Intensive Chemotherapy Protocols Research Articles

A reduction in tumor volume exceeding 65% predicts a good histological response to neoadjuvant chemotherapy in patients with Ewing sarcoma.

No consensus exists for tumor volume response criteria in patients with Ewing sarcoma. This study aimed to identify an optimal cutoff for predicting a good histological response by analyzing tumor volume changes and tumor necrosis after neoadjuvant chemotherapy. We performed a retrospective analysis of 184 Ewing sarcoma patients, analyzing tumor volume changes before and after neoadjuvant chemotherapy. Patients were divided into two groups based on histological response: good (tumor necrosis ≥ 95%) and poor (tumor necrosis < 95%) responders. The receiver operating characteristic (ROC) area under the curve (AUC) method was used to determine the optimal thresholds for predicting the histological response. Additionally, the prognostic value of this cutoff for relapse-free survival was assessed. Out of 184 patients, 83 (45%) had tumor necrosis ≥ 95%, while 101 (55%) had tumor necrosis < 95%. ROC analysis identified the optimal cutoff for a good histological response as over 65% tumor volume reduction (AUC = 0.69; p < 0.001). Patients with volume reduction of ≥ 65% had a higher likelihood of a good histological response than those with lesser reductions (p = 0.004; odds ratio = 2.61). Multivariable analysis indicated a correlation between poor histological response and reduced relapse-free survival (hazard ratio = 2.17; p = 0.01), while tumor volume reduction itself did not impact survival. We reported that a tumor volume reduction of ≥ 65% was able to predict a good histological response in Ewing sarcoma patients. We recommend preoperative tumor volume assessment to identify patients at greater risk for poor histological response who could benefit from more intensive chemotherapy protocols or additional radiotherapy.

Concanavalin A staining: a potential biomarker to predict cytarabine sensitivity in acute myeloid leukemia

Acute myeloid leukemia (AML) is a cancer of the myeloid lineage of blood cells, with an overall 5-year survival rate of 25%, mainly due to therapy-resistant relapses in &amp;gt; 50% of patients. The standard treatment for AML comprises cytarabine (AraC) with anthracyclines. Biomarkers to determine AraC sensitivity are currently lacking, thus hampering the rational choice of optimal treatment protocols, which would be especially warranted in the case of primary refractory disease. In the current study, we hypothesized that AraC-resistant AML cells harbor a different “sugar decoration”, i.e., glycosylation profile, compared with sensitive cells, which could be used as biomarker for AraC sensitivity. Therefore, we analyzed the expression of glycosylation-related genes in publicly available AML datasets, whereby the high expression of mannosylation-related genes (6 out of 13) was significantly associated with a worse survival in patients treated with AraC-based intensive chemotherapy protocols. In line with these data, the AraC-resistant AML cells expressed higher levels of high mannose N-glycans, as detected by mass spectrometry-based glycomics. Concanavalin A (ConA), a lectin that specifically recognizes α-mannoses in N-glycans, bound more strongly to AraC-resistant cells, and the extent of the ConA binding was correlated with AraC sensitivity in a panel of AML cell lines. Furthermore, the ConA staining could discriminate AraC sensitivity in vitro between two patient-derived AML samples taken at diagnosis. Therefore, the ConA staining may be a potential novel biomarker to predict AraC sensitivity in AML.

Intensive chemotherapy with dual induction and ALL-like consolidation for childhood acute myeloid leukemia: a respective report from multiple centers in China.

Pediatric acute myeloid leukemia (AML) has poor prognosis and high rate of relapse and mortality, and exploration of new treatment options is still critically needed. To summarize the outcome of our new treatment strategies for pediatric AML, which is characterized by dual induction and acute lymphoblastic leukemia (ALL) elements consolidation. Retrospective, single-arm study. From July 2012 to December 2019, an intensive chemotherapy protocol was used for newly diagnosed children with AML, which contains dual induction, three courses of consolidations based on high-dose cytarabine, and two courses of consolidations composed of high-dose methotrexate, vincristine, asparaginase, and mercaptopurine (ALL-like elements). Blasts were monitored by bone marrow smears at intervals, and two lumbar punctures were performed during chemotherapy. We retrospectively analyzed the efficacy and safety of this study. The last follow-up was on 26 May 2023. A total of 70 pediatric AMLs were included. The median age at diagnosis was 6.7 (0.5-16.0) years. The median initial WBC count was 23.74 × 109/L, 11 of whom ⩾100 × 109/L. After dual induction, there were 62 cases of complete remission (CR), 5 cases of partial remission, and 3 cases of nonremission. The CR rate was 88.57%. The median follow-up time was 5.8 (0.2-9.4) years, the 5-year overall survival was 78.2% ± 5%, the event-free survival (EFS) was 71.2% ± 5.6%, and the cumulative recurrence rate was 27.75%. The 5-year EFS of patients with initial WBC < 100 × 109/L (n = 59) and ⩾100 × 109/L (n = 11) were 76.4% ± 5.7% and 45.5% ± 15% (p = 0.013), respectively. A total of 650 hospital infections occurred. The main causes of infection were respiratory tract infection (26.92%), septicemia (18.46%), stomatitis (11.85%), and skin and soft-tissue infection (10.46%). This intensive treatment protocol with dual induction and ALL-like elements is effective and safe for childhood AML. Initial WBC ⩾ 100 × 109/L was the only independent risk factor in this cohort. It is a retrospective study, and no registration on ClinicalTrials.gov.

Initial Experiences in Adolescents and Young Adults with T-Cell Acute Lymphoblastic Leukemia/Lymphoma Treated with the Modified BFM 2002 Protocol in a Resource-Constrained Setting

T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LBL) in adolescents and young adults (AYAs) is a clinically aggressive malignancy and life-threatening at diagnosis. Intensive chemotherapy protocols, inspired by the Berlin-Frankfurt-Münster (BFM) regimen, along with central nervous system (CNS) prophylaxis, have achieved a 75 to 85% 5-year disease-free survival rate. However, in cases of marrow and CNS relapses, second-line chemotherapy is usually ineffective. This study aimed to assess the safety and efficacy of the BFM 2002 protocol and to correlate clinical profiles and prognostic factors with survival outcomes in AYA T-ALL/LBL patients. We retrospectively analyzed data from T-ALL/LBL patients treated at the Department of Medical Oncology, Sri Aurobindo Institute of Medical Sciences (SAIMS), Indore, between 2018 and 2021. Twenty-one patients aged 15 to 29 years were studied for their clinical course and laboratory parameters over 36 months. Diagnosis and risk stratification were performed following the guidelines of the BFM 2002 protocol. All patients received treatment and monitoring according to this pediatric-inspired protocol. The median age of the patients was 17 years (range: 15–28 years). Eleven patients presented with mediastinal lymph node enlargement, 10% exhibited CNS involvement, and none had testicular involvement. Eleven patients had marrow blasts greater than 25%, indicative of acute lymphoblastic leukemia. All 21 patients were treated according to the intensive modified BFM 2002 protocol and achieved morphological remission after a median follow-up of 24 months (range: 18–36 months). Seventeen patients achieved minimal residual disease (MRD) negativity post-induction. MRD at day 33 showed a significant association with the probability of disease relapse (p = 0.0015). There were five deaths (24%), one due to toxicity and four due to relapse. The study recorded an 18-month overall survival of 76%. These results were achieved despite financial constraints. Data were entered into a spreadsheet, and statistical analysis was performed using IBM SPSS version 23. Continuous data are presented as ranges and medians, while categorical variables are shown as percentages and numbers. A chi-squared test for association, with a significance level set at p &lt; 0.05, was conducted as indicated. AYA T-ALL/LBL requires intensive treatment regimens. With biological characterization of LBL/ALL and close therapy monitoring, encouraging outcomes can be achieved even in resource-limited settings.

Treating relapsed B cell-precursor ALL in children with a setting-adapted mitoxantrone-based intensive chemotherapy protocol (TMH rALL-18 PROTOCOL) - experience from Tata Memorial Hospital, India.

The outlook of relapsed ALL in low- and middle-income countries (LMICs) is dismal due to high treatment-related toxicities and inadequate resources. We report our experience of using a locally adapted mitoxantrone-based protocol for non-high risk (HR) relapsed B-ALL (rALL). A retrospective cum prospective study of standard and intermediate risk (SR and IR) rALL patients treated on TMH rALL-18 protocol (adapted from COG/UKALLR3/Int-Re-ALL protocols) between November 2018 and January 2021 was analyzed. The protocol comprising of 7 blocks of multi-agent chemotherapy including mitoxantrone in induction followed by local irradiation and maintenance, underwent serial modifications based on our experience with initial patients. Eighty-two patients (SR rALL, 3; IR rALL, 79) were treated on TMH rALL-18 protocol. Of 321 grade 3/4 reported toxicities, around 43% (138 toxicities) were noted during induction. Induction chemotherapy was outpatient-based; however, 68 patients (82.9%) required supportive care admissions. Twelve out of 19 patients with gram negative bacilli sepsis (included 7 MDRO) died during reinduction. Five remission deaths were seen during block 3 after which cytarabine was dose reduced (3g to 2g/m2). Post-reinduction minimal residual disease was negative in 54 (80.6%) out of 67 evaluable patients. At a median follow-up of 24months (95% CI 22-27), the estimated 2-year event-free and overall survival of the entire cohort was 58% (95% CI 48.1-69.9) and 60.3% (95% CI 50.5-72). Until the time, targeted therapies are freely accessiblein LMICs, strengthening supportive careas well as local adaptation of protocols that strike a fine balance between efficacy and tolerability are mandated.

Lethal AML? Calcium signalling to the rescue!

Acute myeloid leukemia (AML) is characterized by genetic aberrations in hematopoietic precursors of the myeloid lineage which lead to their defective maturation/function. While intensive chemotherapy protocols result in complete remission in 50 % to 80 % of AML patients, relapse occurs in the majority of cases. While calcium signalling is a well-known contributor to cancer hallmarks, few AML related studies have focused on relevant calcium targets. Our purpose here is to highlight calcium channels and associated signalling pathways involved in AML, in order to promote the development of treatments specifically targeting these pathways.

P1221: DIFFUSE LARGE B-CELL LYMPHOMA RICHTER SYNDROME IN CHRONIC LYMPHOCYTIC LEUKEMIA – A RETROSPECTIVE ANALYSIS OF TREATMENT OUTCOMES IN POLISH ADULT LEUKEMIA STUDY GROUP

Background: Richter syndrome (RS) is a recognized uncommon manifestation and evolution of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with a dismal prognosis. It occurs in 2-10% of CLL patients. It is associated with a clonal evolution and progression, generally with a transformation of the original CLL clone to diffuse large B-cell lymphoma (DLBCL) or, less frequently, to Hodgkin Lymphoma (HL). Despite the advances in understanding pathogenesis of the disease, the DLBCL variant of RS (DLBCL-RS) is associated with a dismal prognosis with a median survival < 1 year. The treatment options and risk factors of worse outcome for RS still need to be further expanded. Aims: To study the characteristic and treatment outcomes of patients with DLBCL-RS. Methods: The retrospective analysis of 99 patients diagnosed with DLBCL-RS treated in hematology centers of the Polish Adult Leukemia Study Group (PALG) between 2011 and 2021. Results: Clinical data of 124 patients with Richter syndrome was collected. Ninety-nine patients were diagnosed with DLBCL-RS (79.8%) and further analyzed. Median time since CLL diagnosis to Richter transformation was 43.0 months (range 0-252.0). At the time of transformation 31.3% patients had CLL Rai stage IV, 74.7% were ECOG< 2, while the median Cumulative Illness Rating Scale (CIRS) was 4 (range 0-16). Thirty-seven patients transformed during CLL treatment, 56.7% of them were receiving novel agents (Brutons tyrosine kinase inhibitor or BCL2 inhibitor). Median time of observation after transformation was 10.7 months (range 0-98.6). Median overall survival (OS) after DLBCL-RS diagnosis was 17.3 months (95% Cl 11.9-46.8) and median progression-free survival (PFS) 13.5 months (95% Cl 9.6-22.7). Seventy-six patients (76.8%) had RS treated with intensive chemotherapy protocols, mainly R-CHOP-like regimens for the first line treatment. Only 42.3% had response to the treatment (25/76 complete responses and 11/76 partial responses). Worth mentioning is that in the group of patients with response two patients had ibrutinib monotherapy and one had rituximab-ibrutinib. In forty patients RS was primarily resistant to administered treatment and 65% of them died due to progression or treatment related complications. In the primary resistant DLBCL-RS p53 pathway aberration was noted in 47.5% of patients (17p deletion in 13 patients or TP53 mutation in 6 patients). Better results were achieved for patients who proceeded to autologous hematopoietic stem cell transplantation (auto-HSCT; n=8) and allogeneic HSCT (allo-HSCT; n=10). The median OS in auto-HSCT recipients was 46.1 months, while in allo-HSCT the median OS reached 18.3 months (3 patients died due to allo-HCST-related complications). Significantly lower OS (3.4 months, 95% Cl 14.13-not reached) was observed for RS in heavily pretreated CLL patients (>3 lines of therapy preceding transformation) compared to those treated with up to 3 lines of therapy (23.7 months) (p=0.0002). Median OS for treatment naïve patients at DLBCL-RS diagnosis was not reached. Other factors identified as predictors of poor OS in univariate analysis were ECOG ≥2 (p=0.0014), hemoglobin level <10 g/dl (p=0.017) and platelet count <100x109/L (p=0.0065). Summary/Conclusion: Our study represents the largest dataset of DLBCL-RS patients in Polish hematology centers and confirms the poor outcomes and prognosis associated with RS. The worst treatment results were observed in RS receiving >3 lines of CLL therapy preceding transformation. Only proceeding to hematopoietic stem cell transplantation may improve the prognosis.

CKS1 inhibition depletes leukemic stem cells and protects healthy hematopoietic stem cells in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aggressive hematological disorder comprising a hierarchy of quiescent leukemic stem cells (LSCs) and proliferating blasts with limited self-renewal ability. AML has a dismal prognosis, with extremely low two-year survival rates in the poorest cytogenetic risk patients, primarily due to the failure of intensive chemotherapy protocols to deplete LSCs, and the significant toxicity towards healthy hematopoietic cells. Whilst much work has been done to identify genetic and epigenetic vulnerabilities in AML LSCs, little is known about protein homeostasis in drug resistance and relapse. By targeting the proteostatic regulator CKS1, we demonstrate a dual role for CKS1-dependent protein degradation in reducing AML blasts in vivo, and importantly depleting LSCs, whilst inhibition of CKS1 has the opposite effect on normal hematopoiesis, protecting normal hematopoietic stem cells from chemotherapeutic toxicity. Together these findings demonstrate CKS1-dependent proteostasis is a key vulnerability in malignant stem cell biology.

A challenging case of an adolescent and young adult patient with high-risk acute lymphoblastic leukemia: the need for a multidisciplinary approach: a case report

BackgroundAdolescents and young adults diagnosed with acute lymphoblastic leukemia are treated according to pediatric-based regimens to achieve better results. However, implementation of intensive chemotherapy protocols in this age group is associated with increased treatment-related toxicities, affecting almost every organ and system. In this case, the focus of our interest was on rather rare entities: steroid-induced psychosis that seldom develops in children and adolescents, and choroid plexus hemosiderosis, infrequently identified as a first sign of iron overload.Case presentationThe aim of this paper is to present a challenging case of a 15-year-old Caucasian male patient treated for high-risk acute lymphoblastic leukemia and who experienced various adverse incidents during intensive chemotherapy, thus necessitating a high-quality multidisciplinary approach. Slow minimal residual disease clearance was an additional concerning issue. Induction and re-induction were complicated by steroid-induced hyperglycemia that required multiple-week insulin. During consolidation, acute kidney injury on the basis of chronic kidney disease was verified, demanding subsequent drug dose modifications. By the end of re-induction, after dexamethasone cessation, infrequent steroid-induced psychosis, presented as incoherent speech, aggressive behavior, and mood swings, required intensive psychiatric support. Neurological evaluation of seizures revealed uncommon choroid plexus hemosiderosis by brain magnetic resonance imaging, warranting appropriate selection of iron chelation therapy in the context of preexisting nephropathy. Ultimately, iron deposits of moderate intensity were verified by liver magnetic resonance imaging, while heart tissue remained intact. The early diagnosis and adequate treatment of aforementioned difficult toxicities resulted in complete recovery of the patient.ConclusionsTreating adolescents with high-risk acute leukemia and multiple therapy-related morbidities remains a challenge, even in the era of extensive and effective supportive therapy. Superior survival rates might be achieved by prompt recognition of both frequent and rarely encountered adverse episodes, as well as well-timed and appropriate management by a well-coordinated multidisciplinary team.

Put in a "Ca2+ll" to Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a clonal disorder characterized by genetic aberrations in myeloid primitive cells (blasts) which lead to their defective maturation/function and their proliferation in the bone marrow (BM) and blood of affected individuals. Current intensive chemotherapy protocols result in complete remission in 50% to 80% of AML patients depending on their age and the AML type involved. While alterations in calcium signaling have been extensively studied in solid tumors, little is known about the role of calcium in most hematologic malignancies, including AML. Our purpose with this review is to raise awareness about this issue and to present (i) the role of calcium signaling in AML cell proliferation and differentiation and in the quiescence of hematopoietic stem cells; (ii) the interplay between mitochondria, metabolism, and oxidative stress; (iii) the effect of the BM microenvironment on AML cell fate; and finally (iv) the mechanism by which chemotherapeutic treatments modify calcium homeostasis in AML cells.

Treating relapsed B-all in in children with mitoxantrone based intensive chemotherapy protocol (TMH rall protocol)-experience from Tata Memorial Hospital

Treating relapsed B-all in in children with mitoxantrone based intensive chemotherapy protocol (TMH rall protocol)-experience from Tata Memorial Hospital

Clinical profile, outcome and challenges in the management of pediatric Burkitt lymphoma: a single center experience

This study was conducted with the aim to assess the clinico-pathological profile, treatment outcomes and the challenges faced in Low Middle Income Countries (LMIC) during management of pediatric Burkitt lymphoma cases on intensive chemotherapy protocol. This was a single center retrospective analysis of pediatric Burkitt lymphoma cases (age <18 years) managed uniformly with Lymphomes Malins B (LMB) 96 chemotherapy protocol between January 2015 and September 2019. 40 cases were analyzed with a median age 11.5 years (range 4–18 years) and male: female ratio =4.7:1. Patients belonging to different LMB risk groups were: A-3 (7.5%), B-31 (77.5%), and C-06 (15%). 25 (62.5%) patients had abdominal disease at presentation. The survival analysis of different treatment risk groups showed statistically significant difference in mean Overall Survival (OS) between group A-100%, group B- 87%±6.1% and group C-44.4%±16.2%; (p value = .016). On multivariate analysis of prognostic factors affecting survival, CNS involvement (p value = .03) and median time from diagnosis to treatment initiation more than 30 days (p value = .04) were significantly associated with poor outcome. Incidence of culture positive febrile neutropenia episodes was 28.2% of which 69.2% infections were caused due to carbapenem resistant gram-negative organisms. In our study, although the outcomes in risk group A and B patients were comparable to LMB 96 treatment results, the outcome in risk group C was considerably poor primarily due to advanced disease at presentation and delayed diagnosis. The critical challenges that we faced in our cohort were delayed diagnosis, treatment cost affordability, poor nutritional status, and high infection related mortality.

Acute myeloid leukemia with inv(3)(q21.3q26.2)/t(3;3)(q21.3;q26.2): Study of 61 patients treated with intensive protocols.

Inv(3)(q21.3q26.2)/t(3;3)(q21.3;q26.2) is a rare poor prognosis cytogenetic abnormality present in acute myeloid leukemia (AML) and other myeloid neoplasms. The aim of this study was to evaluate the outcome of a cohort of 61 patients with newly diagnosed AML with inv(3)/t(3;3) treated with homogeneous intensive chemotherapy protocols conducted by the Spanish PETHEMA and CETLAM cooperative groups between 1999 and 2017. In this retrospective study the main clinical and biologic parameters were collected. The complete response (CR) rate, the cumulative incidence of relapse (CIR) and the overall survival (OS) were calculated. An analysis of prognostic factors for survival was performed. Sixty-one patients received induction and only 18 (29%) achieved CR (median age, 46years). Allogeneic hematopoietic stem cell transplantation (alloHSCT) was performed in 36 patients (59%), 15 with active disease. One- and 4-year CIR were 52% and 56%. One- and 4-year OS probabilities were 41% and 13%. By multivariate analysis monosomal karyotype (MK) was associated with poorer OS (HR 2.0, P=.017). Inv(3)/t(3;3) AML is a poor prognosis entity with low response to standard chemotherapy and to alloHSCT because of frequent and early relapse. MK was associated with a poorer prognosis. Improved therapeutic strategies are clearly needed.

Prognostic Implications of Specific Comorbidities in Mantle Cell Lymphoma Patients, a Swedish Lymphoma Registry Study

PurposeThe prognosis for patients with mantle cell lymphoma (MCL) is rather dismal where particularly elderly patients, often with comorbidities, have difficulties tolerating the intensive treatments needed for long-term remission. Our aim was to describe the frequency and spectrum of comorbidities among patients with MCL in a population-based setting, and assess the impact of comorbidities on treatment choice, lymphoma-specific and overall survival as well as causes of death in MCL patients by age and sex.MethodsIn the nationwide Swedish Lymphoma Register, we identified 1,385 MCL patients (1,009 males and 376 females) diagnosed 2000-2015 at all ages. Comorbid diseases within 10 years prior to diagnosis were identified from the national Swedish In- and Outpatient registers and included somatic diseases defined according to the Charlson comorbidity index (CCI; 0, 1 and 2+), with the addition of psychiatric disorders. Comorbidities were both categorized and presented individually. Hazard ratios (HR) with 95% confidence intervals (CIs) comparing lymphoma-specific and all-cause mortality among patients with different levels of CCI were estimated from flexible parametric survival models, adjusted for calendar year of diagnosis, age at diagnosis, sex, educational level, and MCL international prognostic index (MIPI). Model-based predictions were used to obtain cumulative probabilities of death due to lymphoma and other causes.ResultsIn the cohort, 24% were <59 years of age, 32% between 60-69, 30% between 70-79 and 14% >80 years. In total, 606 out of 1,385 patients (44%) had a history of one or more comorbidities at the time of diagnosis, among which 388 (28%) had a CCI=2+. The most common specific comorbidities were prior malignancy (17%), (prostate cancer was most frequent), and prior coronary heart disease (14%). Moreover, 9% of the patients had diabetes, 7% had pulmonary disease, 3% renal disease, 3% connective tissue disease and 1% had dementia. In addition, 2% had a psychiatric disorder. With a mean follow-up of 3.7 years (range: 0.0-15.6), 633 (46%) patients died from lymphoma. Lymphoma was the major cause of death among males, irrespective of CCI (Figure 1A). Lymphoma was also the major cause of death among females with CCI=0 whereas among females with comorbidities (CCI≥1), approximately half of the patients died due to other causes (Figure 1B). A CCI=2+ was associated with worse overall and lymphoma-specific survival (adjusted lymphoma-specific HR=1.31; 95% CI: 1.04-1.65). Specific comorbidities associated with significantly worse lymphoma-specific survival were history of coronary heart disease, connective tissue disease, renal disease, dementia and psychiatric disorders (Figure 1C). Patients aged below 70 years at diagnosis who presented with no comorbidities were primarily treated according to the NLG-MCL2/3 protocol* (177 out of 437, 41%). However, this was not the case among patients in the same age range but with CCI=1 (24 out of 177, 34%) or CCI=2+ (13 out of 112, 12%). Primary treatment concepts for comorbid patients were CHOP, bendamustine, or chlorambucil with the addition of rituximab.*NLG-MCL2/3= R-maxi-CHOP alternating with high dose cytarabine, rituximab, and consolidation with high-dose therapy and autologous stem-cell transplantationConclusionsA large fraction of MCL patients are elderly and comorbidity was present in almost half of the patients overall. A CCI of 2+ was an independent negative prognostic factor. Lymphoma-death was the major cause of death among males, motivating the need for MCL-specific treatment irrespectively of a high burden of comorbidities, while approximately 50% of comorbid-females died due to other reasons. Patients with comorbidities were less often treated according to intensive first-line chemotherapy protocols. In the introduction and development of new treatment regimens, consideration of toxicity and tolerability specifically in patients with comorbidities is warranted, particularly in patients with coronary heart disease, connective tissue disease and renal disorders.. [Display omitted] DisclosuresEkstroem Smedby:Janssen Pharmaceuticals: Other: The Department have recieved partial funding from Janssen Pharmaceuticals. Eloranta:Janssen Pharmaceuticals: Other: S Eloranta is currently employed as a project coordinator and her salary is funded via a public-private real world evidence collaboration between Karolinska Institutet and Janssen Pharmaceuticals.

Targeting a Specific Glycosylated Epitope of CD43 with a New Humanized Monoclonal Antibody for the Treatment of Pediatric and Adult T-Cell Acute Lymphoblastic Leukemia (T-ALL)

Introduction: T-cell acute lymphoblastic leukemia (T-ALL) accounts for about 20% of pediatric and adult ALL cases. Despite the use of intensive chemotherapy protocols, 25% of children and 50% of adult patients fail to respond or relapse. The 3-years prognosis for these patients is poor and novel treatment options are needed. The targeting of tumor-associated antigens by monoclonal antibodies (mAb) is among the most investigated immune-therapeutic strategies. Accordingly, we developed a new humanized mAb (hUMG1), directed against a heavy glycosylated epitope of CD43 which presents a high reactivity against T-ALL cells. Here we investigated the pre-clinical therapeutic activity and the mechanisms of action of hUMG1 in experimental models of T-ALL.Methods: The expression of hUMG1 target was assessed by flow cytometry on tumor cell lines and primary samples from either T-ALL patients (n=48) or healthy donors (n =6). Humanized mAbs were generated by combining the variable domains of the murine antibody to the corresponding human IgG1 constant domains. Through immunohistochemistry (IHC) we screened several tissue microarrays (TMA) including human, cynomolgusmonkey and macacus rhesus (according to FDA/CE guidelines), rat and mouse normal tissues. Complement-mediated cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and cellular phagocytosis (ADCP) on T-ALL cells were evaluated by flow cytometry. Six different in vivo models on NSG mice (3 with administration of NK-92-CD16+ effectors) have been generated to evaluate mAbs activity in different disease settings: orthotopic, subcutaneous advanced disease (treatments started at 100 mmc) and subcutaneous limited disease (treatments started the day after injection).Results: By screening different cancer cell lines, we observed hUMG1 target to be highly expressed on malignant T-ALL cells. We then tested T-ALL patient-derived blasts from 48 samples (40 pediatric and 8 adults) collected at diagnosis. The antigen was expressed on 23 out of 48 (48%), and most of them belonged to the subset of cortical (EGIL TIII) T-ALL group. By contrast the target antigen was not expressed on normal bone marrow cells from healthy donors. The analysis of the TMA including human normal tissues revealed a specific binding for thymus cortical lymphocytes only, leading us to hypothesize an acceptable safety profile. A humanized mAb, named hUMG1, and an afucosylated version of this mAb (aUMG1) were then developed. By gene expression profiling, western blot and flow cytometry, we observed that target binding by hUMG does not exert any direct activity on neoplastic cells. Subsequently, to investigate CDC, ADCC or ADCP, T-ALL cells were cultured in the presence of complement, peripheral blood mononuclear cells or macrophages, at increasing concentrations of both antibodies. Neither hUMG1 nor aUMG1 were able to induce CDC on target cells. Conversely, both mAbs induced CD16 downregulation, IFN-g production and degranulation on NK cells (more evident with aUMG1) and significant cytotoxicity against both T-ALL cell lines and primary blasts. Additionally, both mAbs induced ADCP. Lastly we observed a mAb-dependent activation of monocytes in the presence of target cells, as demonstrated by the reduction of CD16+ “non-classical” monocytes. Furthermore, we demonstrated potent activity of both mAbs in different T-ALL in vivo models. In an orthotopic model we observed 5 out of 20 treated mice free of disease after 100 days from injection as compared to none of the control group. In both subcutaneous models, we observed a strong ability of our antibody to delay tumor growth and to increase mice survival. Of note, the addition of NK-92-CD16+ strongly improved the activity of aUMG1. In the attempt to bring this antibody from bench to bedside, we assessed, through IHC, the expression of the hUMG1 target in healthy tissues from cynomolgus monkey, macacus rhesus, rat and mouse. We did not observe any reactivity, suggesting that the mAb target is very specific for human cells.Conclusion: Here, we demonstrated that hUMG1 mAb recognizes an antigen specifically expressed on the majority of T-ALL, and its binding is able to mediate effective cytotoxicity against leukemia in vitro and in vivo, indicating that this antibody, in particular the aUMG1 version, may represent a novel promising immune-therapeutic tool for the treatment of T-ALL patients. DisclosuresNo relevant conflicts of interest to declare.

Treatment of Older Patients with Acute Lymphoblastic Leukaemia.

The outcome of adult acute lymphoblastic leukaemia (ALL) has improved significantly during the past decade, mainly due to intensive paediatric-based chemotherapy. Less improvement has been observed in older patients. A significantly lower rate of complete remissions, higher early mortality, higher relapse rate and poorer survival is observed in older compared with younger ALL patients. Most importantly, intensive chemotherapy with or without stem-cell transplantation is less well tolerated in older patients. In addition, there is an increasing incidence of poor prognostic factors with increasing age. Progress has been made with the development of age-adapted, moderately intensive chemotherapy protocols for Ph/BCR-ABL-negative ALL and combinations of tyrosine kinase inhibitors with chemotherapy in Ph/BCR-ABL-positive ALL. Future progress can be expected from new targeted therapies, particularly novel immunotherapies, moderately intensified consolidation strategies and reduced intensity stem-cell transplantation. For this purpose, prospective clinical trials for older patients are urgently needed.

Western strategy for EGJ carcinoma.

In this paper, the epidemiological and clinicobiological behavior of esophagogastric junction (EGJ) adenocarcinoma in the West is compared and contrasted to that in the East, and an overview is provided of current therapeutic strategies employed for this type of tumor in Western countries. It is well known that multimodal treatment is the therapeutic standard in locally advanced EGJ adenocarcinoma, but whether neoadjuvant/perioperative chemotherapy (CT) or neoadjuvant chemoradiotherapy (CRT) is the optimal approach is still debated. Neoadjuvant CRT improves local control in locally advanced Siewert type I and II tumors, so it should be considered the treatment of choice. In the subset of these patients with microscopic systemic disease at diagnosis, more intensive exclusive chemotherapy protocols could be of benefit. Therefore, there is an urgent need to identify these patients before planning the treatment. For Siewert type III tumors, perioperative chemotherapy is the standard. While there is general agreement on the optimal surgical approach for Siewert types I and III (a two-field Ivor Lewis operation and a total gastrectomy with distal esophagectomy, respectively), no standard surgical treatment has been defined for Siewert type II tumors. When data from Western series on proximal and circumferential resection margins and on nodal spread in Siewert type II tumors are taken into account, the optimal surgical approach appears to be Ivor Lewis esophagectomy. Whether the extent of esophageal invasion can correctly predict nodal involvement in middle-upper mediastinal stations as a means to restrict indications for transthoracic esophagectomy requires further investigation in the West.

Treatment of older patients with acute lymphoblastic leukemia.

The treatment of older patients with acute lymphoblastic leukemia (ALL) is an unmet medical need. With increasing age, ALL patients have a significantly lower clinical remission rate, higher early mortality, higher relapse rate, and poorer survival compared with younger patients. This is only partly explained by a higher incidence of poor prognostic factors in the older age group. Most importantly, intensive chemotherapy with or without stem cell transplantation (SCT) is less well tolerated in older patients. Some progress has been made with delivering age-adapted, moderately intensive chemotherapy protocols for Ph/BCR-ABL-negative ALL and combinations of tyrosine kinase inhibitors with chemotherapy in Ph/BCR-ABL-positive ALL. For the future, optimizing supportive care, introducing targeted therapies, novel immunotherapies, moderately intensified consolidation strategies, and reduced intensity SCT are promising approaches. Prospective clinical trials for older patients are urgently needed to test these approaches.

Prognostic Significance and Risk Stratification in Acute Myeloid Leukaemia Patients in the Absence of Successful Cytogenetic Analysis

Cytogenetic analysis is a key tool in risk stratification of patients with acute myeloid leukaemia (AML). Sometimes samples are not sent or metaphase analysis fails (~10% cases). In these situations, a cytogenetic risk score cannot be assigned, preventing risk stratification. It has been suggested that in the absence of cytogenetic data, both missing and failed, patients have a poor outcome (Mederios et al (Br. J. Haematol. 2014 164(2): 245-50); Lazarevic et al (Eur. J. Haematol. 2015 94(5): 419-23)). In this study, we investigated the characteristics and prognostic significance of the provision of samples, and their successful analysis across the MRC UK series of AML trials (AML10 - AML16).Data from 14265 non-APL patients recruited to successive UK AML trials (1988 - 2012) were analysed. Patients were classified based on whether a sample was sent for cytogenetic analysis and the outcome of the analysis. Rates of successful cytogenetic analysis were higher in patients treated on intensive chemotherapy protocols (intensive: 11104/13081 (85%); non-intensive 850/1184 (72%), p<.0001). In intensively treated patients, there was a significant association between increasing age and missing or failed cytogenetic samples (p<.0001). Stratification of intensively treated patients with successful cytogenetics, according to the criteria of Grimwade et al (Blood 2010 116(3):354-65), into favourable (18%), intermediate (62%) and adverse risk (19%) were analysed for outcomes and showed 10 year survival of 66%, 30% and 12%, respectively. Survival at 10 years was 24% when no sample was sent compared to 32% when a sample failed cytogenetic analysis. Survival for patients with failed cytogenetics was not significantly different from those with intermediate risk cytogenetics in either univariate analysis (p=0.10) or after adjustment for age, performance status, white cell count and secondary disease (p=0.06). Outcomes were significantly better than those for adverse risk patients (p<.0001 for both analyses). For those with no sample, survival was significantly worse than for the intermediate risk (p<.0001 in both analyses), although the effect size was not large (HR 1.18 in adjusted analyses), yet significantly better than adverse risk patients (p<.0001, HR 0.57). While outcomes worsened with increasing age, a similar pattern was seen across all age groups (favourable/intermediate/adverse/no sample/failed: age<16 81%/57%/49%/63%/62%; age 16-59 67%/36%/13%/30%/41%; age 60+ 32%/12%/2%/8%/9%).In the most recent trial, AML17 (2009-14) of younger patients, 97% had successful cytogenetic analysis, compared to 86% in AML10-15. Here too, there was no suggestion of poor outcomes for those patients with no cytogenetic result. These results indicate that cytogenetic analysis is possible in the vast majority of younger patients, and suggest that absence of cytogenetic information is not in itself an adverse prognostic factor. This poor prognosis identified in other studies may be due to selection bias in the decision to send samples. The experience of AML17 demonstrates that, when cytogenetic analysis is required to guide treatment decisions, if results can be provided in real time, high levels of compliance can be achieved, not only in sending, but also in the quality of samples. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prognostic Role of Minimal Residual Disease before and after Hematopoietic Stem Cell Transplantation in Childhood Acute Lymphoblastic Leukemia

Background and ObjectivesCurrently, more than 80% of children with acute lymphoblastic leukemia (ALL) can be cured through intensive and risk-adapted chemotherapy protocols. Allogeneic hematopoietic stem cell transplantation (HSCT) is considered beneficial for approximately 10% of the patients who are at very-high risk at frontline therapy and for the majority of patients after relapse. In this retrospective study, we aimed to assess the prognostic role of minimal residual disease (MRD) before HSCT and at different time points after transplantation in children with ALL.Patients and MethodsWe analyzed 64 pediatric ALL patients given HSCT: 22/64 were in first complete remission (1CR) and 42/64 in second complete remission (2CR). Genomic DNA was obtained from bone marrow aspirates collected at diagnosis/relapse, before HSCT (pre-HSCT) and at the first and third trimesters after HSCT (post-HSCT1 and post-HSCT3). MRD was measured by quantitative real-time PCR assays based on patient-specific junctional regions and interpreted according to the EuroMRD guidelines. The association between MRD and survival was assessed by chi-square test.ResultsAll evaluated patients were analyzed for MRD before transplantation (pre-HSCT). MRD was negative in 26/64 patients and positive in 38/64 patients. As for cases with positive MRD, 17/38 showed MRD levels ≥1x10-3 and 21/38 <1x10-3. Any detectable MRD positivity at pre-HSCT was significantly associated with a poor prognosis: 28/38 patients with positive MRD are dead, whereas 22/26 with negative MRD are alive in CR (P < 0.001). Among the 42 patients in 2CR, 14/42 had negative pre-HSCT MRD and 28/42 were MRD positive. The negativity of MRD before transplantation was found to be significantly associated with a good prognosis: 13/14 patients with negative MRD are alive in CR, while 23/28 with positive MRD are dead (p < 0.001). Post-HSCT1 MRD was analyzed in 53 patients: 17/53 were MRD positive and 36/53 were MRD negative. Based on MRD status, the prognosis was significantly different: 26/36 patients with negative post-HSCT1 MRD are alive in CR, whereas 14/17 of patients with positive MRD are dead (P < 0.001). Post-HSCT3 MRD was assessed in 41 patients and 19/41 were found positive. Persistence of MRD was associated with a poor prognosis also at this time-point (P = 0.001).ConclusionsThese results confirm that MRD assessment has a critical role both before and after transplantation. Negative MRD before transplantation is strongly associated with a good prognosis, particularly in 2CR patients. Since persistence of MRD after HSCT is significantly associated with a worse outcome, these patients could benefit from early discontinuation of immunosuppression, adoptive T-cell therapy and use of new drugs. DisclosuresNo relevant conflicts of interest to declare.