemia (ALL) have excellent overall survival (OS) compared to adult ALL even in the young adult group. The difference in OS was thought to be due to the difference in treatment protocol with the pediatric-inspired protocol being more intensive and with minimal residual disease (MRD) driven. Strong data has emerged over the past decade from different ALL study groups from Europe and North America to support the use of pediatric-inspired protocol for young adult up to age 30-40 years.HyperCVAD protocol, designed by MD Anderson group in early 90s, has been our standard treatment for adult ALL including young adult since year 2000. Over the past decade, a locally designed pediatric-inspired and MRD driven protocol - known as MASPORE Protocol was used with increasing frequency for those age 30 years and below. MASPORE protocol has higher cumulative dose of vincristine and methotrexate, and use of L-Asparaginase compared to HyperCVAD.In this retrospective study, we aimed to evaluate the safety, tolerability and efficacy of MASPORE protocol in relation to the standard adult ALL protocol - HyperCVAD in young adult aged 18-30 years who were diagnosed with Philadelphia-negative (Ph-) ALL.Method:Patients aged 18 to 30 years old with Ph- ALL who had received HyperCVAD or MASPORE regimen were retrospectively identified via our institution database. Clinical data, toxicity profile, and treatment outcome were collected, compared and analyzed.High risk disease was defined as high white blood cell (WBC) (>30x109/L for B-ALL, and >100x109/L for T-ALL), failure to achieve complete remission (CR) after induction, failure to achieve MRD target at 4 weeks and 8 weeks (in MASPORE group), hypodiploidy, t(9;22), t(4;11) and other MLL-gene rearrangement. An intensified chemotherapy regimen would be given to those high-risk disease in MASPORE regimen, while HyperCVAD regimen has a fixed intensity irrespective of risk.Results:A total of 30 consecutive Ph- ALL patients aged between 18 to 30 years old who were treated with HyperCVAD or MASPORE protocol were included in the analysis. 16 were treated with MASPORE protocol while 14 were treated with HyperCVAD protocol. The median age was 22 years old (Range: 18 - 29 years old). Median follow-up for MASPORE was 37.0 months and HyperCVAD was 85.0 months. HyperCVAD-treated patients were mainly from year 2004 to 2011, while more than 80% of MASPORE patients were treated after year 2013.18 patients had B-ALL, 11 with T-ALL and 1 with mixed phenotypes. 2 patients (1 in each group) had high cytogenetic risk. Median WBC was 14.1 (range: 1.9-287) and 10.1 (range: 1.2-242) for HyperCVAD and MASPORE respectively.All patients achieved CR at the end of induction with no early death (within 60 days of induction). Overall relapse rate was 33.3% with lower relapse rate observed in in MASPORE (18.8%) compared to 50.0% in HyperCVAD. (p-value: 0.07). 4 in HyperCVAD and 3 in MASPORE received allo-SCT subsequently.Median OS in MASPORE was not reached. Median OS for HyperCVAD was 26.3 months (95% CI: 3.6-49.1 months). Overall survival at 3 years were 84.0% and 46.2% in the MASPORE and HyperCVAD, respectively, p=0.038 (Figure 1).Median Leukemia Free Survival (LFS) in MASPORE was not reached. Median LFS in HyperCVAD was 12.5 months (95% CI: 4.2-20.8 months). LFS at 3 years were 75.8% and 38.5% in the MASPORE and HyperCVAD respectively, p=0.089 (Figure 2).6 patients in MASPORE had thrombotic events (3 with cerebral venous thrombosis and 3 with deep vein thrombosis (DVT)) while only 1 patient had DVT in HyperCVAD group. 11 patients in MASPORE group had at least 1 episode of grade 3 or more transaminitis, compared to 3 patients in HyperCVAD. 7 patients in HyperCVAD group had at least one episode of bacteremia during the course of treatment compared to 4 patients in the MASPORE group. Two treatment-related death were observed, both from HyperCVAD group.ConclusionsMASPORE protocol was well tolerated albeit higher rate of thrombotic events and transaminitis which most likely related to L-asparaginase, but with lower incidence of bacteremia and treatment related death. It showed a superior overall survival compared to HyperCVAD protocol and a trend towards improved leukemia free survival. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Preclinical Investigation of the p53-MDM2 Antagonist Idasanutlin (RG7388) Demonstrates Significant Activity in High Risk Adult Acute Lymphoblastic Leukemia

Outcomes for adult patients with acute lymphoblastic leukemia (ALL) are dismal and have not kept pace with their pediatric counterparts, with five-year survival rates of less than 45%. TP53 mutations are infrequent in ALL, but activity of the oncoprotein MDM2 may otherwise phenotypically disrupt and circumvent normal p53 function, positing the p53-MDM2 signaling axis as a potential therapeutic target for the engagement of intrinsic cell death programs. Given the clinical safety and responses to p53-MDM2 antagonist idasanutlin (RG7388) in other hematological cancers and solid tumors, we aimed to evaluate the therapeutic potential of idasanutlin in ALL. Single-agent activity of idasanutlin was investigated in 17 high-risk ALL patient and patient-derived xenograft samples (aged 4 to 51 years), both B-ALL (n=15) and T-ALL (n=2), including KMT2A-rearranged, TCF3-rearranged, and Philadelphia-positive ALL. An ex vivo coculture of ALL blasts and hTERT-immortalized mesenchymal stem cells (MSC) was employed to support growth of the ALL blasts during short-term culture, complemented by a fluorescent image-based microscopy platform which identifies and discriminates the two cellular compartments using random forest machine learning algorithms based on cellular nuclear staining. Idasanutlin demonstrated sub-micromolar, dose-dependent anti-leukemic activity against 15 of 17 samples tested, with half maximal effective concentrations (EC50) in the range of 10 to 220 nM (mean EC50 = 45.1nM); the two exceptions were later determined to harbor homozygous inactivating TP53 mutations; p.Y220C and p.S241P within the p53 DNA binding domain. The idasanutlin EC50 concentrations determined are clinically achievable, well below the peak plasma concentrations reported in patients for other disease indications. Furthermore, idasanutlin concentrations below 10µM had no impact upon MSC survival. Conforming to p53-MDM2 auto-regulatory feedback mechanisms, we demonstrated that idasanutlin efficiently stabilized and activated p53 at the protein level within 6 hours when treated with their respective idasanutlin EC50, to a level greater than 4-fold increased relative to their respective vehicle-only controls (p=0.001, n=7). Further, p53-regulated transcriptional target gene products, MDM2 and p21, were increased by 5-fold and 2-fold respectively, validating engagement of the p53 pathway by idasanutlin (p=0.036 and 0.125, respectively). By contrast, idasanutlin did not elicit increased expression of either p53-regulated transcriptional target gene product in the identified TP53-mutant patient samples (n=2). On-target specificity of idasanutlin was further confirmed in a NALM6 isogenic cell line model, whereby the TP53 wildtype line was sensitive to idasanutlin (EC50 = 74nM) and effectively activated p53 signaling whereas the TP53 homozygous null line was highly resistant (EC50 = ~10µM). To determine whether the decreased cell numbers and engagement of p53 signaling observed were accompanied by cell death, the capacity of idasanutlin to induce apoptosis in the ALL samples was next investigated. Patient-derived ALL samples (n=6) were treated with vehicle or idasanutlin at their respective EC50s for 24 and 48 hours, and then analyzed by flow cytometry. There was an increase in annexin-V positive cells within 24 hours compared to the vehicle-only treated cells (mean±SD 14.3±6.6% vs 27.0±21.2% respectively (p=0.125). By 48 hours significant apoptosis was attained, with a mean±SD of 59.0±23.8% annexin-V positive cells compared to the mean of vehicle-treated cells at 29.1±11.6% (p=0.004). Cleaved poly(ADP-ribose) polymerase (PARP) levels were also increased greater than 3-fold compared to vehicle-only control cells as assessed by immunoblotting (p=0.045, n=3), corroborating these findings. These data emphasize the potential of pharmacologically targeting the p53-MDM2 axis in ALL, demonstrating potent, on-target, cytotoxic activity in a range of high-risk ALL cytogenetic subgroups. Taken together, these findings support further preclinical investigations into idasanutlin and other p53-MDM2 antagonists and potential combinations to improve the treatment of adult ALL. Disclosures Irving: F. Hoffmann-La Roche: Research Funding.

Acute lymphoblastic leukaemia (ALL) things come to those who wait: 60years of progress in the treatment of adult ALL.

SummaryThe UK has made a well‐recognised contribution to the international effort to understand and treat acute lymphoblastic leukaemia (ALL) in adults. Work done in the UK by numerous personnel over many years has been instrumental in developing novel risk stratifications, evaluating treatment strategies for adult patients with de novo and relapsed disease and in making novel scientific contributions. The UK has championed and achieved very high levels of recruitment to clinical trials and, in particular, is known for success in large, investigator‐initiated randomised controlled trials. This historical review charts the progress of clinical research in adult ALL from its inception to the present day.

Pegaspargase Can Safely be Administered in Adults Age 40 and Older with Acute Lymphoblastic Leukemia

Pegaspargase Can Safely be Administered in Adults Age 40 and Older with Acute Lymphoblastic Leukemia

Testing for minimal residual disease in adults with acute lymphoblastic leukemia in Europe: a clinician survey

BackgroundIn acute lymphoblastic leukemia (ALL), the presence of minimal residual disease (MRD) after induction/consolidation chemotherapy is a strong prognostic factor for subsequent relapse and mortality. Accordingly, European clinical guidelines and protocols recommend testing patients who achieve a complete hematological remission (CR) for MRD for the purpose of risk stratification. The aim of this study was to provide quantitative information regarding real-world clinical practice for MRD testing in five European countries.MethodsA web-based survey was conducted in March/April 2017 in France, Germany, Italy, Spain, and the UK. The survey was developed after consultation with specialist clinicians and a review of published literature. Eligible clinicians (20 per country; 23 in Spain) were board-certified in hemato-oncology or hematology, had at least five years’ experience in their current role after training, had treated at least two patients with B-cell precursor ALL in the 12 months before the survey or at least five patients in the last five years, and had experience of testing for MRD in clinical practice.ResultsMRD testing is now standard practice in the treatment of adult ALL across the five European countries, with common use of recent treatment protocols which specify testing. Respondents estimated that, among clinicians in their country who conduct MRD testing, 73% of patients in first CR (CR1) and 63% of patients in second or later CR (CR2+) are tested for MRD. The median time point reported as most commonly used for the first MRD test, to establish risk status and to determine a treatment plan was four weeks after the start of induction therapy. The timing and frequency of tests is similar across countries. An average of four or five post-CR1 tests per patient in the 12 months after the first MRD test were reported across countries.ConclusionsThis comprehensive study of MRD testing patterns shows consistent practice across France, Germany, Italy, Spain, and the UK with respect to the timing and frequency of MRD testing, aligning with use of national protocols. MRD testing is used in clinical practice also in patients who reach CR2 + .

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

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.

Rapamycin restores p14, p15 and p57 expression and inhibits the mTOR/p70S6K pathway in acute lymphoblastic leukemia cells.

The aim of the present study was to investigate the effects of rapamycin and its underlying mechanisms on acute lymphoblastic leukemia (ALL) cells. We found that the p14, p15, and p57 genes were not expressed in ALL cell lines (Molt-4 and Nalm-6) and adult ALL patients, whereas mTOR, 4E-BP1, and p70S6K were highly expressed. In Molt-4 and Nalm-6 cells exposed to rapamycin, cell viability decreased and the cell cycle was arrested at the G1/S phase. Rapamycin restored p14, p15, and p57 gene expression through demethylation of the promoters of these genes. As expected, rapamycin also increased p14 and p15 protein expression in both Molt-4 and Nalm-6 cells, as well as p57 protein expression in Nalm-6 cells. Rapamycin additionally decreased mTOR and p70S6K mRNA levels, as well as p70S6K and p-p70S6K protein levels. However, depletion of mTOR by siRNA did not alter the expression and promoter methylation states of p14, p15, and p57. These results indicate that the inhibitory effect of rapamycin may be due mainly to increased p14, p15, and p57 expression via promoter demethylation and decreased mTOR and p70S6K expression in ALL cell lines. These results suggest a potential role for rapamycin in the treatment of adult ALL.

Toward Effective Targeted Therapy for the Treatment of Adult Acute Lymphoblastic Leukemia

Through the effectiveness of combination chemotherapy and allogeneic stem cell transplantation (ASCT), the cure of acute lymphoblastic leukemia (ALL) in children evolved from the 1970s from an anecdotal wonder to a quantifiable reality. Although giving less spectacular results than those seen in children, these therapeutic approaches have been applied to adults over the last two decades, leading to an improved response rate and survival [1]. Retrospective comparisons demonstrating that adolescents with ALL significantly benefit from pediatric rather than adult chemotherapy regimens yielded to the recent development of pediatric-inspired regimens for adult ALL involving greater dose densities of many chemotherapeutic agents, such as l-asparaginase, vincristine, corticosteroids and methotrexate [2]. However, additional gains are unlikely to be achieved by simply intensifying therapy further, due to the offset of unacceptable toxicities. Furthermore, new procedures for ASCT modestly improve the outcome of adult ALL, while introducing higher risks of acute and late complications. There was therefore a clear and compelling rationale for developing therapies that specifically target the molecular abnormalities that cause leukemia. Encouraging signs have recently emerged with the development of novel therapeutic agents, opening a new era of treatment in adult ALL. Several points of intervention have been identified that may respond to targeted drugs. Concomitantly, the biology of leukemia stem cell (eradication of which is considered as the relevant goal of leukemia therapy) was better understood. Several primary studies with targeted agents have demonstrated impressive clinical activity, even in heavily pretreated patients. Others have demonstrated synergistic effects with chemotherapy and the feasibility of such combinations in clinical trials. The era of targeted therapy for ALL started about 15 years ago with the development of the first inhibitor of tyrosine kinase (TKI), imatinib mesylate [3]. Imatinib mesylate and then the other inhibitors of the ABL tyrosine kinase activity of the fusion protein BCR-ABL have revolutionized the treatment of Philadelphia chromosome-positive (Ph) ALL [4,5]. TKIs are now integral components of therapy for Ph ALL. The current consensus is that they improve patient

The Number Of Peg-Asparaginase Doses Administered Is a Determinant Of Relapse Risk In Adult ALL Treated With a Pediatric-Like Regimen

IntroductionAsparaginase (ASN) is an essential drug in treating acute lymphoblastic leukemia (ALL). Pediatric studies have highlighted the significance of adequate and prolonged depletion of asparagine in preventing leukemia relapse. However, similar studies are lacking in adults as ASN is used less frequently mainly due to increased toxicities associated with age. The objective of this study was to evaluate the association between the number of pegaspargase (PEG-ASN) doses administered in a pediatric-inspired regimen and the risk of late leukemia relapse in adult ALL. MethodsWe reviewed patients with adult ALL who were treated at our institution with a modified BFM regimen (Douer D et al. Blood. 2012;120:1495) between 2004 and 2013. This regimen plan was to administer a total of 6 doses of PEG-ASN (2000 units/m2 per dose) administered through 2 cycles of induction, 4 cycles of consolidation and 2 cycles of delayed re-induction. The (PEG-ASN) dose was based on pharmacokinetic and asparagine depletion data previously established for adults (Douer D et al. Blood. 2007;109:2744-50). The study included patients aged 18 to 59 years who received all 8 cycles of the planned treatment courses and were started on POMP maintenance therapy. We excluded patients who relapsed, died, underwent HSCT or were lost follow up before starting maintenance therapy. Relapse was defined as recurrence of disease at any site (bone marrow, CNS, or extramedullary sites). The endpoint considered in the analyses was leukemia free survival (LFS). LFS was defined as the duration of time between the date when the maintenance therapy started and date of first relapse or date of death. ResultsWe identified 60 patients who met the eligibility criteria. Median age was 32 years (range 18- 59) and 42 patients were males. Median presenting WBC at diagnosis was 7000/dL (range 1-350). Six patients had T-cell ALL and 37 patients were classified as high-risk (age > 35 years, initial WBC> 30,000/dL in B-cell ALL and > 100,000/dL in T-cell ALL, and/or unfavorable cytogenetics). The average number of PEG-ASN doses administered was 5 (range 0-6). Among all included patients, 43 had received all 6 doses, 2 received 5 doses, 4 received 4 doses, 5 received 3 doses, 3 received 2 doses, 2 received 1 dose and 1 received no PEG-ASN. Reasons for not completing all doses of PEG-ASN included anaphylaxis, pancreatitis, life-threatening thrombosis, and prolonged delay in treatment due to hyperbilirubinemia. The two- and five-year LFS from the time of starting maintenance therapy were 62±7% and 52±8%, respectively, for all patients. Patients risk category (standard risk vs. high risk) was not significantly associated with LFS. However, a significant association was found between the number of doses of PEG-ASN that patients received during the induction/consolidation cycles and LFS (Figure 1). Patients who received a higher number of doses of PEG-asp had significantly better LFS compared to those who received a lower number of doses (trend test: p=0.009). [Display omitted] ConclusionIn adult patients with ALL who had remained in first remission throughout the entire induction and consolidations period of a pediatric-like regimen, less prior exposure to PEG-ASN (<3 doses) was associated with increased late relapse risk after starting maintenance therapy. These results support the importance of ASN treatment in adult ALL. Disclosures:Douer:Sigma Tau: Membership on an entity's Board of Directors or advisory committees.

Accumulation Of Gene Alterations Of TP53, Crebbp and IKZF1 Is a Prognostic Factor In Adult Acute Lymphoblastic Leukemia

▪ AimsMutations of the genes associating with cell differentiation or proliferation are recognized as factors of tumorigenesis or prognosis in hematological malignancies. In pediatric acute lymphoblastic leukemia (ALL), alterations of IKZF1 (a factor of lymphocyte differentiation), TP53 (a cell cycle regulator) and CREBBP (a histone modifier) are found as possible prognostic markers for stratification of treatments. On the other hand, in adult ALL, clinical significance of such alterations remains to be determined. In the present work, we examined whether the mutations in those genes affected the incidence and prognosis in adult ALL patients. MethodsWe investigated 87 adult patients with newly diagnosed ALL treated with JALSG protocols between 1986 and 2011. Age ranged from 15 to 86 years, with a median of 51 years. We obtained cDNA and genomic DNA from the peripheral blood or bone marrow mononuclear cells at diagnosis. CREBBP mutations are dominantly identified in the histone acetyltransferase (HAT) domain. HAT domain in the CREBBP gene was amplified by PCR using cDNA and was subjected to direct sequencing. Additionally other histone modifiers, EZH2, EED, and UTX, were sequenced as the same as in CREBBP. TP53 exons 5 – 8 and 10, in which mutations were commonly reported, were sequenced using genomic DNA. We amplified IKZF1 using RT-PCR for detecting aberrant dominant negative isoforms: Ik6 and Ik10. Genomic deletions of IKZF1 were assessed with RQ-PCR or genomic DNA PCR. We compared clinical profiles between patients with and without such gene mutations. The present study was approved by the Institutional Review Boards and informed consent was obtained from each patient according to guidelines based on the revised Declaration of Helsinki. ResultsIn 87 adult patients with ALL, alterations of CREBBP, EED, TP53 and IKZF1 were detected in 7 (9.5%), 3 (4.8%), 6 (6.9%) and 42 (50%), respectively. None of EZH2 and UTX mutation was found. The alterations of CREBBP and IKZF1 at diagnosis in adult patients were more frequent than those in pediatric patients ever reported. Some gene mutations were not found frequently. Each gene mutation per se did not significantly affect prognosis. We tried to predict the prognosis by scoring gene mutations and chromosomal abnormalities. Philadelphia chromosome (Ph) has great impact to prognosis of patients with ALL. We scored the number of mutated genes and Ph for each patient. As the score was higher, adult patients with ALL had poorer relapse-free survival (P=0.0439) and OS (P=0.4819), but statistical significance was not detected in this small cohort. Conclusions and DiscussionSingle gene mutations, such as IKZF1, can predict the prognosis in pediatric ALL. In adult ALL, however, only few gene mutations are reported to be promising prognostic factors which have impacts to treatment outcomes. Scoring system may be a useful method for predicting prognosis and stratifying treatment in adult ALL. Our study implies the possibility that a variety and heterogeneity of genetic alterations in adult ALL are associated with the pathogenesis for treatment resistance and prognostic marker of adult ALL. Disclosures:No relevant conflicts of interest to declare.

Thromboembolic and Hemorrhagic Complications In Adult Patients With Acute Lymphoblastic Leukemia (ALL) Treated With Asparaginase-Containing Combination Chemotherapy: A Single Center Experience

BackgroundL-asparaginase (LASP) depletion of asparagine reduces antithrombin (AT) and fibrinogen and is associated with thromboembolic (TE) and hemorrhagic events (HE). AT replacement in pediatric ALL patients demonstrated safety and potential benefit as thromboprophylaxis in a prospective, randomized trial.(Mitchell et al, 2003) Current consensus supports AT replacement when AT activity is below 60%.(Stock et al, 2011) The incidence of TE and HE in adults receiving AT repletion during LASP or pegylated asparaginase (PEGASP) requires further investigation. MethodsThis single center, retrospective, observational study was approved by the Mayo Clinic Institutional Review Board. Consecutive adult patients with a confirmed diagnosis of ALL receiving LASP or PEGASP containing chemotherapy regimens between January 2000 and October 2012 were evaluated. Patients with documented thrombophilia and pre-existing TE or HE were excluded. Patients receiving AT concentrate (ATC) compared to those that did not and were evaluated up to 60 days after the last LASP or PEGASP dose for objectively confirmed TE and HE. ResultsOf the 74 patients screened, 54 (73%) met inclusion criteria. Forty-seven (87%) received ATC and were evaluable. The remaining 7 (13%) did not meet follow up duration and were excluded from further analysis. Twenty-three (49%) patients received LASP, 20 (42%) received PEGASP and 4 (9%) received both. Distribution per treatment protocols was; CALGB 9111 (n=16 (34%), Larson et al, 1998), E2993 (n=12 (25%), Goldstone et al, 2008), C10403 (n=8 (17%), NLM: NCT00558519), CCG 1941 (n=6 (13%), Gaynon et al, 2006) and Augmented HyperCVAD (n=5 (11%), Faderl et al, 2011). A total of 1465 AT activity levels were analyzed, resulting in 378 doses of ATC. Ten patients (21%) experienced a clinical event, with all events occurring during cycle 1 of chemotherapy (table 1). Median time from last LASP or PEGASP dose to TE was 13 days (range 3-56) with a median of 4 days (range 3-13) from last ATC dose to TE. Median AT activity level at time of TE was 56% (range 47-72). Thrombotic events included; line-related deep vein thrombosis (LRDVT, n=7), cerebral venous sinus thrombosis (CVST, n=1) and pulmonary embolism (PE, n=1). One patient with cerebral hemorrhage constituted the only HE. All LRDVT occurred in central venous catheters and management included; line removal (n=3), anticoagulation (n=1), line removal and anticoagulation (n=2) and no intervention (n=1). The single case of PE was managed with anticoagulation. Two patients had a recurrent LRDVT in different locations during subsequent chemotherapy in spite of ongoing ATC supplementation. ConclusionsThe incidence of TE in adult ALL patients receiving LASP or PEGASP during induction chemotherapy with AT thromboprophylaxis was 19%. LRDVT was the most common TE with a comparable incidence to adult ALL patients not receiving ATC (15%) (Grace et al 2011). There was a small incidence of non-LRDVT (4%) and HE (2%). As induction-phase chemotherapy and placement of central lines are independent risk factors for thrombosis, the cost-effectiveness of AT replacement for prevention of TE during adult ALL treatment requires prospective evaluation. Disclosures:No relevant conflicts of interest to declare.

Flow Cytometric Evaluation Of Minimal Residual Disease In Adult Acute Lymphoblastic Leukemia Using a Simplified, Single-Tube Approach

▪Flow cytometry for detection of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL) has been widely used in pediatric patients to quantify therapeutic response and to assess the risk of relapse. Flow cytometry for MRD provides roughly the same level of sensitivity (0.01%) as molecular methods but at lower cost and with faster turnaround time. MRD assessment in ALL currently requires an evaluation of 20 or more parameters divided among multiple tubes.In part due to the assessment complexity, the use of flow cytometry for MRD detection in adult ALL patients has been relatively limited. We developed a 6-color, single-tube, flow cytometry assay to detect MRD in bone marrow (BM) aspirate specimens from adult ALL patients. The 73 patients included 52 patients with B-ALL (71%), 19 patients with T-ALL (26%) and 2 patients with T/myeloid leukemia (3%) and were treated with one of several standard chemotherapeutic regimens or targeted therapies. Patients were tested for MRD by flow cytometry after induction or re-induction therapy and serially thereafter. The 6-marker MRD panel was customized for each patient based on the 18-20-marker diagnostic immunophenotype.Sixty-three percent of B-ALL patients (n=33) had lymphoblasts with an aberrant immunophenotype; expression of a myeloid marker (e.g., CD13, CD15 or CD33) was the most common aberrancy. The remaining 37% of B-ALL patients (n=19) had disease with a hematogone immunophenotype, which comprised surface expression of CD10, CD19, CD20, CD34, CD38 and CD45; in the majority of these cases, leukemic cells were distinguishable from normal hematogones based on the intensity of surface marker expression. Forty-seven percent of T-ALL patients (n=9) had an aberrant immunophenotype, most often characterized by CD33 expression.One-hundred forty-six consecutive specimens analyzed for MRD by flow cytometry were classified as positive (23%), negative (72%) or uncertain (5%). Of the 34 samples classified as positive, 14 (41%) showed morphologic (i.e., BM aspirate or biopsy) evidence of disease; nineteen (65%) samples did not show morphologic evidence of disease and 1 sample did not have a concurrent morphologic assessment. Of the 105 samples classified as negative by flow cytometry, 103 (98%) were also negative by morphology and 1 sample did not have a concurrent morphologic assessment. One sample that was negative by flow cytometry had morphologic evidence of disease in the biopsy (10-20% blasts) but not the aspirate, suggesting that aspirate sampling artifact was responsible for the discrepancy. None of the 7 samples classified as uncertain by flow cytometry had morphologic evidence of disease; five out of 7 uncertain classifications were in B-ALL patients with hematogone immunophenotypes. Overall, MRD flow cytometry showed 86% concordance with the results of morphologic assessment.We evaluated outcomes in all patients with negative morphologic results and any positive MRD flow cytometry result(s). Of the 73 patients in this study, 61 had morphology-negative results that were either MRD-negative (n=45) or MRD-positive (n=16). Patients in this group were at various points of treatment post-induction or re-induction. Four out of 45 patients (9%) with MRD-negative results relapsed during a median follow-up period of 22 months, and 8 out of 16 patients (50%) with an MRD-positive result relapsed during a median follow-up period of 15 months (odds ratio for relapse 10.3, 95% confidence interval 2.5-42.4, P=0.001). In addition, relapse-related and overall mortality (Figure 1) were higher in patients with MRD-positive results (P=0.0023 and P=0.0016, respectively, by the log-rank test).In summary, we present a simplified, single-tube, flow cytometry assay that can be used to detect MRD in adult ALL at relatively low cost with rapid turnaround time; our approach was applicable to cases with either hematogone or aberrant immunophenotype, yielding a definitive result in 95% of cases. Notably, the presence of MRD was associated with relapse and mortality, suggesting that our method of MRD assessment could be used to guide treatment of adult ALL. Further analysis of the correlations between MRD results, clinical management and patient outcomes is ongoing.▪ Disclosures:No relevant conflicts of interest to declare.

Secondary Acute Myeloid Leukemia (sAML) Immediately after Intensive Chemotherapy of Acute Lymphoblastic Leukemia (ALL)

A 20-year-old woman was admitted to our unit, because of pre-B acute lymphoblastic leukemia (ALL). Classical cytogenetics revealed a normal karyotype. In FISH analysis no TEL-AML1 fusion, rearranged MLL gene, or BCRABL were found. The induction and consolidation chemotherapy was conducted according to protocol PALG 5-2007. In the assessment of minimal residual disease using flow cytometry after consolidation 0.02% of the baseline phenotype of lymphoblasts were found. After two weeks of the completion of intensive chemotherapy, the patient was admitted in emergency to hematology inpatient unit, because of secondary acute myeloid leukemia (sAML). The conventional cytogenetic karyotype was complex: 46, XX, der (7) t (5;7;10;?)del(7)(q22), t(11;17)(p11;q21),del(14)(q24q32). After the diagnosis of sAML, induction chemotherapy was given according to the program PALG DAC: cytarabine 329 mg/d 1-7, daunorubicin 90 mg iv/d 1-3, cladribine 8 mg/d 1-5. The patient died due to progression of refractory leukemia in 45 days. The risk of developing of the sAML after treatment of ALL in adults is about 0.5-1% after few years. Our case was unique, because sAML developed rapidly, just after five months of ALL diagnosis, three months after CR1 and two weeks after completion of consolidation chemotherapy.

Characterization of Common Fusion Oncogenes As Prognostic Molecular Identities in Adult Acute Lymphoblastic Leukemia Identifies the Need for Genetic Testing At Presentation, Molecular Prognostication and Differential Treatment

AbstractAbstract 5115 Introduction:Acute lymphoblastic leukemia (ALL) is a heterogeneous lymphoid disorder with many genetic abnormalities of which fusion oncogenes (FGs) are very common with a known role in leukemogenesis (Harrison & Foroni, 2002). Although prognostic significance of FGs is well characterized in pediatric ALL, the role of FGs in adult ALL is not well established (Moorman et al., 2007). Methods:We studied the frequency and association of five most common FGs namely BCR-ABL, MLL-AF4, ETV6-RUNX11, E2A-PBX1 and SIL-TAL1 with disease biology and treatment outcome in adult ALL. FGs were studied at diagnosis in 104 adult ALL patients using RT-PCR (Van-Dongen et al, 1999) and Interphase FISH. Results:FGs were found in 78. 8% (82/104) subjects (Table 1). Overall survival (OS) and relapse free survival (RFS) were 26. 17 and 11. 147 months, respectively (Figures 1–2). Patients with MLL-AF4 (12. 19%) showed an elevated total leukocyte count (TLC), prominent organomegaly, frequent central nervous system (CNS) involvement, and a poor clinical outcome (OS=8. 8 months). SIL-TAL1 (35. 36%) was associated with lymphadenopathy, frequent organomegaly, low platelets count and poor survival. Patients with BCR-ABL (20. 3%) had high TLC (p-value <0. 001), splenomegaly (p-value <0. 001), low platelets count (p-value <0. 001), poor outcome (OS=9. 3 & RFS=6. 3 months) and 10% less chances of CR as compared to BCR-ABL negative cases. ETV6-RUNX1 (4. 8 %) was mostly associated with low TLC, less common organomegaly, high CR rates and higher OS (30. 2 months), but their long term survival negatively affected by late relapses. Patients with TCF3-PBX1 (16. 3%) were associated with younger age (10/17, 59%), lower TLC (14/17, 82%), platelet count higher than 50×109/l (12/17, 71%), less common hepatomegaly (2/17, 12%), less common splenomegaly (3/17, 18%), early CR (11/17, 65%) but high relapse rate (13/17, 76. 1%) and shorter OS (11. 6 months). Conclusions & Discussion:High relapse rates and shorter OS despite favorable prognosis manifested by clinical features and high early CR rates in TCF3-PBX1 highlights the need for their identification at presentation and intensified treatment protocols to manage high relapse rate (Foa et al., 2003). Association of SIL-TAL1 with lymphadenopathy can help in better identification of this adult ALL subgroup at low resource centers. We found much higher frequency of TCF3-PBX1 and lower frequency of ETV6-RUNX1 than previously reported (Van Dongen et al, 1999). Although MLL-AF4 positive ALL is rarely observed in adult ALL, its frequency was 9. 7% in our adult ALL patients, which added to overall poor outcome of adult ALL in our population. Characterization of TCF3-PBX1 as poor prognostic molecular entity in our adult ALL population, low frequency of favorably prognostic ETV6-RUNX1, high frequency of poor prognostic MLL-AF4 and TCF3-PBX1 reflects ethnic and geographic differences in the biology and treatment of adult ALL (Burmeister et al., 2010). Therefore, it identifies the need for molecular testing in routine clinical settings at diagnosis and its implication in molecular prognostication and differential treatment. It also indicates the need for in-depth molecular analysis using advanced techniques and their implication in understanding the leukemogenesis and clinical management of adult ALL.Table 1:Comparison of the clinical characteristic of different FGs in ALL adult patientsClinical featuresBCR-ABL N=21 NO (%)ETV6-RUNX1 N=5 NO (%)MLL-AF4 N=10 NO (%)SIL-TAL1 N=29 NO (%)TCF3-PBX1 N=17 NO (%)Gene not detectedMale15 (71)4 (80)7 (70)24 (83)15 (88)17Female6 (29)1 (20)3 (30)5 (17)2 (12)5Age16y-29 y4 (19)3 (60)6 (60)19 (65)10 (59)1730y-59y13 (62)2 (40)3 (30)9 (31)6 (35)4≥60y4 (19)01 (10)1 (3)1 (6)1WBC<30,00011 (52)4 (80)7 (30)16 (55)10 (58.8)20>30,00010 (48)1 (20)3 (70)13 (45)7 (41.1)1HepatomegalyNo11 (52)2 (40)5 (50)24 (83)15 (88)22yes10 (48)3 (60)5 (50)5 (17)2 (12)0SplenomegalyNo5 (24)5 (100)5 (50)21 (72)14 (82)20Yes16 (76)05 (50)8 (28)3 (18)2LymphadenopathyNo3 (14)4 (80)5 (50)21 (21)2 (12)8yes18 (86)1 (20)5 (50)8 (28)15 (88)14Platelets<50,00020 (95)1 (20)9 (90)6 (21)5 (29)2>50,0001 (5)4 (80)1 (10)23 (79)12 (71)20ImmunophenotypingT-ALL00024 (83)00B-ALL3 (14)2 (40)2 (20)09 (53)2Unknown19 (90)3 (60)8 (80)5 (17)8 (47)20CR<4 weeks4 (19)4 (80)6 (60)20 (69)11 (65)15>4 weeks14 (66)1 (20)2 (20)1 (3)3 (18)3No remission3 (14)02 (20)8 (28)3 (18)4 [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Adult acute lymphoblastic leukaemia in Denmark. A national population‐based retrospective study on acute lymphoblastic leukaemia in Denmark 1998–2008

Since July 2008, children and adults 1-45 years, diagnosed with acute lymphoblastic leukaemia (ALL) in Denmark have been treated according to the common Nordic Society for Paediatric Haematology and Oncology ALL2008 protocol. To explore whether this strategy will improve survival compared with historical controls, we performed a retrospective national population-based study of adult ALL between 1998 and 2008. Patients were identified through the Danish Patobank and the Danish Cancer Registry; data was collected from patient files, and included 277 patients (median age, 47 years, range 15-91 years). The 5-year projected event-free survival (pEFS(5y)) and overall survival (pOS(5y)) for the whole cohort was 27·5% [95% confidence interval (CI) 22·4-33·6] and 34·1% (95% CI 28·7-40·4), respectively. No patient above 65 years survived beyond 5 years from diagnosis. For patients receiving curatively intended treatment, the pEFS(5y) and pOS(5y) were 36·6% and 44·1%, respectively, with a significantly higher pOS(5y) for patients 15-35 years compared with patients 36-65 years (50·7% vs. 38·9%, P = 0·006). Cox multiple regression analysis identified age (Hazard Ratio = 1·7, P < 0·006) as a statistically significant predictor of EFS. The cure rates, not least for the elderly, are unacceptably low, and call for new strategies in the treatment of adult ALL in all age groups.

Emerging Pharmacotherapies for Adult Patients with Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) treatment regimes are amongst the longest, most intensive and complex used in hematooncology. Despite this, while treatment of pediatric ALL is a success story, we are far from being able to ensure a durable response in adult ALL. This is not due to failure of induction therapy as a complete remission (CR) is achieved in over 90% of patients. However the challenge remains in ensuring a sustained remission. Furthermore in the face of relapsed disease, salvage therapies currently offer a poor chance of a good outcome. This article reviews the novel agents which show the most promise in the treatment of adult ALL.

Absolute Lymphocyte Count At Day 28 Independently Predicts Event-Free and Overall Survival in Adults with Newly Diagnosed Acute Lymphocytic Leukemia

Abstract▪2552▪This icon denotes a clinically relevant abstractLong-term survival rates for adults with acute lymphoblastic leukemia (ALL) remain poor at 40% when compared with pediatric ALL pts. This is partly attributed to the lack of predictive markers for risk stratification in adult ALL. Childhood ALL studies have shown that higher absolute lymphocyte count (ALC) during or following induction predicts longer event free survival (EFS). We hypothesized that adult ALL patients with higher ALC following induction therapy will have prolonged EFS and overall survival (OS). Methods:We conducted a retrospective chart review of 230 adult pts (age 18–64 yrs) with de novo ALL diagnosed between 1993–2010 at the Cleveland Clinic and Stanford, 198 of whom were evaluable (112 Cleveland Clinic, 86 Stanford). Prior studies in the pediatric population identified an ALC of 350 cells/μL as a cutoff that was predictive of outcome; we assessed this cutoff as well as other ALC metrics including day 1, 3, 7, 11, 14, 17, 20, 25, and 28 counts, nadirs and area under the curves at various time points, and the rate of ALC decline. We also evaluated the impact of gender, age at diagnosis, cytogenetics (CG), WBC at diagnosis, and transplant. The Kaplan-Meier method was used to summarize OS and EFS and the log-rank test was used for univariable analysis. The Cox proportional hazards model, stratified by institution, was used for multivariable and univariable analyses of measured factors. Patient characteristics:Median age: 38 yrs (range 18–64); Gender: 58% (114) male; CG risk: 62 (31%) poor, 46 (23%) miscellaneous, 54 (27%) normal, 36 (19%) no growth or not done; 178 (90%) B-cell lineage; median WBC at diagnosis 9.5 K/μL (range 0.5–760). Eighty-three percent of pts (165) achieved a CR with induction chemotherapy. The majority of pts (178, 90%) received a vincristine/prednisone/anthracycline-based induction regimen. Four pts (2%) received double-induction on trial S0333 (induction 1: vincristine/prednisone/anthracycline; induction 2: high dose cytarabine/mitoxantrone); eight pts (4%) hyperCVAD; and eight pts (4%) high dose cytarabine/mitoxantrone. Twenty-one pts (11%) received imatinib in combination with chemotherapy. Forty-six pts (23%) received an allogeneic transplant in CR1. Results:The median OS and EFS for this cohort were 29.5 and 24.9 mos, respectively. A number of the metrics were found to be associated with outcome; however we found that ALC at day 28 with a cut-point of <350 cells/μL was the strongest predictor of OS and EFS. The median ALC at Day 28 was 300 cells/μL (range 0–4000 cells/μL). Patients with ALC ≥350 cells/μL had a median OS of 47.4 mos compared to 17.6 mos for patients with ALC <350 cells/μL (HR=1.98, p=.007, Figure 1). Similarly, among pts who achieved a CR, median EFS for those with ALC ≥350/μL on day 28 was 42.1 mos compared to 13.9 mos in pts with ALC <350 cells/μL (HR=2.08, p=.006). Other factors associated with OS and EFS in univariable analyses were age at diagnosis, CG, WBC at diagnosis, and subsequent transplant (all p≤.04). In multivariable analysis the ALC on day 28 (<350 cells vs ≥350 cells/μL, p≤.0004 for OS and EFS) along with WBC at diagnosis (≤6.0 or >50.0 K/μL vs >6.0–50 K/μL, p≤.002 for OS and EFS) and CG (abnormal vs normal, p=.002 for OS and p=.02 for EFS) were independent prognostic factors of both outcomes. Combining these three factors by counting the number of poor features present yields a 3-group risk stratification: favorable (0–1 poor feature, 30% of pts, median OS and EFS not yet reached); intermediate (2 poor features, 45% of pts, estimated median OS and EFS 47.4 and 66.0 mos, respectively); unfavorable (3 poor features, 26% of pts, median OS and EFS 9.0 and 6.5 mos, respectively). [Display omitted] Conclusion:By identifying an additional prognostic marker—ALC—this study aims to optimize the current adult ALL treatment protocol by risk stratification. As an indicator of bone marrow recovery, ALC following induction therapy may demonstrate the body’s immune surveillance against malignant cells. Further characterization of higher risk pts allows for modifications to therapeutic regimens, which may translate into improvements in long-term survival. In addition, this data suggests that targeting the immune system to improve ALC may be a worthwhile strategy in ALL. Disclosures:No relevant conflicts of interest to declare.

Single-Institution Experience with HyperC-VAD Protocol for Adult Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is much rarer in adult age than in childhood, accounting for less than a quarter of acute leukemias, and with an overall survival rate at 5 years below 38%. The authors report the group experience in the treatment of adult ALL with HyperC-VAD protocol. From 2004 to 2007, 21 patients with adult ALL (15 male/6 female), with a median age at diagnosis of 29 years [18;58], were treated: four with ALL-L3/Burkitt lymphoma, six with T cell ALL/lymphoblastic lymphoma, eight with B cell ALL/lymphoblastic lymphoma, and three with ALL with t(9;22). The protocol consists of 4 courses of HyperC-VAD (cyclophosphamide 300mg/m2 IV q12h, on days 1–3; vincristine 2mg IV qd, on days 4 and 11; doxorubicin 50mg/m2 IV, on day 4; dexamethasone 40mg IV/PO qd, on days 1–4 and 11–14) that alternate with 4 courses of HD MTX-ARAC (methotrexate 1g/m2 IV, on day 1; cytarabine 3g/m2 IV q12h, on days 2–3). Those patients with ALL with t(9;22) received imatinib 400mg IV qd, on days 1–14 of each course; and CD20-positive cases received rituximab 375mg/m2 IV qd, on days 1 and 11 (odd courses) or on days 1 and 8 (even courses) of the first 4 courses. All patients received central nervous system prophylaxis in each course with methotrexate 12mg intrathecal on day 2 and cytarabine 100mg intrathecal on day 8. All patients (21/21) achieved complete remission after the first course of chemotherapy. Two patients abandoned the protocol due to neurologic and hematologic toxicity. The relapse rate was 47.6% (10/21), and the overall survival was 61.9% (13/21) – all deaths were due to disease progression. Overall, 131 courses were completed (69 odd courses/62 even courses). The most frequent complication was febrile neutropenia (32.8% - 18 in odd courses; 25 in even courses). The most severe complications were gram-negative septic shock (2 in even courses) and severe axonal polyneuropathy (1 in an odd course; 1 in an even course). Although these results are consistent with the literature, a longer follow up is needed to draw definitive conclusions.