Chromosome-negative Acute Lymphoblastic Leukemia Research Articles

Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia with kinase fusions in Taiwan

Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukaemia (ALL), a high-risk subtype characterised by genomic alterations that activate cytokine receptor and kinase signalling, is associated with inferior outcomes in most childhood ALL clinical trials. Half of the patients with Ph-like ALL have kinase rearrangements or fusions. We examined the frequency and spectrum of these fusions using a retrospective cohort of 212 newly diagnosed patients with childhood B-cell ALL. Samples without known chromosomal alterations were subject to multiplex reverse transcription polymerase chain reaction to identify known Ph-like kinase fusions. Immunoglobulin heavy chain locus (IGH) capture and kinase capture were applied to samples without known kinase fusions. We detected known kinase fusions in five of 212 patients, comprising EBF1-PDGFRB, ETV6-ABL1, ZC3HAV1-ABL2, EPOR-IGH, and CNTRL-ABL1. Two patients with P2RY8-CRLF2 were identified. Patients with non-Ph kinase fusions had inferior 5-year event-free survival and overall survival compared with patients with other common genetic alterations. The prevalence of non-Ph kinase fusions in our Taiwanese cohort was lower than that reported in Caucasian populations. Future clinical trials with tyrosine kinase inhibitors may be indicated in Taiwan because of the inferior outcomes for B-cell ALL with kinase fusions.

EIF3B Associates with Exacerbated Clinical Features, Poor Treatment Response and Survival in Adult Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia Patients.

Objective: This study was undertaken to investigate eukaryotic translation initiation factor 3 subunit B (EIF3B) expression and its clinical value for indicating disease progression and prognosis in adult Philadelphia chromosome negative acute lymphoblastic leukemia (Ph− ALL) patients. Methods: Totally, 76 adult Ph− ALL patients and 30 healthy donors (HDs) were included. Bone marrow (BM) samples before therapy (baseline), after 4-week therapy of Ph− ALL patients and the BM samples of HDs were collected. Then, EIF3B expression in BM was detected by reverse transcription quantitative polymerase chain reaction. Results: EIF3B expression was increased in Ph− ALL patients compared with HDs, which distinguished Ph− ALL patients from HDs (area under the curve [AUC]: 0.928; 95% confidence interval [CI]: 0.882−0.974) by receiver operating characteristic curve. Furthermore, higher baseline EIF3B expression was associated with elevated white blood cell and bone marrow blasts, while it was associated with lower complete remission (CR) within 4 weeks and less allogeneic hematopoietic stem cell transplant achievements in Ph− ALL patients. Additionally, higher baseline EIF3B expression was associated with decreased disease-free survival but not overall survival. However, it was associated with raised 1-year mortality and 3-year mortality in Ph− ALL patients. After 4-week therapy, EIF3B expression was reduced in total Ph− ALL patients. Notably, the reduction of EIF3B expression was more obvious in Ph− ALL patients who achieved CR within 4 weeks compared with Ph− ALL patients who did not achieve CR within 4 weeks. Conclusion: EIF3B overexpression is related to worsened clinical features, poor treatment response and survival in adult Ph− ALL patients.

Detailed Immunophenotypic Profiling of Peripheral Blood Immune Cells in Patients with Hematologic Malignancies after Sars-Cov-2 Infection

Introduction:The spread of SARS-CoV-2 virus continues to pose a major public health threat. Patients with cancer are thought to be at increased risk from SARS-COV-2 infection due to the immunodeficiency that results from the underlying neoplasm and treatment. The immune response to this infection has been the subject of great interest, with an extreme variation in clinical severity between infected individuals. Variation in the immune cell response (B, T, and NK lymphocytes, monocytes, and myeloid derived suppressor cells (MDSCs), among others) and their function have been hypothesized to be responsible for this range of presentation.Methods:Two patients with a history of hematologic malignancies were matched with three non-cancer patients with similar baseline clinical characteristics and severity of COVID related illness. The critical group (CG) was defined as those requiring mechanical ventilation (MV) due to COVID related respiratory failure and the non-critical group (NCG) were hospitalized but did not require MV. All samples studied were obtained from peripheral blood and processed within 4-hours of collection. Peripheral blood mononuclear cell (PBMC) were isolated using ficoll density gradient separation. Flowcytometric analysis using CytekTM Aurora was done on fresh PBMC samples. Thirty antibody-based flow markers were used to identify 54 distinct immune cell populations. IRB approval was obtained.Results:Critical Group (CG):The CG included case 1, a 47 year-old (y.o.) female (F) with a history (hx) of acute myeloid leukemia and had an matched related donor allogeneic hematopoietic stem cell transplant (alloHSCT) 10-years prior remaining in remission, with hematologic recovery, and off immunosuppressants treated with remdesivir and coritcosteroids for COIVD directed therapy; and case 2, a 55 y.o. F with a hx of HIV treated with corticosteroids for COIVD directed therapy (see Figure 1a).Non-Critical Group (NCG):The NCG included case 3, a 73 y.o male (M) with hx of relapsed/refractory Philadelphia chromosome negative Acute Lymphoblastic Leukemia with loss of CD19 and CD22 expression following treatment with blinatumumab and inotuzumab, and most recently treated with decitabine/venetoclax; case 4, a 66 y.o. M with hx of cardiomyopathy; and case 6, a 54 y.o. M with hx of obesity. None of the NCG cases were treated with COVID directed therapy.See Table 1 for further clinical information.Immunophenotypic expression:Flow cytometry gating strategy done as outlined in Fig 1a. Case 1 had a high proportion of B-cells, CD8+ T-cells, and cells with exhaustion markers (CD8+CD94+ T-cells, CD4+PD1+ T-cells, CD4+PD1+CD94+ T-cells, PD1-CD94+ NK T-cells, Lag3+Cd11b- non-TB leukocytes) and MDSC immunophenotypes compared with matched case 2. Case 3 also had a high proportion of exhaustion markers (Lag3+CD39 low B-cells, CD8+PD1+ T-cells, CD8+CD94+PD1+ T-cells, CD4+PD1+CD94+ T-cells, PD1+CD94+ NK T-cells, PD1-CD94+ NK T-cells, Lag3+CD11b+, Lag3+CD11b- non-TB leukocytes) and high expression of immunosuppressive Treg and all MDSC; although high expression of granulocytic MDSC. Case 2 had a significant number of exhaustion and immunosuppressive cells as well. Cases 4 and 5 had a higher predominance of all T-cell subtypes and also had variable expression of exhaustion and immunosuppressive immunophenotypes (See Fib 1b).Conclusion:In our study of one critical and one non-critical patient with a history of hematologic malignancy matched with three non-cancer patients we demonstrate the high predominance of exhaustion markers (Lag3,PD1,CD94) and immunosuppressive cell types (Treg, granulocytic and monocytic MDSC). These findings are consistent with the fact that both CG and NCG, as hospitalized patients, represent the most severely ill COVID patient cohort. Of notable interest to the cancer population, cases 1 and 3 had a significant number of exhaustion and immunosuppressive immunophenotypes, suggestive of baseline exhaustion following alloHSCT even years after engraftment in case 1 and attenuated functional immunity in a patient undergoing active treatment in case 3. Interestingly, case 3 had lower expression of all MDSC, a known treatment effect of decitabine. Paired cytokine measurement and its effect on immunophenotype is underway. Additionally, we plan to present an atlas of the peripheral immune cell response on fifteen additional non-cancer COVID patients.DisclosuresNo relevant conflicts of interest to declare.

Long-Term Follow-up of the Combination of Low-Intensity Chemotherapy Plus Inotuzumab Ozogamicin with or without Blinatumomab in Patients with Relapsed-Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: A Phase 2 Trial

Long-Term Follow-up of the Combination of Low-Intensity Chemotherapy Plus Inotuzumab Ozogamicin with or without Blinatumomab in Patients with Relapsed-Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: A Phase 2 Trial

Ultrasensitive Next-Generation Sequencing-Based Measurable Residual Disease Assessment in Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia after Frontline Therapy: Correlation with Flow Cytometry and Impact on Clinical Outcomes

Ultrasensitive Next-Generation Sequencing-Based Measurable Residual Disease Assessment in Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia after Frontline Therapy: Correlation with Flow Cytometry and Impact on Clinical Outcomes

A Prognostic Model for Survival in Patients with Relapsed/Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia on the Combination of Low-Intensity Chemotherapy Plus Inotuzumab Ozogamicin with or without Blinatumomab

A Prognostic Model for Survival in Patients with Relapsed/Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia on the Combination of Low-Intensity Chemotherapy Plus Inotuzumab Ozogamicin with or without Blinatumomab

Frontline Blinatumomab in Older Adults with Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia.

Outcomes of acute lymphoblastic leukemia (ALL) in older adults treated with chemotherapy are poor. The CD19/CD3 bispecific T-cell engager (BiTE) antibody blinatumomab is approved for refractory, relapsed or minimal/measurable residual disease (MRD)-positive B-cell ALL, but there is little experience in the upfront setting, including in older patients. We retrospectively analyzed outcomes of blinatumomab monotherapy in five newly diagnosed Philadelphia chromosome-negative B-cell ALL patients over 70 years. Three had cytokine release syndrome, treated with dexamethasone and/or tocilizumab, and four patients had neurotoxicity, treated with dexamethasone, without blinatumomab interruption. All five achieved complete remission (CR) after cycle one, three with undetectable MRD. All five were alive at 8 to 15 months. Three remained in MRD-negative CR. Two relapsed after cycle 3, one with extramedullary disease. In our small cohort of patients over 70 years, blinatumomab was safe initial therapy and produced a high response rate.

Hematopoietic Cell Transplantation for Philadelphia Chromosome Negative Adult Acute Lymphoblastic Leukemia in the Modern Era of Immune Therapy.

This review will discuss the data and controversies related to HCT in the front-line and relapsed/refractory setting in the context of newly available targeted immunotherapies. Recent studies in adult Ph-negative ALL support the use of measurable residual disease (MRD) response to front-line therapy to guide consolidation. As such, most MRD-negative patients do not require front-line HCT. Blinatumomab benefits patients with B-ALL with MRD+ complete response (CR) and can be used as a bridge to HCT; whether HCT is still required in this setting is an area of ongoing inquiry. Blinatumomab and inotuzumab result in high rates of MRD negative CR in adults with relapsed/refractory ALL and allow more patients with relapsed disease to receive HCT. Chimeric antigen receptor T cell (CAR-T) therapies may serve as a bridge to HCT or as a stand-alone therapy for relapsed/refractory patients; data suggests there may be greater benefit to consolidating CAR-T with HCT in HCT-naïve adults. The decision to incorporate consolidative allogeneic HCT into front-line therapy should be primarily guided by MRD status and the ALL regimen utilized. Targeted immunotherapies result in high MRD-negative CR rates, allowing more adults with relapsed/refractory ALL to be successfully bridged to HCT; early incorporation of these therapies may also prove valuable in reducing the need for HCT in the front-line setting by increasing MRD negative CR rates.

Treatment of Frail Older Adults and Elderly Patients With Philadelphia Chromosome-negative Acute Lymphoblastic Leukemia: Results of a Prospective Trial With Minimal Chemotherapy

BackgroundThe treatment of acute lymphoblastic leukemia (ALL) in older adults and elderly patients is a challenge, and modern protocols include targeted therapy and immunotherapy in combination with attenuated or minimal chemotherapy. However, frail patients are excluded from these trials, and reports on the outcome of this subgroup of patients are scarce. Our objective was to analyze the outcome of unfit older adults and elderly patients with Philadelphia chromosome-negative ALL included in a prospective trial (ALL-07FRAIL). Patients and MethodsOlder adults and elderly patients with Charlson Comorbidity Index (CCI) ≥ 4 were included. Induction therapy consisted of vincristine and dexamethasone, and maintenance therapy with mercaptopurine and methotrexate for 2 years. ResultsSeventy-two patients with a median age of 67 years (range, 57-89 years) and a median CCI of 5 (range, 4-12) were included. The rates of early withdrawal, early death, resistance, and complete response (CR) were 5%, 10%, 31%, and 54%, respectively. Six patients with CR abandoned the study, 5 died in CR, and 23 relapsed (cumulative relapse incidence 75%). The medians of disease-free and overall survival (OS) were 6.9 months (95% confidence interval [CI], 0.3-13.5 months) and 7.6 months (95% CI, 6.3-8.9 months), respectively. The most frequent toxic events were hematologic (neutropenia 77% and thrombocytopenia 54%, of grade III-IV in all cases). Eastern Cooperative Oncology Group score but not the CCI had significant impact on OS. ConclusionComplete remission with very attenuated chemotherapy can be attained in one-half of older or elderly infirm patients with ALL. These results suggest that some of these patients could benefit from the concomitant or subsequent use of immunotherapy and/or targeted therapy.

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

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.

Treatment of Adults with Relapsed/Refractory Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia with Blinatumomab in a Real-World Setting: Results from the Neuf Study

Treatment of Adults with Relapsed/Refractory Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia with Blinatumomab in a Real-World Setting: Results from the Neuf Study

A Multicenter Phase I Study Combining Venetoclax with Mini-Hyper-CVD in Older Adults with Untreated and Relapsed/Refractory Acute Lymphoblastic Leukemia

A Multicenter Phase I Study Combining Venetoclax with Mini-Hyper-CVD in Older Adults with Untreated and Relapsed/Refractory Acute Lymphoblastic Leukemia

Phase I Study of Escalating Doses of Carfilzomib with Hyper-CVAD in Patients with Newly Diagnosed Acute Lymphoblastic Leukemia/Lymphoma

Introduction: Outcomes remain poor for adults with acute lymphoblastic leukemia (ALL). Hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (Hyper-CVAD) is a high intensity chemotherapy regimen that results in high complete remission (CR) rates and long-term survival in 30-40% of adults with ALL. Approximately 50% of patients achieve measurable/minimal residual disease (MRD) negativity after Hyper-CVAD therapy. Bortezomib, the first proteasome inhibitor, showed potentially synergistic activity in relapsed ALL in combination with chemotherapy. Carfilzomib is a next-generation irreversible proteasome inhibitor with increased specificity and potency compared to bortezomib and with significant activity in multiple myeloma. Therefore, we hypothesized that the addition of carfilzomib to Hyper-CVAD would be safe and could improve outcomes for adults with ALL by increasing the rate of MRD negativity. Methods: The primary objectives of this phase I study (NCT02293109) were to determine safety, tolerability, and recommended phase two dose of carfilzomib added to Hyper-CVAD in patients with newly diagnosed, untreated Philadelphia chromosome negative ALL. The secondary objectives were to determine rate of CR and MRD negativity. Time-to-event analyses were not planned. Patients were aged 18-65 with adequate left ventricular, renal, and liver function and Eastern Cooperative Group Performance Status of 0-2. Patients received four 28-day cycles of standard Hyper-CVAD (i.e. two courses each of Part A and Part B) with the addition of 4 doses of carfilzomib on days 0, 1, 7 and 8 of each of the four cycles. Rituximab was added for patients with CD20 positive disease. After completing study mandated carfilzomib plus Hyper-CVAD, patients continued standard Hyper-CVAD therapy. Dose escalation used a standard 3+3 design with carfilzomib dose levels (DL) of 20mg/m2 (DL1), 27mg/m2 (DL2) and 36mg/m2 (DL3). Dose-limiting toxicities (DTLs) were assessed through completion of one A and one B cycle. Patients not evaluable for DLT were replaced. Adverse events (AEs) were graded using NCI Common Terminology for Adverse Events version 4.03. MRD was tested by multiparameter flow cytometry (MFC) and <0.01% was considered negative. Patients were followed for up to 28 days after completion of therapy. Results: Ten patients were enrolled into DL1 (n=3), DL2 (n=3), and DL3 (n=4). Median age was 38 [range 23-61]. Fifty percent (n=5) were female, and 60% (n=6) were Hispanic. Eighty percent (n=8) had B-ALL, and 20% (n=2) had T-ALL. Fifty percent (n=5) had CD20 positive disease and received rituximab. Seventy percent (n=7) had abnormal cytogenetics, including complex IgH gene rearrangements (n=4). One patient was found to have CNS involvement during standard cycle one CSF assessments. No DLTs were observed in the dose escalation cohorts. One subject was replaced during cycle one for adverse events not meeting DLT criteria. All patients experienced grade 3-4 treatment-emergent AEs at least possibly related to study therapy, including leukopenia (100%, n=10), neutropenia (100%, n=10), anemia (100%, n=10), thrombocytopenia (100%, n=10), lymphopenia (90%, n=9), and febrile neutropenia (70%, n=7) (Table 1). Serious AEs (SAEs) at least possibly related to study therapy occurred in 70% (n=7) of patients and included febrile neutropenia (60%, n=6), leukopenia (20%, n=2), and thrombocytopenia (20%, n=2). There were no grade 5 events, and no cardiac AEs apart from related grade 1 sinus tachycardia in one patient. The median number of cycles on study was four [range 1-4]. Twenty percent (n=2) of patients had a dose modification (both related to AE), and 30% (n=3) had a dose delay (two related to AE). The complete remission rate (CR) was 90% (9/10) after cycle 2 and 100% (10/10) overall (Table 2). The rate of MFC MRD negativity was 70% (7/10) after cycle 4 and 80% (8/10) overall, including 88% (7/8) for B-ALL and 50% (1/2) for T-ALL (Table 2). There were no study-related deaths. Conclusions: The addition of carfilzomib to Hyper-CVAD is safe and tolerable in patients with untreated ALL. No DLTs were observed with carfilzomib doses up to 36mg/m2. The combination shows promising preliminary efficacy with high rates of MRD negative CR compared to historical controls receiving standard Hyper-CVAD. The regimen may be more active in B-ALL. These results support further study of Hyper-CVAD plus carfilzomib in ALL. Disclosures Jonas: AbbVie, Amgen, GlycoMimetics: Other: Travel expenses; AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding. Tuscano:Abbvie: Research Funding; Takada: Research Funding; Amgen: Honoraria; Seattle Genetics: Honoraria; Genentech: Research Funding; Pharmacyclics: Research Funding; Spectrum: Research Funding; Celgene: Honoraria, Research Funding; Novartis: Research Funding. Rosenberg:Amgen: Consultancy, Research Funding. Abedi:Abbie: Speakers Bureau; Takeda: Speakers Bureau; BMS: Speakers Bureau; Gilead: Speakers Bureau; Celgene: Speakers Bureau. OffLabel Disclosure: Carfilzomib was tested for use in a prospective Phase I clinical trial.

Major Deviations in the Delivery of Induction Chemotherapy Are Associated with an Increased Risk of Relapse in Acute Lymphoblastic Leukaemia: Results from UKALL2003

Introduction As survival rates for acute lymphoblastic leukaemia (ALL) in children and young people improve, the need to understand and mitigate toxicity becomes increasingly important. The contribution of toxicity to mortality or significant morbidity is well described. However, the impact of dose reductions, drug omissions or delays in treatment which result from toxicity is poorly understood, other than the established association between effective count suppression during maintenance chemotherapy and a reduction in relapse rate. We report the significance of treatment delays and dose reductions in induction chemotherapy in the UKALL2003 trial. Methods UKALL2003 was a prospective multicenter phase 3 study recruiting patients aged 1-24 years with newly diagnosed Philadelphia chromosome negative ALL in the UK. Data regarding 4 different protocol deviations were prospectively collected at the end of each block of therapy; a) not given allocated regimen, b) <90% of one or more of the protocol drugs administered, c) change of Asparaginase product and d) delay of > 1 week in commencing the next treatment block. Univariable (UVA) and Multivariable (MVA) Cox regression was used to assess the association of each deviation with risk of relapse. To control for immortality bias, this was assessed at the end of each therapy block with only patients alive and relapse free at the end of the block included in the analysis. Patients with Down Syndrome were excluded from all analyses. Results Of 2991 patients without Down Syndrome completing induction chemotherapy, 9 patients did not receive the allocated regimen, 1558 patients received <90% of one or more drugs, 9 patients were switched to an alternative Asparaginase product and 72 had a greater than 1 week delay in commencing consolidation. On UVA, reduction of >90% of one or more drugs and delay of greater than 1 week was significantly associated with an increased risk of relapse with hazard ratios of 1.70 (95% CI 1.11 - 2.60, p=0.014) and 1.99 (95% CI 1.14 - 3.48, p=0.013) respectively. On MVA (complete cases, n=2464), including other factors of established prognostic significance, both deviations remained significantly associated with an increased risk of relapse (Table 1). The impact of a major deviation (defined here as dose reduction of >90% of one or more drugs or treatment delay of >1week) was seen in both the paediatric (<16 years) and older (16-24 years) groups with a slightly larger effect in the older group (HRs 1.73 and 2.40 respectively), though the interaction between age and deviation was not significant (p=0.49)( Figure 1). Patients with dose omissions >90% of one or more drugs in induction were also more likely to have major deviations in subsequent blocks of therapy (p<0.001) and remained at significantly higher risk of relapse when starting the maintenance phase of treatment (n=2343, HR: 1.81 (1.06 - 3.09, p = 0.03). Conclusion Major deviations in the delivery of induction chemotherapy on UKALL2003 were significantly associated with a greater risk of further deviations in subsequent blocks of therapy and a higher risk of relapse. Further improvement in efficacy of ALL therapy in children and young people will require a greater understanding of which toxicities lead to major deviations in therapy and strategies developed to mitigate these risks. Disclosures Rowntree: Novartis: Consultancy.

Turkish Acute Lymphoblastic Leukemia Registry, Retrospective Phase Data

Background and Aim: Significant developments have occurred in clinical management of acute lymphoblastic leukemia (ALL) in adults over recent decades. However, treatment results are still not satisfactory especially in routine practice. The aim of the study was to evaluate the general clinical features, treatment details and outcomes of a large group of patients followed up in multiple centers in Turkey with a diagnosis of ALL. Materials and Methods: A retrospective analysis of the data of patients with ALL was made, which are diagnosed and treated between January 2003 and June 2017 by different protocols in hematology clinics of ten different centers. A total of 288 patients, aged between 17 and 76 years old were included in the study. In this retrospective, multicenter analysis of patients with ALL, classification of patients was done by treatment period, Philadelphia chromosome positivity, treatment regimen and receiving allogeneic hematopoietic stem cell transplantation (alloHSCT). Results: The majority of cases were B-cell in origin, 224 patients were B-ALL and 64 of the patients were T-ALL (Table 1). Median follow-up duration for all patients was 18.2 months (range, 0.03-161.0 months). After induction chemotherapy, 219 patients (76.0%) achieved complete remission, 32 patients were evaluated as treatment refractory (11.2%), and 37 patients (12.8%) deceased. Median OS was 47.7 months (95% CI: 36.1-59.2) and median DFS was 23.4 months (95% CI: 6.7-40.0) for all patients. The 3-year OS and DFS rates were 56% and 45%, respectively. The 5-year OS and DFS rates were 43% and 35%, respectively. Median OS was 33.9 months (95% CI: 17.4-50.3) in Ph+ ALL patients and 73.7 months (95% CI: 33.9-113.5) in Ph chromosome-negative (Ph-) ALL patients (p=0.48). Median DFS was 7.1 months (95% CI: 5.0-9.3) in Ph+ ALL patients and 34.6 months (95% CI: 16.0-53.2) in Ph-ALL patients. DFS was statistically significant longer in Ph- patients than Ph+ patients, (p=0.008). The 5-year OS was 50% in Ph- patients and 16% in Ph+ patients, respectively. The 5-year DFS was 35% in Ph- patients and 11% in Ph+ patients, respectively (Figure 1). Median OS was 53.4 months (95% CI: 37.9-63.5) in patients receiving the pediatric regimen and 42.9 months (95% CI: 19.9-66.6) in patients receiving other intensive regimens (p=0.05). Median DFS was 16.9 months (95% CI: 3.9-23.6) in patients receiving the pediatric regimen and 13.3 months (95% CI: 6.5-20) in patients receiving other intensive regimens (p=0.78). The 5-year OS was 45% in patients who received the pediatric regimen and 43% in patients who received other intensive regimens. The 5-year DFS was 23% in patients who received the pediatric regimen and 25% in patients who received other intensive regimens (Figure 2). The 2-year periods between 2003 and 2017 for treatment regimens are shown in (Figure 3). From 2003 to 2017, the usage of pediatric regimens increased in ALL patients. The count of patients diagnosed with ALL and the treatment protocols used were observed to vary over time. While adult intensive regimens were used more common in the past, there is a tendency to use pediatric regimens in present time. Conclusion: In conclusion, multicenter studies are of great importance for defining the specific clinical features of a particular disease. The results of this study will make a significant contribution to the literature as they reflect real life data providing valuable information about the Turkish ALL patient profile. Disclosures No relevant conflicts of interest to declare.

Efficacy and toxicity of reduced vs. standard dose pegylated asparaginase in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia

Incorporation of asparaginase (ASNase) and pegylated asparaginase (PEG-ASP) into pediatric-inspired regimens for adults with acute lymphoblastic leukemia (ALL) has led to improved treatment outcomes albeit with increased toxicities. This study compared the efficacy and safety of the Children’s Oncology Group standard PEG-ASP (SD) dosing (>1000, median 2500 IU/m2/dose) in adult Philadelphia chromosome-negative ALL patients receiving multiagent chemotherapy vs reduced dose PEG-ASP (RED) (≤1000, median 500 IU/m2/dose) during induction. 51 patients were included, 26 in RED and 25 in SD (median age 49 vs 37 years, p = .027). Median day 7 ASNase activity level for RED was 0.16 IU/mL. All 11 patients who received PEG-ASP 1000 IU/m2 and 9/11 patients who received 500 IU/m2 achieved an ASNase level ≥0.1 IU/mL. Patients receiving RED experienced fewer total grade 3/4 toxicities during induction compared to SD (p = .02) while still attaining therapeutic ASNase levels. RED permits safer ASNase use in adults with ALL and should be tested in a larger cohort prospectively.

Minimal residual disease in adults with Philadelphia chromosome negative acute lymphoblastic leukemia in high-risk

目的探讨高危Ph阴性急性淋巴细胞白血病（Ph−ALL）中微小残留病（MRD）对预后和治疗策略的影响。方法回顾性分析2008年1月1日至2017年12月31日收治的初治成人高危Ph−ALL并获得完全缓解（CR）患者的临床资料，通过Cox回归模型和Landmark分析，寻找预后相关因素。结果177例患者纳入研究，其中男性99例（56%），中位年龄40（16~65）岁，95例（54%）在第1次完全缓解（CR1）后接受异基因造血干细胞移植（移植组）。多因素分析显示，巩固治疗1个疗程后MRD阴性（HR=0.52，95%CI 0.30~0.89，P=0.017）、诱导化疗4周达到CR（HR=0.43，95%CI 0.24~0.79，P=0.006）是影响患者无病生存（DFS）的有利因素，CR1移植是影响患者DFS（HR=0.13，95%CI 0.08~0.22，P<0.001）和总生存（OS）（HR=0.24，95%CI 0.15~0.41，P<0.001）的共同有利因素。121例患者进入Landmark分析，在巩固治疗1个疗程后MRD阴性的85例患者中进行多因素分析显示，巩固治疗3个疗程后MRD阴性是影响患者DFS（HR=0.18，95%CI 0.05~0.64，P=0.008）和OS（HR=0.14，95%CI 0.04~0.50，P=0.003）的有利因素。在巩固治疗1个疗程和3个疗程后MRD均阴性的患者中，移植组患者3年DFS率有高于化疗组的趋势（75.2%对51.3%，P=0.082），但3年OS率相近（72.7%对68.7%，P=0.992）。巩固治疗1个疗程和3个疗程后MRD至少1次阳性的患者中，移植组的3年DFS率（64.8%对33.3%，P=0.006）和3年OS率（77.0%对33.3%，P=0.028）均显著高于化疗组，与这两个时间点MRD均阴性的移植患者的预后差异无统计学意义（P>0.05）。结论在高危成人Ph−ALL患者中，巩固治疗1个疗程后MRD阴性是预后良好的独立影响因素。巩固治疗1个疗程和3个疗程MRD均阴性的患者，接受移植或化疗的生存率相似。移植显著改善了巩固治疗1个疗程和3个疗程后MRD至少一次阳性患者的预后。

Prognostic impact of cytogenetic abnormalities in adult patients with Philadelphia chromosome-negative ALL who underwent an allogeneic transplant.

Although cytogenetic abnormalities at diagnosis are recognized as an important prognostic factor in patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL), the prognostic impact has not been evaluated in allogeneic stem cell transplant (allo-SCT) recipients. Thus, we assessed 373 Ph-negative ALL patients who underwent allo-SCT. The high-risk (HR) group included those with t(4;11), t(8;14), low hypodiploidy, and complex karyotype, and the standard risk (SR) group included all other karyotypes. Among the 204 patients who underwent a transplant during the first remission (167 in the SR group and 37 in the HR group), the overall survival (OS) rates were similar between these groups (64.1% vs. 80.0% at 5 years, respectively; p = 0.12). Conversely, among the 106 patients who underwent a transplant while not in remission (84 in the SR group and 22 in the HR group), patients in the SR group showed a significantly superior OS rate compared to the HR group (15.4% vs. 4.5% at 5 years, respectively; p = 0.022). These results suggested that treatment outcomes of Ph-negative ALL patients with HR cytogenetic abnormalities may improve following allo-SCT, especially in the first remission. Innovative transplant approaches are warranted in patients who are not in remission.

Improved Outcome of a Pediatric-Inspired Protocol for High-Risk Adolescent and Young Adult Acute Lymphoblastic Leukemia Patients Using Peg-Asparaginase and Escalating Dose of Methotrexate: Tolerability and Outcome

BackgroundTreatment of acute lymphoblastic leukemia (ALL) in adolescent and young adult (AYA) patients using traditional adult chemotherapy protocols give low overall survival (OS) rates. Data are growing regarding the use of pediatric-inspired chemotherapy protocols in AYA patients with improvement in OS. Patients and MethodsTo assess efficacy and tolerability of using a pediatric-inspired protocol in AYA patients, we initiated our local prospective trial using a modified version of the Children’s Cancer Group 1900 protocol for newly diagnosed high-risk Philadelphia chromosome-negative ALL patients. ResultsA total of 40 patients were enrolled in the study (from 2015 to 2018). The median age was 18 years (range, 14-34 years). The complete remission rate after induction was 37 patients [93%] and after a median follow-up of 5 years, OS, disease-free survival (DFS), and event-free survival were 75%, 72%, and 60%, respectively. Use of this protocol was well tolerated with manageable toxicities. Pegylated asparaginase was given to all patients during the induction phase and was well tolerated. ConclusionThe use of a pediatric-inspired protocol for high-risk AYA ALL patients was effective and well tolerated with improvement in OS and DFS compared with historical data using adult protocols in such populations.

Blinatumomab as a bridge to trasplantation in refractory Philadelphia chromosome negative b-cell acute lymphoblastic leukemia: a case report

Blinatumomab is a first class bispecific T-cell engager that has been shown to achieve negative minimal residual disease in patients with relapsed or refractory pre-B acute lymphoblastic leukemia after conventional chemotherapy. Nevertheless, there is little evidence about its role as an off label enhancer of cytological remission prior to stem cell transplantation (SCT). We describe the case of a patient with an excellent performance status who was allowed to undergo alogenic SCT after a single blinatumomab cycle, as well as the management of adverse events and the observed results.