Management Of Acute Lymphoblastic Leukemia Research Articles

Infections after chimeric antigen receptor (CAR)-T-cell therapy for hematologic malignancies.

Chimeric antigen receptor (CAR)-T-cell therapies have revolutionized the management of acute lymphoblastic leukemia, non-Hodgkin lymphoma, and multiple myeloma but come at the price of unique toxicities, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and long-term "on-target off-tumor" effects. All of these factors increase infection risk in an already highly immunocompromised patient population. Indeed, infectious complications represent the key determinant of non-relapse mortality after CAR-T cells. The temporal distribution of these risk factors shapes different infection patterns early versus late post-CAR-T-cell infusion. Furthermore, due to the expression of their targets on B lineage cells at different stages of differentiation, CD19, and B-cell maturation antigen (BCMA) CAR-T cells induce distinct immune deficits that could require different prevention strategies. Infection incidence is the highest during the first month post-infusion and subsequently decreases thereafter. However, infections remain relatively common even a year after infusion. Bacterial infections predominate early after CD19, while a more equal distribution between bacterial and viral causes is seen after BCMA CAR-T-cell therapy, and fungal infections are universally rare. Cytomegalovirus (CMV) and other herpesviruses are increasingly breported, but whether routine monitoring is warranted for all, or a subgroup of patients, remains to be determined. Clinical practices vary substantially between centers, and many areas of uncertainty remain, including CMV monitoring, antibacterial and antifungal prophylaxis and duration, use of immunoglobulin replacement therapy, and timing of vaccination. Risk stratification tools are available and may help distinguish between infectious and non-infectious causes of fever post-infusion and predict severe infections. These tools need prospective validation, and their integration in clinical practice needs to be systematically studied.

A new insight updates in diagnosis and management of acute lymphoblastic leukemia, cytogenetics, immunophenotyping, and proteomic profile

Acute lymphoblastic leukemia (ALL) is a severely invasive hematological cancer that results from the rapid increase and accumulation of lymphoid blasts in the blood, bone marrow (BM), and other organs. The pervasiveness of ALL has made it the prevalent childhood acute leukemia making up approximately 80% of leukemia in children and about 20% in adults. Due to the prevalence of ALL, more accurate diagnosis and prognostic methods are required. Proteome analysis uses a variety of analytical techniques, including protein sequencing, structural or expression proteomics, protein modification, sub-cellular protein localization, protein-protein interactions, and biological functional proteomics. Analysis of cell-signaling pathways and activation/deactivation are crucial to follow up the development, remission, or relapse of ALL. As a result, this review emphasizes cytogenetics and immunophenotyping while also highlighting the proteomic profile, clinical symptoms, diagnosis, and management of ALL. Also, it evaluates the procedures and techniques for the testing of bodily fluids (peripheral blood, cerebrospinal fluid, and BM) from ALL patients at various stages of disease, as well as the use of proteomic platforms in discovering sensitive and specific biomarkers for ALL.

Effectiveness and safety of CD22 and CD19 dual-targeting chimeric antigen receptor T-cell therapy in patients with relapsed or refractory B-cell malignancies: A meta-analysis.

The efficacy of CD22 or CD19 chimeric antigen receptor T (CAR-T) cells in the management of acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) was observed. Because antigen loss and lack of CAR-T-cell persistence are the leading causes of progressive disease following single-antigen targeting, we evaluated CD22/CD19 dual-targeting CAR-T-cell therapy efficacy and safety in relapsed/refractory B-cell malignancies. The Web of Science, PubMed, Cochrane, and Embase databases were searched until July 2022. Patients confirmed with any relapsed/refractory B-cell hematological malignancies were included regardless of age, gender, or ethnicity, receiving CD22 and CD19-dual-targeting CAR-T-cell therapy. The studies conducted on patients with coexisting other cancer were excluded. We used random-effect models to explore the outcome, and heterogeneity was investigated by subgroup analysis. Fourteen studies (405 patients) were included. The pooled overall response (OR) and complete remission (CR) were 97% and 93%, respectively, for ALL patients. The 1-year proportions of overall survival (OS) and progression-free survival (PFS) were 70% and 49%, respectively. For NHL, OR occurred in 85% of patients, and 57% experienced CR. The results illustrated that the 1-year OS and 1-year PFS were 77% and 65%, respectively. The subgroup analysis showed that the dual-targeting modality achieved higher CR in the following cases: coadministration of CD22/CD19-CAR-T cells and third-generation CAR-T cells combined with ASCT and BEAM pretreatment. The ALL and NHL groups seemed similar in treatment-related toxicity: all grade cytokine release syndrome (CRS), severe CRS, and neurotoxicity occurred in 86%, 7%, and 12% of patients, respectively. Our meta-analysis demonstrated that the CD22/CD19 dual-targeting CAR-T-cell strategy has high efficiency with tolerable adverse effects in B-cell malignancies.

Diagnosis and treatment of acute lymphoblastic leukemia in Latin America

ABSTRACT Objective to discuss the status and challenges associated with the management of acute lymphoblastic leukemia (ALL) in Latin America. Methods This review summarizes various insights gained from information regarding diagnostic approaches and treatment strategies in adult patients with ALL in Latin American Countries. Results Information regarding ALL in Latin America is scarce; however, many efforts have been made to overcomes these barriers. Nevertheless, major obstacles to successful treatment in Latin America and LMIC remain poor adherence, abandonment of treatment, and lack of supportive therapy and new therapeutic agents. Conclusion Further improvements in survival should be pursued by developing more Latin American registries, forming cooperative groups, developing educational models to facilitate earlier diagnosis and prevention of complications, better support therapy and management of infections, and adapting treatment strategies.

Innovative Approaches to the Management of Acute Lymphoblastic Leukemia Across the Age Spectrum.

Adults compose nearly half of all patients diagnosed with acute lymphoblastic leukemia (ALL) and historically have had poor survival compared with pediatric patients. Recently approved therapies, such as monoclonal antibodies, CAR T-cell constructs, and next-generation tyrosine kinase inhibitors, have improved survival in relapsed and refractory ALL, and studies are now examining incorporating these treatments and others into the upfront setting. In adolescent and young adult patients, use of pediatric-based regimens has already improved survival compared with historical controls, and the addition of monoclonal antibodies, such as inotuzumab ozogamicin and blinatumomab, may further enhance this survival benefit. In older adults, approaches have centered on minimizing conventional chemotherapy to decrease toxicity by incorporating monoclonal antibodies and other novel therapies to increase efficacy. With the addition of tyrosine kinase inhibitors to chemotherapy for patients with Philadelphia chromosome-positive ALL, survival of this once poor-prognosis ALL subtype now approaches or exceeds outcomes of other subtypes of adult ALL. Further refinements in the backbone treatment regimen and optimal consolidation approaches will likely improve survival further. Although allogeneic hematopoietic stem cell transplant was previously routinely used as consolidation for adults with ALL, incorporation of measurable residual disease and other risk stratification strategies has enabled better identification of patients who will benefit from allogeneic hematopoietic stem cell transplant. Ongoing clinical trials investigating these approaches will continue the evolution of treatment approaches for adults with ALL, with further improvement in outcomes anticipated.

The Promise of Single-cell Technology in Providing New Insights Into the Molecular Heterogeneity and Management of Acute Lymphoblastic Leukemia.

Drug resistance and treatment failure in pediatric acute lymphoblastic leukemia (ALL) are in part driven by tumor heterogeneity and clonal evolution. Although bulk tumor genomic analyses have provided some insight into these processes, single-cell sequencing has emerged as a powerful technique to profile individual cells in unprecedented detail. Since the introduction of single-cell RNA sequencing, we now have the capability to capture not only transcriptomic, but also genomic, epigenetic, and proteomic variation between single cells separately and in combination. This rapidly evolving field has the potential to transform our understanding of the fundamental biology of pediatric ALL and guide the management of ALL patients to improve their clinical outcome. Here, we discuss the impact single-cell sequencing has had on our understanding of tumor heterogeneity and clonal evolution in ALL and provide examples of how single-cell technology can be integrated into the clinic to inform treatment decisions for children with high-risk disease.

Chimeric antigen receptor T cell: A cancer immunotherapy.

During present decade, targeted drug therapy has been the epitome for treatment of cancer. Drugs like Imatinib, a tyrosine kinase receptor inhibitor and Trastuzumab, an human epidermal growth factor receptor-2/neu inhibitor, has been developed and accepted widely for management of chronic myeloid leukaemia and breast cancer respectively. Recent development among the various immunotherapies is adoptive cell transfer (ACT). Research on development of various types of ACT immunotherapy is going on, but so far, Chimeric antigen receptors T cell therapy (CAR-T) has achieved the maximum advancement in terms of clinical development. CARs are the modified receptors that integrates specificity and responsiveness onto immune cells to enhance the recognition of cancer cells. For the CAR-T, the T cells are sequestered from a blood of a participant via apheresis. DNA of particular antigen is injected into harvested T cells to generate CARs on cell surface. Following surface manifestation of receptors, multiplication is carried out in enriched media followed by infusion into patient. After infusion, CAR-T cells targeted and exterminate the cancer cells. Initially, only two drugs targeting CD19 as genetically modified autologous immunotherapy has been approved in CAR-T therapy i.e., Tisagenlecleucel and Axicabtagene Ciloleucel, which are discussed in detail in current review. Recently two more drugs got approval i.e., brexucabtagene ciloleucel and lisocabtagene maraleucel, both are directed against CD19, similar to tisagenlecleucel. CAR-T cell therapy is approved for management of Acute Lymphoblastic Leukaemia, Chronic Lymphocytic Leukaemia and lymphoma. CAR-T cell persistence responsible for effectiveness and safety concerns are barriers for their wide application among patients. Growth factor receptors and cluster of differentiation are new drugs targets that are being explored as effective immunotherapy against cancers.

MRD in adult Ph/BCR-ABL-negative ALL: how best to eradicate?

Evaluation of minimal residual disease (MRD) during first-line treatment and after salvage therapy is part of the standard management of acute lymphoblastic leukemia (ALL). Persistent or recurrent MRD is one of the most relevant prognostic factors and identifies a group of patients with resistance to standard chemotherapy. These patients have a high risk of relapse despite continued first-line therapy. Although stem cell transplantation (SCT) is an appropriate strategy, patients with high MRD show an increased relapse rate even after SCT. Approximately one-quarter of adult ALL patients develop an MRD failure, defined as MRD above 0.01% after standard induction and consolidation. The best time point and level of MRD for treatment modification are matters of debate. In order to eradicate MRD and thereby improve chances for a cure, new targeted compounds with different mechanisms of action compared to chemotherapy are being utilized. These compounds include monoclonal antibodies, chimeric antigen receptor T cells, and molecular targeted compounds. Essential factors for decision-making, available compounds, and follow-up therapies are discussed.

ACUTE Lymphoblastic Leukemia (ALL) and COVID-19 Infection. a Campus ALL Report

▪Introduction. The recent spread of the COVID-19 infection has represented an important challenge in the management of acute lymphoblastic leukemia (ALL) patients.Aims and methods. To investigate the incidence, features, source of contagion and outcome of patients with ALL who developed a COVID-19 infection, a survey was conducted among 34 hematology centers throughout Italy within the Campus ALL network. The period covered by the survey spanned from February 2020 to April 2021 and included 756 adult ALL patients actively followed during this time period.Results. Sixty-three of the 756 ALL patients (8.3%) developed a COVID-19 infection, with an equal distribution among the various regions. The majority of cases (90.5%) was recorded during the second wave of the pandemic, between September 2020 and April 2021. The source of the infection was nosocomial in 26 cases (41.3%), familial in 23 (36.5%), unknown in 13 (20.6%) and work-related in 1 (1.6%).The infected patients were prevalently male (n=43, 68.2%) with a similar distribution among age groups: 21 patients aged 18-35 years, 17 35-50, 15 50-65 and 10 older than 65. Seventeen patients (27%) had a diagnosis of T-ALL, 28 (44.4%) of Ph- B-ALL and 18 (28.6%) of Ph+ ALL. Thirty-six (57.1%) of the infected patients had no concomitant comorbidities, whereas 27 (42.9%) had one or more comorbidities.The infection was documented at the onset of the disease in 4 patients (6.3%), during induction in 10 (15.9%), consolidation in 13 (20.6%), chemotherapy maintenance in 11 (17.5%), after allogenic transplant in 15 (23.8%), during maintenance with tyrosine kinase inhibitors (TKI) treatment or off-treatment in 8 (12.7%) and at relapse in 2 (3.2%). Of the infected patients, 9 were asymptomatic, 10 had only isolated fever, 36 had respiratory symptoms and 8 presented other symptoms, including - but not limited to - ageusia and anosmia. As a consequence, management of the infection was variable: 29 (46%) patients did not require hospitalization, 28 (44.4%) were hospitalized in a COVID ward and 13 of them required respiratory assistance; finally, 6 (9.5%) patients were transferred to an ICU. Importantly, in 54 patients (85.7%) there were no sequelae, in 1 patient a pulmonary fibrosis was documented and in 1 patient the delay in treatment led to a relapse of the disease, while 7 (11.1%) succumbed to the infection. Finally, in 6 cases (9.5%) the infection was still ongoing at the time of the survey, and at the last update (July 2021) it had resolved in all. Since a key aspect in the management of ALL is the adherence to the timing of treatment, we also investigated if COVID-19+ patients stopped treatment during the infection. Out of the 42 evaluable patients (patients who had undergone an allogeneic transplant or were off-treatment were excluded from this analysis), ALL treatment was suspended in 28 (66.6%). Importantly, while in Ph+ ALL only very few patients stopped treatment (3/12), in Ph- B-ALL the majority did interrupt it (18/22, p<0.001); likewise, also in T-ALL most patients suspended treatment (7/8).Conclusions. The incidence of SARS-CoV-2 infection in adult ALL patients in Italy over a 15 month period has been similar to that observed in the general population and has been recorded mostly during the second wave of the pandemic. The contagion was mainly nosocomial, suggesting that outward care should be pursued as much as possible in ALL. The infection was manageable, with 46% of patients not requiring any medical intervention and an overall death rate of 11%. Strikingly, in line with previous reports 1, it appears that Ph+ ALL patients were more manageable, with less treatment interruptions. These findings underline the advantage of the TKI-based induction/consolidation strategy without systemic chemotherapy in Ph+ ALL used in the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) protocols and further point to a possible protective role of TKIs in COVID-19-infected patients.1.Foà R et al, Br J Haematol. 2020;190(1):e3-e5 DisclosuresChiaretti: Incyte: Consultancy; novartis: Consultancy; pfizer: Consultancy; amgen: Consultancy. Bonifacio: Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Marco: Jazz: Consultancy; Insight,: Consultancy; Janssen: Consultancy. Curti: Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. Delia: Gilead: Consultancy; Amgen: Consultancy; abbvie: Consultancy; Jazz pharmaceuticals: Consultancy. Forghieri: Jannsen: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Jazz: Honoraria. Lussana: Amgen: Honoraria; Astellas Pharma: Honoraria; Pfizer: Honoraria; Incyte: Honoraria.

Concordance of peripheral blood and bone marrow measurable residual disease in adult acute lymphoblastic leukemia

AbstractMonitoring of measurable residual disease (MRD) is essential to the management of acute lymphoblastic leukemia (ALL) and is typically performed through repeated bone marrow (BM) assessments. Using a next-generation sequencing (NGS) MRD platform, we performed a prospective observational study evaluating the correlation between peripheral blood (PB) and BM MRD in adults with ALL receiving cellular therapies (hematopoietic cell transplantation [HCT] and chimeric antigen receptor T-cell [CAR-T] therapies). Among the study cohort (N = 69 patients; 126 paired PB/BM samples), we found strong correlation between PB and BM MRD (r = 0.87; P < .001), with a sensitivity and specificity of MRD detection in the PB of 87% and 90%, respectively, relative to MRD in the BM. MRD became detectable in the PB in 100% of patients who subsequently relapsed following HCT, with median time from MRD+ to clinical relapse of 90 days, and in 85% of patients who relapsed following CAR T, with median time from MRD+ to clinical relapse of 60 days. In adult patients with ALL undergoing cellular therapies, we demonstrate strong concordance between NGS-based MRD detected in the PB and BM. Monitoring of ALL MRD in the PB appears to be an adequate alternative to frequent invasive BM evaluations in this clinical setting.

High-dose methotrexate: Treatment experience in patient with B-cell philadelphia-positive acute lymphoblastic leukemia

High-dose methotrexate (HDMTX) is gaining importance in the management of acute lymphoblastic leukemia (ALL). Its efficacy and toxicity depends on dose strength, route of administration, and infusion time. HDMTX toxicities can be controlled by continuous monitoring of urine pH and adequate supportive care (hyper-hydration, alkalinizing agents, and leucovorin rescue). A patient suffering from B cell Ph + ALL was kept on Berlin-Frankfurt-Munster-90 protocol and administered methotrexate 8 g/cycle by intravenous infusion with normal saline over 6 h. He developed leucopenia and severe anemia after receiving the first cycle of chemotherapy, which was treated with subcutaneous filgrastim 300 mcg OD for 5 days and 1 pint red blood cell. After the third cycle, patient developed mucositis and treated with leucovorin and local anesthetics; and continued the chemotherapy. In conclusion, the patient was continuously monitored for urine pH and tolerated the HDMTX well when provided adequate supportive care.

Monitoring Measurable Residual Disease Using Peripheral Blood in Acute Lymphoblastic Leukemia: Results of a Prospective, Observational Study

Monitoring Measurable Residual Disease Using Peripheral Blood in Acute Lymphoblastic Leukemia: Results of a Prospective, Observational Study

Randomized, Parallel Group, Open-Label Bioequivalence Trial of Intramuscular Pegaspargase in Patients With Relapsed Acute Lymphoblastic Leukemia.

PURPOSEPegylated asparaginase is comparatively safer than native asparaginase in the management of acute lymphoblastic leukemia (ALL). However, the high price and nonavailability in low- and middle-income countries limits its use. In 2014, the first generic of pegaspargase (Hamsyl) was approved in India for use as a second-line treatment option for ALL. The aim of this study was to assess whether the generic pegaspargase (the test product) was bioequivalent with the reference product (Oncaspar).PATIENTS AND METHODSThis study was an open-label, parallel-group, comparative pharmacokinetic study in pediatric patients with relapsed ALL receiving their first dose (1,000 IU/m2) of pegaspargase administered intramuscularly. Patients were randomly assigned 1-to-1 to either the test or the reference product. The 2 formulations were considered equivalent if the 90% CIs for area under the plasma asparaginase activity–time curve (AUC0-t) geometric mean test-to-reference ratio was within 75% to 133%.RESULTSTwenty-nine patients (6-18 years of age) were enrolled in this study, of whom 24 completed the study criteria and were considered for safety analysis (5 patients were ineligible for the assessment). Three patients were excluded from analysis, because of presence of anti-asparaginase antibodies, leaving 21 patients who were considered for bioequivalence pharmacokinetics data. The point estimate of AUC0-t for the test-to-reference ratio was 95.05 (90% CI, 75.07% to 120.33%). Maximum plasma concentration, trough concentrations (day 14), half-life, volume of distribution, drug clearance, and changes in the asparagine and glutamine levels were not significantly different between products. Adverse events were comparable in both groups.CONCLUSIONGeneric and reference pegaspargase had equivalent pharmacokinetics with comparable safety. This could be a safe and cost-effective alternative for patients with ALL, especially in low- and middle-income countries.

Recent Advances in the Management of Acute Lymphoblastic Leukaemia.

The last few years have seen unprecedented advances in treatment options for patients diagnosed with acute lymphoblastic leukaemia (ALL) in adulthood. New targeted drug therapies have been shown in randomised trials to offer significant survival improvements above standard-of-care (SoC) for relapsed disease, whilst being relatively well tolerated. Chimeric antigen receptor T cell therapy (CAR-T) has offered spectacular promise amongst the young adult population, with the possibility of cure for refractory disease. It has reversed the paradigm that transplant is the only curative option at relapse. Data is awaited regarding its effectiveness in the older adult population. Nelarabine represents an advance, but there remains a pressing need to develop new therapies with efficacy against T-ALL, especially in the relapse setting.Outcomes for younger adults have improved with the adoption of paediatric-like regimens, with a focus on dose intensity and heavy use of pegylated asparaginase. Defining who falls into the "young adult" category and would benefit from this approach remains a controversial area. In elderly patients with ALL, the introduction of tyrosine kinase inhibitors (TKIs) and reduction in standard chemotherapy intensity (especially for those with Philadelphia-positive disease) have significantly reduced treatment-associated mortality and resulted in durable remissions with good quality of life.Bone marrow transplantation remains a key therapy in adult ALL, and is still the treatment of choice for relapsed disease. The mortality associated with a myeloablative approach can be substantially lowered by reduced intensity conditioning, without an apparently significant reduction in efficacy.

Linfoma Linfoblástico cutáneo de células precursoras B: Una presentación infrecuente de los linfomas en niños

Los linfomas linfoblásticos primarios cutáneos son una enfermedad infrecuente que ocurre predominantemente en la edad pediátrica; y se presentan con lesiones cutáneas sin enfermedad sistémica identificable al momento del diagnóstico. La enfermedad tiene un comportamiento agresivo y el tratamiento debe basarse en protocolos derivados de manejo de las leucemias linfoblásticas agudas con lo cual se ha demostrado buenas tasas de supervivencia.&#x0D; Los autores presentan el caso de una niña con un linfoma linfoblástico de células precursoras B primario cutáneo localizado en cara manejado con protocolo basado en BFM para leucemias linfoblásticas con buena evolución.

Practical guidance for the management of acute lymphoblastic leukemia in the adolescent and young adult population.

The outstanding therapeutic progress achieved with modern pediatric regimens in childhood acute lymphoblastic leukemia (ALL) led efforts to explore whether a similar treatment approach could be equally effective and safe in older patients, starting initially with older adolescents and young adults (AYA), variably defined in different studies by an age between 15–18 and 25–39 years. Several comparative and noncomparative trials of this type have been carried out during the last two decades, enrolling thousands of patients. Almost without exception, the new strategy improved patients’ outcomes compared with traditional adult treatments in B-lineage and T-lineage Philadelphia (Ph) chromosome-negative B-ALL, while the use of tyrosine kinase inhibitors (TKI) led to comparative progress in Ph+ ALL, a former high-risk subset more typically observed in older age groups. At present, highly effective pediatric-based regimens warrant 5-year survival rates of 60–70% in AYA patients. In view of these data, the same approach was progressively extended to older patients, improving the results up to 55 years of age. Issues of treatment compliance and drug-related toxicity have thus far prevented a comparable therapeutic advancement in patients aged >55 years. This critical review updates and summarizes with pertinent examples this global, positive therapeutic change, and examines how to promote further progress with new targeted therapies that include novel immuno-therapeutics and other agents developed against the many molecular dysfunctions detectable in various ALL subsets. Substantial progress is expected to occur soon, bringing AYA survival figures very close to that of children, and also to improve the outcome of ALL at all ages.

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.

A Retrospective Review of Mercaptopurine Metabolism Reveals High Rate of Patients with Suboptimal Metabolites Successfully Corrected with Allopurinol

Introduction: 6-Mercaptopurine (6-MP) is the most frequently used chemotherapy agent in the management of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL). Skewed drug metabolism can decrease the effectiveness of 6-MP while also resulting in unnecessary toxicities. Each individual's ability to metabolize 6-MP into the desired therapeutic product, 6-thioguanine nucleotide (6-TGN), is directly opposed by the development of the hepatotoxic byproduct, 6-methyl-mercaptopurine (6-MMPN). Certain individuals, referred to as 'shunters,' preferentially generate high levels of 6-MMPN resulting in decreased production of 6-TGN. Current guidelines suggest holding or lowering 6-MP doses in the setting of toxicity. However this approach results in decreased intensity of 6-MP treatment, potentially risking an increase in disease relapse. Allopurinol, a drug used to manage hyperuricemia, can alter 6-MP metabolism to maximize 6-TGN production while reducing the hepatotoxic metabolite, 6-MMPN. Methods: We performed a single institution, IRB approved, retrospective cohort study to quantify and characterize the rate of shunters treated in our center. Chart review was conducted of ALL and LL patients treated for at least one year of maintenance therapy at our center over a 10 year period from January 1, 2009 to June 1, 2019. Incidents of hypoglycemia (glucose &lt;74), hepatic inflammation (ALT &gt;123), and hypogammaglobulinemia (IgG &lt;400) were recorded. If available, metabolite levels were collected, noting levels of 6-MMPN from 6,000 -10,000 and greater than 10,000 pmol/8 x 108 RBC. If the patient was started on allopurinol, we noted the effects of the intervention on the aforementioned lab values and their clinical course. Stata was utilized for all statistical analysis. Results: We performed a chart review on 42 eligible patients and included demographic information (Table 1). Using lab data, we documented potential markers of toxicity (Table 2). Seventy four percent of patients had a least one episode of documented hypoglycemia, and 88% had at least one episode of elevated ALT &gt; 3 times the upper limit of normal. Metabolites were checked in 66% (28/42) of our patients. 6-MMPN levels were &gt; 10,000 in 82.1% (23/28). Shunting was observed in 54% of the patients; meaning one half of the patients were eligible for allopurinol combination therapy. Allopurinol was initiated by the primary team for metabolite and laboratory derangements in 12 of 23 patients. All patients who received allopurinol had normalization of laboratory values with combined treatment. Discussion: In our population of pediatric and young adults treated for leukemia and lymphoblastic lymphoma, over half of the patients were shunters with metabolite derangements and associated signs of toxicity. Current guidelines in the Children's Oncology Group (COG) leukemia protocols recommend checking metabolites in the context of increased sensitivity to 6-MP, as in the case of TPMT and NUDT15 deficient patients, but do not specifically address the more common problem of skewed metabolism. Previous gastroenterology publications suggest there may be as many as 15% of shunters in their population of patients being prescribed 6MP. We found a much higher incidence of shunters among our leukemia population, many of whom had concurrent toxicities. The patients who received allopurinol during their treatment period showed adequate count suppression with reversal of undesired toxicities, suggesting that combination therapy may be beneficial for many more patients in the future. All of these patients remain in remission through 1 Jun 2019, the longest being 6 years post-treatment. Based on our institutional experience, we propose an algorithm for the use of allopurinol in conjunction with chemotherapy for patients with ALL or LL who have inappropriate 6-MP metabolism (Figure 1) to optimize their treatment while decreasing 6-MP associated toxicities. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Allopurinol inhibits the enzyme, xanthine oxidase, and is commonly used for prevention of tumor lysis syndrome and gout. However, it is understood that allopurinol also affects the metabolism of 6-Mercaptopurine. Allopurinol directs 6MP metabolism towards 6-TGN, the desired product, and away from 6-MMPN. 6-MMPN is associated with increased toxicity in patients. We describe in our abstract the incorporation of allopurinol therapy in many of our patients with abnormal 6-MP metabolism

PB1666 WHERE IS THE PLACE OF PET/CT IN DIAGNOSTIC IN PATIENTS WITH LYMPHOBLASTIC LYMPHOMA AND ACUTE LYMPHOBLASTIC LEUKEMIA WITH EXTRAMEDULLARY INVOLVEMENT?

Background:Positron emission tomography/computed tomography (PET/CT) is emerging as an essential diagnostic tool in characterizing suspicious neoplastic lesions and staging malignant diseases. Most studies regarding the possible role of FDG‐PET/CT in the management of acute lymphoblastic leukemia (ALL) patients are very limited. But one can suggest the high role of PET/CT in the assessment of residual lesions after chemotherapy in patients with lymphoblastic lymphoma (LBL) and ALL with extramedullary involvements.Aims:The aim of the study was to estimate the ability to accumulate 18F‐FDG radiopharmaceuticals by tumor cells in PET/CT in patients with ALL/LBL and assess the prognostic value of the PET/CT after the consolidation therapy (with or without autologous stem cell transplantation (autoSCT)) in patients with Ph‐negative ALL/LBL who received therapy according to the protocols of the Russian research group ALL‐2009/ALL‐2016.Methods:PET/CT was performed in 3 patients with different types of newly diagnosed ALL before the start of the therapy and after the end of induction. Characteristic of patients were: the first‐ male, 55 age, with BII type Ph‐negative ALL, with t(6;11) with generalized bone involvement and ossalgia; the second ‐ female, 33 age, with BII type Ph‐positive ALL, p190type of transcript without extramedullary involvement; and the third‐ female, 28 age, with TIII type ALL, with TCR A/D rearrangement, with massive mediastinal lesion, bilateral renal and ovarium involvement.PET/CT was applied in 10 patients with Ph‐negative ALL/LBL after the end of consolidation by ALL‐2009/ALL‐2016 protocols. The characterization of patients (Table): 6/4 (60%/40%) M/F, 9/1 (90%/10%) B/T type Ph‐negative ALL, 8/1/1 (80%/10%/10%) with mediastinum/lymph nodes/renal and ovarium involvements, 3/7 (30%/70%) with or without bone marrow involvement, nobody with CNS involvement, 5/5 (50%/50%) with or without autoSCT, 3/7 (30%/70%) with or without radiotherapy in consolidation.Results:The results of PET/CT in three patients with different variants of newly diagnosed ALL/LBL were analyzed and it was shown that all patients had metabolic activity of 18F‐FDG in all morphologically and immunohistochemically (immunophenotypically) confirmed lesions (SUV 3,9‐8,7).An analysis of the results of PET/CT after the consolidation therapy with/without autoSCT in patients with Ph‐negative ALL was performed, and it has shown that all patients had PET‐negative remission of the disease and MRD negative status in bone marrow by flow cytometry. With a median follow‐up of 20.5 months (from 15 to 44 months), only one patient out of 10 patients had isolated CNS relapse after 10 months of remission. In another 9 patients, with a median CR duration of 19 months (from 14 to 43 months), complete clinical and hematological remission is maintained.Summary/Conclusion:The results demonstrated that all specific lesions in ALL/LBL patients, medullary and extramedullary, were capable to accumule 18F‐FDG in PET. This fact provides opportunities for further studies of this method in assessing the completeness of remission in patients with extramedullary lesions. The value of PET/CT in ALL/LBL patients with central nervous system involvement remained unexplored. If the suggestions arising from this report are confirmed, FDG‐PET/CT may be included in future clinical practice for disease staging, evaluating the response to the chemotherapy in identified lesions and in the restaging for recurrence of extramedullary disease.image

Acute lymphoblastic leukemia in routine practice: A Turkish multicenter study

Objective:Significant developments occurred in the clinical management of acute lymphoblastic leukemia (ALL) in adults in recent decades. However, treatment results are still not satisfactory, especially in routine practice. The objective of this study was to evaluate the general clinical features, treatment details, and outcomes of a large group of patients followed 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, the patients having been diagnosed and treated between January 2003 and June 2017 by different protocols in the 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 performed based on treatment period, Philadelphia chromosome positivity, treatment regimen, and administration of allogeneic hematopoietic stem cell transplantation (allo-HSCT).Results:The majority of cases were B-cell in origin, while 224 patients had B-ALL and 64 of the patients had T-ALL. Median follow-up duration for all patients was 18.2 months (range: 0.03-161 months). Philadelphia chromosome positivity was determined in 49 patients (21.9%), and 54 patients (18.8%) were receiving allo-HSCT. After induction chemotherapy, 219 patients (76.0%) achieved complete remission, 32 patients (11.2%) were evaluated as treatment refractory, and 37 patients (12.8%) were deceased. Median overall survival was 47.7 months (95% confidence interval: 36.1-59.2) and median disease-free survival was 23.4 months (95% confidence interval: 6.7-40.0) for all patients.Conclusion:Multicenter studies are extremely important 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.