High Rates Of Treatment-related Mortality Research Articles

The Impact of Baseline Genetic Profile and Treatment on Hematological Toxicity in CEBPA-Mutated Acute Myeloid Leukemia

Background: CEBPA-mutated acute myeloid leukemia (AML) is a separate entity in the updated WHO and ICC classifications. Previously identified by double mutations, the clinical profile and favorable outcome were correlated with in-frame mutations in bZIP domain. Beyond mutations recurrent in myeloid neoplasms (involving TET2, FLT3, NRAS), CEBPA-mutated AML is enriched in gene mutations (i.e., GATA2, CSF3R, WT1) rarely observed in CEBPA-wild type AML. No conclusive findings have been drawn for the prognostic impact of additional mutations. Of note, somatic GATA2 mutations have been associated with invasive fungal infections in myeloid neoplasms. Although overall correlating with favorable prognosis, an unexpectedly high rate of treatment-related mortality (TRM) in CR has been described in a large multicenter study on intensively treated CEBPA-mutated patients (pts) (Schlenk et al Blood 2013;122(9):1576). Aims: The aim of our study was to correlate baseline and treatment characteristics with the outcome and hematological toxicity in an intensively treated cohort of CEBPA-bZIP mutated AML pts. Methods: Pts entering the study had a diagnosis of CEBPA-bZIP AML confirmed according to 2022 WHO and ICC criteria. Pts were characterized by next-Generation deep amplicon sequencing with Ion Torrent platform (ThermoFisher Scientific) covering a panel of 40 genes. Sequence alignment and filtering were performed by NextGENe version 2.4.2.1 (SoftGenetics). The first two chemotherapy cycles were categorized according to the delivery of an anthracycline (ANTHRAC) and cytarabine (ARA-C) at high dose (HDAC). The study was approved by the local institutional review board. Results: From 2004 to 2023, 49 pts with CEBPA-bZIP mutated AML met the inclusion criteria at project study sites (Firenze, Bergamo). Their features are detailed in Table 1. CR rate was achieved in 45 of 49 pts (91.8%), with a DFS and OS of 74.3% and 82.4% at 5 y, respectively. Based on NGS, at least one additional mutation was identified in 18 (36.7%) pts (NGS+), the majority of them involving GATA2 (n=14, 28.6%). As per treatment, 44 pts received at least two cycles, of which no (n=2, 4.6%), one (n=14, 31.8%), or two (n=28, 63.6%) ANTHRAC-containing cycles. As regarded HDAC, 19 (43.2%), 17 (38.6%) and 8 (18.2%) pts received no, one or two HDAC-containing cycles, respectively. No significant differences emerged for DFS or OS between NGS+ and NGS- groups (P=0.33 and 0.52, respectively). To gain insight into potential causes of toxicity during CR, we focused on hematopoietic recovery after induction and consolidation. NGS+ pts showed slower neutrophil (ANC) recovery (median, 22 days to >500/uL after induction and 25 days after consolidation) compared to NGS- group (19 days, P=0.018; 18 days P=0.058, respectively). Such effect was enhanced by treatment with ANTHRAC-containing cycles: NGS+ pts receiving two cycles required significantly longer time to recover from first consolidation cycle, both for ANC (30 days) and platelet count (34 days) vs 22 (P=0.012) and 27 (P=.010) days, respectively, of other categories (Figure 1). A proportion of 45.5% (5/11) NGS+/ANTHRAC-2 pts could not complete the planned chemotherapy program due to hematological toxicity compared to 19.3% (6/31, P=0.09) in other categories. No significant prolongation of recovery was observed for HDAC. Conclusions: CEBPA-bZIP mutated AML is featured by high response rate and favorable outcome. Delayed hematopoietic recovery was observed in pts bearing additional mutations (especially GATA2) when treated with anthracyclines in first two cycles. Our findings suggest the cumulative dosage of anthracyclines should be limited in CEBPA-mutated/NGS+ patients to spare hematological toxicity on turn impairing the therapeutic plan.

Survival Analysis of Adults with Acute Lymphoblastic Leukemia in Ecuador

Background Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults. Unfortunately, in Ecuador there are no survival studies in patients ≥15 years with ALL, thus, this is the first national report. The aim of the study was to describe clinical-demographic characteristics and overall survival (OS). Methods Medical records of 628 patients from 8 reference hospitals in Ecuador with acute lymphoblastic leukemia (ALL) aged ≥15 years, diagnosed between January/2015 and December/2022, were retrospectively reviewed. A high-risk group was defined as: age ≥ 35 years ; ≥ 30,000/mm3 leukocytes in B-cell acute lymphoblastic leukemia (B-ALL) or ≥ 100,000/mm3 leukocytes in T-cell acute lymphoblastic leukemia (ALL- T) ; CNS infiltration at diagnosis, and/or if EMR was not reached (<0.01%) negative at the end of induction. If none of these factors were present, it was classified as standard risk. OS and treatment-related mortality were evaluated. Before carrying out this study, the approval of a national research ethics committee was obtained, as well as the approval of the 8 participating centers. Results 628 patients with ALL were included in the study. Summary of clinical and demographic data Table 1. In this cohort of patients, 9 different regimens of intensive chemotherapy were used. 454/517 (87.8%) patients with B-ALL were considered high risk. 595/628 (94.5%) patients received intensive chemotherapy. 150/595 (25.2%) and 54/595 (9.0%) patients died during the induction and consolidation phase respectively, reaching a mortality related to the treatment of 34.2%. In 290/401 (72.3%) with B-ALL achieved a complete response (CR) after induction, also 199/401 (49.1%) patients achieved minimal residual disease (MRD) negative (<0.01%). 16/235 (6.8%) patients with B-ALL considered high risk who achieved CR received allogeneic hematopoietic stem cell transplantation (HSCT). 32/35 (91.4%) patients with T-cell acute lymphoblastic leukemia (T-ALL) received intensive chemotherapy, of which 17/24 (70.8%) achieved CR, MRD negative (<0.01%), in 8/20 (40.0%) and 3/17 (17.6%) who achieved CR received HCT. The median OS was 12 months (95% CI 9.8-14.1) with a 5-year OS of 25.6%. The median OS for intensive chemotherapy patients with B-ALL was 12 months (95% CI 9.8 - 14.1) with a 5-year OS of 25.8% and 8 months (95% CI 5.9 - 10.0) with a 5-year OS of 23.5% for T-ALL. The 5-year OS for patients with HSCT was 78.4% (median survival not reached). The median OS for patients with B-ALL who received intensive high-risk chemotherapy was 12 months (95% CI 9.7-14.2) while median survival was not reached in the standard-risk group (p=<0.01). Figure 1. In patients with ALL-B, regimens with or without L-asparaginase achieved a 5-year OS of 26.4% vs 22.9% (p=0.588), respectively. In multivariate analysis for patients with ALL-B on intensive chemotherapy, age [HR 1.02 (95% CI 1.00 - 1.04) p=0.014] was significantly associated with OS, as well as those patients who did not achieve negative an MRD [HR 1.82 (95% CI 1.23-2.69) p=<0.01]. Otherwise, the adolescent and young adults (AYA) group, BCR:ABL fusion, CNS infiltration and leukocyte number at debut, L-asparaginase chemotherapy regimens, and being classified as high-risk group did not show statistical differences associated with OS . Conclusion The reported OS rates in this cohort are considerably low when compared to with international available data, being mainly negatively affected by the high treatment-related mortality rate, and the small number of patients who reach a HSCT.

Acrue: A Phase 2, Open-Label Study of Acalabrutinib in Combination with Rituximab in Elderly and/or Frail Patients with Treatment-Naive Diffuse Large B-Cell Lymphoma

Background and Significance: Patients aged ≥80 years with diffuse large B-cell lymphoma (DLBCL) account for approximately 18% of DLBCL cases in the United States (Morrison et al. Future Oncol. 2018). Standard-of-care chemoimmunotherapy (CIT) regimens such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), including reduced doses of CHOP (R-miniCHOP), are not well tolerated in elderly and/or frail patients, leading to high treatment-related mortality rates (Boslooper et al. Leuk Lymphoma. 2014; Freudenberger et al. Ann Hematol. 2021; Peyrade et al. Lancet Oncol. 2011). Therefore, safe, effective, and convenient treatment alternatives to CIT are needed. Acalabrutinib is a highly selective, second-generation Bruton tyrosine kinase inhibitor approved for the treatment of patients with relapsed/refractory mantle cell lymphoma and in patients with chronic lymphocytic leukemia. Acalabrutinib monotherapy has demonstrated encouraging activity in patients with DLBCL in phase 1b (NCT02112526) and phase 2 (NCT04002947) studies (Strati et al. Haematologica. 2021; Roschewski et al. Blood. 2021). However, neither of these studies were conducted specifically in a population of elderly and/or frail patients. Study Design and Methods: ACRUE (NCT05952024) is a phase 2, open-label, single-arm, global, multicenter study of acalabrutinib plus rituximab in elderly and/or frail patients with treatment-naive (TN) DLBCL who are unable to tolerate standard CIT ( Figure). Eligible patients are aged ≥80 years or aged 65-79 years with impairment in ≥1 activity of daily living (ADL) or instrumental ADL (IADL), or with cardiac/renal/liver function impairment or other comorbidities that render them unable to tolerate CIT. Furthermore, patients must have histologically confirmed CD20-positiveDLBCL (not otherwise specified), according to WHO 2016 classification, an Ann Arbor classification of stage II, III, or IV disease, an Eastern Cooperative Oncology Group performance status of 0-2, and ≥1 measurable lesion. Patients with active central nervous system involvement by lymphoma, leptomeningeal disease, or spinal cord compression, or significant cardiovascular disease within 6 months of screening are excluded. Target enrollment is 80 patients. Patients will receive acalabrutinib plus rituximab combination for 8 cycles (acalabrutinib 100 mg orally twice daily beginning on day 1 of cycles 1-8; rituximab 375 mg/m 2 intravenously on C1D15, then 1400 mg subcutaneously, on day 1 of cycles 2-8; cycles 1-8 are 21 days/cycle), followed by acalabrutinib monotherapy until disease progression, unacceptable toxicity, or 24 months (cycles 9-28 are 28 days/cycle). The primary endpoint is the percentage of patients with grade 3-4 treatment-emergent adverse events. The key secondary endpoint is investigator-assessed objective response rate per Lugano 2014 criteria. Other secondary endpoints include progression-free survival, event-free survival, overall survival, duration of response, and Timed Up and Go test. Exploratory biomarker analyses may include genomic characterization of baseline samples to evaluate predictors of survival, and of progression samples to evaluate genomic resistance mechanisms. Descriptive safety and efficacy data will be summarized. If patients discontinue treatment prior to completing 28 cycles of therapy, they will be followed every 12 weeks after their last treatment dose for up to 2 years. Patients who are still on treatment at the end of the study and are deriving clinical benefit may receive continued treatment, with assessments reverting to standard of care. Enrollment is planned to begin Q4 of 2023 in approximately 40 sites from North and South America and Asia. Summary: This study will help determine if acalabrutinib plus rituximab combination therapy is tolerable and effective in elderly and/or frail patients with TN DLBCL who are unable to tolerate CIT.

A modified CALGB 10403 in adolescents and young adults with acute lymphoblastic leukemia in Central America.

Mexico and Central America have a high incidence of acute lymphoblastic leukemia (ALL) in adolescents and young adults. Historically, this patient group has been treated using adult-based regimens, which entails a high rate of treatment-related mortality and a poor overall survival (OS). The use of the CALGB 10403, a pediatric-inspired regimen, has been proven effective in this patient subgroup. Nonetheless, low- and middle-income countries (LMICs) may present limited access to standard care treatments implemented elsewhere, warranting the need for further research to improve outcomes among vulnerable populations. In this study, we present the outcomes in terms of safety and effectiveness of using a modified CALGB 10403 regimen to reflect drug and resource availability in LMICs. Modifications included the use of Escherichia coli asparaginase,6-mercaptopurine instead of thioguanine and the use of rituximab among patients with CD20+. A total of 95 patients with a median age of 23 (range, 14-49) years treated with this modified scheme were prospectively assessed at 5 centers in Mexico and 1 in Guatemala. Among these, 87.8% achieved a complete response after induction. During follow-up, 28.3% of patients relapsed. Two-year OS rate was 72.1%. Factors associated with worse OS included hyperleukocytosis (hazard ratio [HR], 4.28; 95% confidence interval [CI], 1.81-10.10) and postinduction minimal residual disease (HR, 4.67; 95%CI, 1.75-12.44). Most patients presented hepatotoxicity (51.6% and 53.7% during induction and consolidation, respectively), and the treatment-related mortality was 9.5%. Overall, results highlight that implementing a modified CALGB 10403 regimen in Central America is feasible, and it is associated with improvements in clinical outcomes and a manageable safety profile.

Chronic Neutrophilic Leukemia: A Comprehensive Review of Clinical Characteristics, Genetic Landscape and Management

Chronic neutrophilic leukemia (CNL) represents a rare disease, that has been classified among the BCR/ABL-negative myeloproliferative neoplasms. The disease is characterized by marked leukocytosis with absolute neutrophilia and its clinical presentation may vary from asymptomatic to highly symptomatic with massive splenomegaly and constitutional symptoms. CNL prognosis remains relatively poor, as most patients succumb to disease complications or transform to acute myeloid leukemia. Recent studies have demonstrated that CSF3R mutations drive the disease, albeit the presence of other secondary mutations perplex the genetic landscape of the disease. Notably, the presence of CSF3R mutations has been adopted as a criterion for diagnosis of CNL. Despite the vigorous research, the management of the disease remains suboptimal. Allogeneic stem cell transplantation represents the only treatment that could lead to cure; however, it is accompanied by high rates of treatment-related mortality. Recently, ruxolitinib has shown significant responses in patients with CNL; however, emergence of resistance might perturbate long-term management of the disease. The aim of this review is to summarize the clinical course and laboratory findings of CNL, highlight its pathogenesis and complex genetic landscape, and provide the context for the appropriate management of patients with CNL.

AML SCT-BFM 2007: Results of the Prospective Hematopoietic Stem Cell Transplantation (HCT) Trial of the Berlin-Frankfurt-Münster (BFM) Study Group for Children with Very High Risk Acute Myeloid Leukemia

BACKGROUNDPediatric AML represents a rare and heterogeneous disease. Within the BFM study group, HCT for this patient cohort was performed with considerable inter-center variability. AML SCT-BFM 2007 was based on a transplantation consensus and aimed to prospectively generate a reliable body of data on which further transplantation technologies could be based. METHODSAML SCT-BFM 2007 was conducted according to current legislation as an international multicenter clinical trial (EudraCT: 2007-004517-34, NCT00606723), data were collected via a specifically developed remote data entry (RDE)-based data bank, and verified against source data by an on-site monitoring program. Children with cytogentic and molecular high-risk features achieving a complete first remission (CR1) and those in CR2 after a first relapse qualified for HCT from a matched donor (MD). A MD was defined to be identical when at least 9/10 alleles on the HLA-A, B, C, DRB1 and DQ loci did match. A myeloablative conditioning regimen consisting of Busulfan (age adjusted i.v. dosing: 3.2 - 4,8 mg/kg BW on days -7 through -4), Cyclophosphamide (60mg/kg iv on days -3 and -2), and Melphalan (140 mg/m2 on day -1) termed BuCyMel was used. For GVHD prophylaxis CSA and short term MTX were given, for unrelated donors anti-thymocyte globulin (ATG Neovii) was added. Children with refractory primary disease or refractory relapse were eligible for early transplantation. A cytoreductive regimen containing Fludarabine (30mg/m2/d i.v.), Amsacrine (100 mg/m2/d i.v.) and Cytarabine (2g/m2/d i.v.) all on days -12 through -9 (FLAMSA) was immediately followed by a reduced intensity conditioning (RIC) consisting of 4 Gy TBI and Cyclophosphamide (60 (unrelated)/40 (related) mg/kg/d i.v.) on days -4 and -3. After early taper of immunosuppression (MMF halted by day 40 and CSA after taper by day 90) increasing doses of prophylactic donor lymphocyte infusions (DLI) were given on days 120, 150, and 180. Standard statistical methods were used for the analysis of event-free survival (EFS, events: relapse, death from any cause), overall survival (OS), cumulative incidence of treatment related mortality (TRM) and relapse (CIR) after HCT. RESULTSRecruitment was conducted between 5/2010 and 2/2016. 97 children underwent HCT after conditioning with BuCyMel. Median neutrophil engraftment was achieved after 21 days (range 9-38). 3-year EFS and OS were 62%, standard error (SE) 5%, and 73%, SE 5%. CIR was 22%, SE 4%. Median time to relapse was 8 months (range 1-66) after HCT. TRM was 15%, SE 4%, with 8/15 patients dying before day 100. TRM correlated with age with a rate of 9% in children younger than 12 years (n = 68) and 31% in older children and adolescents (Fig. A). This resulted in a stop of using BuCyMel for older children and adolescents in 6/2014. The rate of acute graft versus host disease (aGVHD) grade II-IV was 22%, chronic GVHD developed in 11%. Median neutrophil engraftment for children transplanted for refractory disease (n= 35) was 23 days (range 10-34). 3-year EFS and OS were 46%, SE 8%, and 51%, SE 9%. EFS for primarily refractory disease was 53%, SE 11%, whereas EFS for refractory relapses (n = 7) was 29%. Relapse rate was 43%, SE 9%, and TRM reached 11%, SE 5% (Fig. B). Acute and chronic GVHD rates were at 26% and 17%. CONCLUSIONWithin a well-defined trial concept HCT from a matched donor using BuCyMel for conditioning results in an EFS of 60% with a low TRM rate in younger children. The identical approach is associated with a high TRM rate of 31% in older children and adolescents. Whether the use of alternative conditioning strategies in this population can reduce mortality while maintaining the relapse-free survival rates remains to be determined. In high-risk patients with refractory disease, early use of RIC HCT followed by the infusion of prophylactically given DLI can induce long-term remissions in more than 50% of children without increasing the risk for GVHD. [Display omitted] DisclosuresSauer:Neovii: Research Funding. Lang:Miltenyi Biotec GmbH: Patents & Royalties, Research Funding. Bader:Novartis, Medac, Amgen, Riemser, Neovii: Consultancy, Honoraria, Research Funding. Handgretinger:Miltenyibiotec GmbH: Patents & Royalties: Co-patent holder of TcR alpha/beta depletion technologies, Research Funding.

Autologous stem cell transplantation in scleroderma

Patients with severe rapidly progressive systemic sclerosis (SSc) have a poor prognosis. Standard immunosuppressive therapies may have modest effects on stabilizing disease, but they fail to improve overall survival. Hematopoietic stem cell transplant (HSCT) is the first treatment to induce disease-modifying therapeutic benefits in rapidly progressive SSc patients. HSCT in rapidly progressive SSc can induce regression of fibrosis in skin and lung, and increase survival. Initially, HSCT was associated with high treatment-related mortality rates. Improvements in patient screening, a better understanding of the risks associated with different treatment regimens, and centre experience have improved the AHSCT safety profile for patients with scleroderma.

MBCL-28. LONG-TERM FOLLOW-UP RESULTS OF REDUCED DOSE CRANIOSPINAL RADIOTHERAPY AND TANDEM HIGH-DOSE CHEMOTHERAPY IN PATIENTS WITH HIGH-RISK MEDULLOBLASTOMA

BACKGROUNDIn this study, we report the follow-up results of reduced-dose of craniospinal radiotherapy (CSRT) followed by tandem high-dose chemotherapy (HDCT) in patients with high-risk medulloblastoma (MB).METHODSNewly diagnosed high-risk MB patients (metastatic disease, postoperative residual tumor > 1.5 cm2 or large cell/anaplastic histology) over 3 years of age were enrolled in this study. Two cycles of pre-RT chemotherapy, RT including reduced-dose CSRT (23.4 or 30.6 Gy), 4 cycles of post-RT chemotherapy and tandem HDCT were given. NanoString and DNA sequencing were done with archival tissues.RESULTSForty patients were enrolled, and molecular subgrouping was possible in 21 patients (2 WNT, 3 SHH, 8 Group 3 and 8 group 4). All patients including two patients who experienced progression during the induction chemotherapy underwent HDCT. Relapse/progression occurred only in four patients (10-year cumulative incidence 10.4 ± 0.3%). However, six patients died from treatment-related mortality (TRM) (4 acute TRMs and 2 late TRMs) resulting in 18.5 ± 0.5% of 10-year cumulative incidence. Taken together, the 10-year event-free survival and overall survival were 71.1 ± 8.0% and 68.9 ± 8.5%, respectively. Late effects were evaluated in 25 patients and high-tone hearing loss, endocrine dysfunction, dyslipidemia, and growth retardation were common.CONCLUSIONSStrategy using tandem HDCT following reduced-dose CSRT showed promising results in terms of low relapse/progression rate, however, the high TRM rate indicates that modification of HDCT regimen and careful selection of patients who can have benefit from HDCT will be needed in the future study.

Promising survival rate but high incidence of treatment-related mortality after reduced-dose craniospinal radiotherapy and tandem high-dose chemotherapy in patients with high-risk medulloblastoma.

BackgroundIn this study, we report the follow‐up results of reduced dose of craniospinal radiotherapy (CSRT) followed by tandem high‐dose chemotherapy (HDCT) in patients with high‐risk medulloblastoma (MB).MethodsNewly diagnosed high‐risk MB patients (metastatic disease, postoperative residual tumor >1.5 cm2, or large cell/anaplastic histology) over 3 years of age were enrolled in this study. Two cycles of pre‐RT chemotherapy, radiotherapy (RT) including reduced‐dose CSRT (23.4 or 30.6 Gy), four cycles of post‐RT chemotherapy, and tandem HDCT were administered. NanoString and DNA sequencing were performed using archival tissues.ResultsIn all, 40 patients were enrolled, and molecular subgrouping was possible in 21 patients (2 wingless, 3 sonic hedgehog, 8 Group 3, and 8 group 4). All patients including two patients who experienced progression during the induction chemotherapy underwent HDCT. Relapse/progression occurred only in four patients (5‐year cumulative incidence [CI] 10.4 ± 0.3%). However, six patients died from treatment‐related mortality (TRM) (four acute TRMs and two late TRMs) resulting in 18.5 ± 0.5% of 5‐year CI. Taken together, the 5‐year event‐free survival and overall survival were 71.1 ± 8.0% and 73.2 ± 7.9%, respectively. Late effects were evaluated in 25 patients and high‐tone hearing loss, endocrine dysfunction, dyslipidemia, and growth retardation were common.ConclusionsThe strategy using tandem HDCT following reduced‐dose CSRT showed promising results in terms of low relapse/progression rate; however, the high TRM rate indicates that modification of HDCT regimen and careful selection of patients who can benefit from HDCT will be needed in the future study.

Blinatumomab As a Successful Bridge to Hematopoietic Stem Cell Transplant in a Down Syndrome Patient with Relapsed B-Precursor Acute Lymphoblastic Leukemia

Introduction Children with Down syndrome (DS) carry a 20-fold higher risk of developing acute lymphoblastic leukemia (ALL) than other children and have increased rates of treatment-related mortality (TRM) and relapse. The prognosis for relapsed DS-ALL patients is grim with long-term survival rates of 20%. Blinatumomab, a CD19/CD3 bispecific antibody, is FDA approved for relapsed pediatric pre-B ALL, and recently approved for patients with minimal residual disease (MRD). However there are few reports of the use of blinatumomab in DS-ALL patients, and no reports of blinatumomab as a bridge to stem cell transplant (SCT) in this population. Case Description A 19 year old male with DS presented with thrombocytopenia and was diagnosed with pre-B ALL. Upfront therapy included fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, pegaspargase, and rituximab for 8 cycles, and he achieved complete remission (CR). Maintenance therapy included 26 months of 6-mercaptopurine, vincristine, methotrexate, and prednisone. He relapsed 5 months after completion of therapy and was found to have a P2RY8-CRLF2 fusion. IgH gene rearrangement analysis by next generation sequencing (LymphoTrack assay) demonstrated clonal rearrangement. Re-induction therapy included vincristine, pegaspargase, and prednisone. He completed 2 additional courses of chemotherapy but continued to have MRD both by flow cytometry and LymphoTrack. Given persistent MRD with CD19+ lymphoblasts, he was treated with blinatumomab at the FDA recommended dosing; he had no signs of toxicity. He achieved negative MRD by flow cytometry and LymphoTrack after 1 cycle. He then proceeded to a T-cell depleted peripheral blood SCT from a 10/10 matched sibling after conditioning with total body irradiation, thiotepa, and cyclophosphamide. Post-SCT course was uncomplicated and he is now 1 year post-SCT with no evidence of leukemia and 100% donor chimerism. Conclusion Blinatumomab is clinically effective and safe for patients with relapsed/refractory pre-B ALL, yet there is limited information on its use in DS-ALL patients. These patients have been largely excluded from blinatumomab trials given their altered immune system and unknown level of innate T cell dysfunction, potentially altering the efficacy of blinatumomab. We present here the case of a 22 year old male with relapsed DS-ALL who remained MRD positive after several cycles of re-induction chemotherapy, but achieved a CR following 1 cycle of blinatumomab with no toxicities, and safely proceeded to SCT. Although this is a single case, it demonstrates clinical efficacy of blinatumomab in relapsed DS-ALL, suggesting that these patients' T cells can be engaged to recognized CD19-positive leukemic blasts. Furthermore, blinatumomab represents a particularly attractive bridging therapy to SCT for DS-ALL patients who experience high rates of TRM with traditional agents.

Immunotherapy in myeloma: how far have we come?

The treatment of multiple myeloma (MM) has evolved substantially over the past decades, leading to a significantly improved outcome of MM patients. The introduction of high-dose therapy, especially, and autologous stem cell transplantation, as well as the development of new drugs, such as immunomodulatory drugs (IMiDs) and proteasome inhibitors have contributed to the improvement in survival. However, eventually most MM patients relapse, which indicates that there is a need for new agents and novel treatment strategies. Importantly, the long-term survival in a subset of MM patients after allogeneic stem cell transplantation illustrates the potential of immunotherapy in MM, but allogeneic stem cell transplantation is also associated with a high rate of treatment-related mortality. Recently, a better insight into several immune-evasion mechanisms, which contribute to tumor progression, has resulted in the development of active and well-tolerated novel forms of immunotherapy. These immunotherapeutic agents can be used as monotherapy, or, even more successfully, in combination with other established anti-MM agents to further improve depth and duration of response by preventing the outgrowth of resistant clones. This review will discuss the mechanisms used by MM cells to evade the immune system, and also provide an overview of currently approved immunotherapeutic drugs, such as IMiDs (e.g. lenalidomide and pomalidomide) and monoclonal antibodies that target cell surface antigens present on the MM cell (e.g. elotuzumab and daratumumab), as well as novel immunotherapies (e.g. chimeric antigen receptor T-cells, bispecific antibodies and checkpoint inhibitors) currently in clinical development in MM.

Validation of Kantarjian (2010) Model for Intensive Chemotherapy in Older Adults with Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) carries a poor prognosis in older adults. Limited clinical trial data exist to support the use of conventional cytarabine-based regimens in this population, and practice standards have been extrapolated from studies in younger patients. Intensive chemotherapy in older adults is associated with high rates of treatment-related mortality and poor overall survival. In 2010, Kantarjian and colleagues developed a risk model for 8-week mortality using adverse prognostic risk factors, including age ≥80 years, complex karyotype (≥3 abnormalities), poor performance status (ECOG score ≥2), and serum creatinine >1.3 mg/dL. This study validates the Kantarjian model for progression-free survival (PFS) and overall survival (OS) in older patients with AML treated with intensive chemotherapy.Methods: Adults aged ≥70 years with AML (≥20% blasts in bone marrow or peripheral blood) who received intensive chemotherapy at UPMC Hillman Cancer Center between 2000 and 2011 were evaluated. Patients were stratified into low, intermediate, and high-risk groups according to the Kantarjian (2010) model and analyzed for PFS and OS using the Kaplan-Meier method. Differences in PFS and OS between risk groups were assessed with the log-rank test. ECOG performance status was estimated using historical data at the time of diagnosis. Additional variables, including AML type (primary vs. secondary), percent blasts at diagnosis, percent CD34-positive blasts, hemoglobin, leukocytes, platelets, LDH, AST, ALT, total bilirubin, albumin, and Charlson comorbidity index (CCI) were tested for added prognostic value when incorporated into the model, using Cox proportional-hazards regression for PFS and OS.Results: Clinical data were collected for 68 patients. Of these, 26 patients, all of whom were diagnosed prior to 2003, were excluded from the final analysis due to insufficient electronic health records. The remaining 42 patients were used for the validation study. Median age at diagnosis was 73 years (range: 70-87). Twenty-seven patients (64%) had primary AML, whereas 10 (24%) had AML evolving from another hematologic disorder and 5 (12%) developed AML after radiation or chemotherapy for another malignancy. Eleven (26%) patients had ≥3 karyotypic abnormalities and the remaining 31 (74%) had fewer than 3. Thirty-three (79%) patients had an ECOG performance status of 0 or 1, and the remaining 9 (21%) did not have sufficient historical data to estimate ECOG score and were given a score of 0. In total, there were 23, 16, and 3 patients categorized into the low, intermediate, and high-risk groups, respectively. These groups had non-overlapping PFS and OS curves (p <0.001 for both endpoints). The low, intermediate, and high-risk groups had median PFS of 9.6, 5.1, and 2.1 months and median OS of 14.0, 6.3, and 2.1 months, respectively. None of the additional variables were found to add significant prognostic value to the existing model.Discussion: The Kantarjian (2010) model is a valid method of risk-stratifying older adults with respect to PFS and OS, and may be useful when weighing the risks and benefits of intensive chemotherapy in these patients. In this study, we did not identify other disease characteristics or measures of organ function that significantly improved the model, although our analysis is limited by small sample size. We note that all patients in our study had an ECOG score of 0 or 1, implying selection of healthier patients for induction chemotherapy at our institution. Our results suggest that patients in the intermediate and high-risk groups may not derive significant PFS and OS benefit from intensive chemotherapy when the risks of morbidity and mortality from treatment are considered. DisclosuresNo relevant conflicts of interest to declare.

A Phase I Trial of 90Y-BC8-DOTA (Anti-CD45) Monoclonal Antibody in Combination with Fludarabine and TBI As Conditioning for Allogeneic Peripheral Blood Stem Cell Transplant to Treat High Risk Multiple Myeloma

Introduction: Novel agents and autologous stem cell transplant (auto-SCT) have resulted in a survival benefit among patients with multiple myeloma (MM), but almost all ultimately relapse. Allogeneic transplant (allo-SCT) provides a tumor-free graft and graft-versus-myeloma (GVM) effect, but myeloablative conditioning regimens are associated with high rates of treatment-related mortality (TRM). In contrast, reduced intensity allo-SCT conditioning regimens are associated with lower TRM, but patients receiving these regimens tend to have a higher risk of relapse. Radioimmunotherapy (RIT) offers the potential to deliver high doses of targeted radiation while minimizing toxicity to normal tissue. When incorporated into reduced intensity allo-SCT, RIT may improve responses without the associated toxicity historically associated with myeloablative conditioning. We studied 90Yttrium conjugated to an IgG1 murine anti-CD45 monoclonal antibody (MAb) (BC8), in conjunction with a reduced intensity-conditioning regimen prior to allogeneic SCT. We used CD45 as a target due to its ubiquitous expression in hematopoietic stem cells. We used the high-energy (2.8 MeVmax) beta-emitter, 90Y to facilitate a bystander crossfire effect and eliminate malignant plasma cells.Methods: This is a single-arm, open label, dose-escalation, phase I trial designed to estimate the safety, feasibility and maximum tolerated dose (MTD) of 90Y-BC8-DOTA MAb when combined with fludarabine (flu) and low dose total body irradiation (TBI) followed by HLA‐matched, related or unrelated allo-SCT for patients with high risk MM. Inclusion required patients to have at least one high risk MM-associated disease characteristic at diagnosis (del13 or hypodiploidy by conventional cytogenetics, t(4;14), t(14;16), del 17 by FISH, beta-2 microglobulin >3.5 mcg/mL, LDH >1.5 times upper limit of normal, plasma cell leukemia or progressive disease following primary therapy), and/or disease progression after auto-SCT. To determine the dose of 90Y-BC8-DOTA, patients first underwent a biodistribution step using a trace-labeled infusion of 111Indium-BC8-DOTA followed by gamma camera imaging and bone marrow biopsy. On pre-transplant day -12, patients received 90Y-BC8-DOTA at a dose calculated from the trace-labeled 111Indium-BC8-DOTA biodistribution, followed by Flu (30 mg/m2/day) on days -4 to -2. TBI (2 Gy) was administered on day 0, prior to growth factor mobilized donor peripheral blood stem cell infusion. GVHD prophylaxis consisted of mycophenolate mofetil and cyclosporine initiated on day 0 and day -3, respectively. The MTD was defined as the dose of 90Y-BC8-DOTA MAb associated with a true dose-limiting toxicity (DLT) rate of 25%, where a DLT is defined as Bearman grade III/IV regimen-related toxicity. Doses of 90Y were escalated in increments of 2 Gy depending on the occurrence of DLT.Results: A total of 15 patients were enrolled. Patient characteristics and outcomes are summarized in Table 1. One patient was withdrawn from the study prior to receiving the therapy dose after testing positive for human anti-mouse antibodies. The remaining 14 patients went on to receive 90Y-BC8-DOTA (0.5 mg/kg antibody) at escalating 90Y dose levels of 6 to 32 Gy to the liver, which is the normal critical organ. Six patients (43%) experienced grade 3-4 toxicity, predominantly GI and metabolic/electrolyte disturbances. No DLTs were observed. Because no DLTs were seen, the MTD could not be estimated. All patients achieved platelet and neutrophil engraftment, and 13 patients (93%) were >95% donor in the CD3, CD33 and CD56 compartments at day +28. Estimates of overall and progression-free survival at 2 years were 77% and 78%, respectively (Figure 1). Eleven patients who completed the study regimen are alive at 2.6 months to 4.1 years. Of these, 6 patients are in complete remission, 2 have persistent disease, and 3 have relapsed at 4 months, 6 months, and 3 years post-transplant. Three patients died: 2 due to progressive disease and 1 due to respiratory failure in the setting of liver GVHD.Conclusion: The inclusion of 90Y-BC8-DOTA into a reduced intensity allo-SCT conditioning regimen is feasible and no dose-limiting toxicities have been observed. The efficacy of this regimen is promising compared with historical control rates of conventional allo-SCT for MM and should be explored in a phase II trial. [Display omitted] DisclosuresOrozco:Actinium Pharmaceuticals: Other: Research Funding to Institution for sponsored Clinical Trials. Gopal:Seattle Genetics: Consultancy, Research Funding. Becker:GlycoMimetics, Inc.: Research Funding. Press:Roche: Honoraria, Research Funding; BMS: Honoraria; Bayer: Consultancy. Bensinger:Janssen: Membership on an entity's Board of Directors or advisory committees.

The hypomorphic TERT A1062T variant is associated with increased treatment-related toxicity in acute myeloid leukemia.

Hypomorphic germline variants in TERT, the gene encoding the reverse transcriptase component of the human telomerase complex, occur with a frequency of 3-5% in acute myeloid leukemia. We analyzed the clinical and prognostic impact of the most common TERT A1062T variant in younger patients with acute myeloid leukemia intensively treated within two prospective multicenter trials. Four hundred and twenty patients (age 17-60years) were analyzed for the TERT A1062T variant by direct sequencing. Fifteen patients (3.6%) carried the TERT A1062T variant. Patients with the TERT A1062T variant had a trend towards less favorable and more intermediate 2/adverse karyotypes/genotypes according to the European Leukemia Net classification. In univariate and multivariate analysis, patients with the TERT A1062T variant had a significantly inferior overall survival compared to wild-type patients (6-year overall survival 20 vs. 41%, p=0.005). Patients with the TERT A1062T variant showed a high rate of treatment-related mortality: 5/15 (33%) died during induction therapy or in complete remission as compared to 62/405 (15%) of the wild-type patients. In patients with the TERT variant, 14/15 (93%) suffered from non-hematological/non-infectious grade 3/4 adverse events (mostly hepatic and/or mucosal) as compared to 216/405 (53%) wild-type patients (p=0.006). In multivariate analysis, the TERT A1062T variant was an independent risk factor predicting for adverse events during induction chemotherapy. In conclusion, the TERT A1062T variant is an independent negative prognostic factor in younger patients with acute myeloid leukemia and seems to predispose those patients to treatment-related toxicity.

Improved Outcome of a Reduced Toxicity-Fludarabine, Cyclophosphamide, plus Antithymocyte Globulin Conditioning Regimen for Unrelated Donor Transplantation in Severe Aplastic Anemia: Comparison of 2 Multicenter Prospective Studies

Hematopoietic stem cell transplantation (HSCT) is a curative therapy for severe aplastic anemia (SAA); however, the optimal conditioning regimen for HSCT with an unrelated donor has not yet been defined. A previous study using a fludarabine (FLU), cyclophosphamide (Cy), and antithymocyte globulin (ATG) conditioning regimen (study A: 50 mg/kg Cy once daily i.v. on days −9, −8, −7, and −6; 30 mg/m2 FLU once daily i.v. on days −5, −4, −3, and −2; and 2.5 mg/kg of ATG once daily i.v. on days −3, −2, and −1) demonstrated successful engraftment (100%) but had a high treatment-related mortality rate (32.1%). Therefore, given that Cy is more toxic than FLU, we performed a new phase II prospective study with a reduced-toxicity regimen (study B: 60 mg/kg Cy once daily i.v. on days −8 and −7; 40 mg/m2 FLU once daily i.v. on days −6, −5, −4, −3, and −2; and 2.5 mg/kg ATG once daily i.v. on 3 days). Fifty-seven patients were enrolled in studies A (n = 28) and B (n = 29), and donor type hematologic recovery was achieved in all patients in both studies. The overall survival (OS) and event-free survival (EFS) rates of patients in study B was markedly improved compared with those in study A (OS: 96.7% versus 67.9%, respectively, P = .004; EFS: 93.3% versus 64.3%, respectively, P = .008). These data show that a reduced-toxicity conditioning regimen with FLU, Cy, and ATG may be an optimal regimen for SAA patients receiving unrelated donor HSCT.

Outcome of allogeneic transplantation in newly diagnosed and relapsed/refractory multiple myeloma: long-term follow-up in a single institution.

Allogeneic stem cell transplantation (allo-SCT) has the potential to induce long-term remission in multiple myeloma (MM), but the role of allo-SCT in MM is controversial due to the high rate of treatment-related mortality (TRM). However, although proteasome inhibitors and immunomodulatory drugs have improved the outcome of patients with MM, high-risk patients still have a very poor prognosis. This indicates the need for new treatment strategies and identification of patients who might benefit from allo-SCT. We therefore analyzed the outcome of one hundred and forty-seven patients with MM who received an allo-SCT at our institution (58 in first line, 89 in relapsed/refractory setting) after a median follow-up of 88.8 months. For the first-line setting, median progression-free survival (PFS) and overall survival (OS) were remarkably good, with a CR rate of 48.3%, median PFS of 30.2 months, and 10-yr OS of 51%. We found no difference in outcome for patients with high-risk metaphase cytogenetics or FISH del(13q14), but efficacy in current standard high-risk patients could not be determined. The outcome in the relapsed/refractory setting was poor, especially in the subgroup of patients relapsing within 18 months after auto-SCT. Therefore, if applied at all in these patients, improvement of allo-SCT is needed, focusing on reduction of TRM and more effective immunotherapy.

Prognosis and progress in immunotherapies for organ involvements in systemic autoimmune diseases.

Treatment of organ involvements accompanied by systemic autoimmune diseases is still challenging for clinicians, reminding the existence of unmet needs. Among them, lupus nephritis (LN), neuropsychiatric lupus, interstitial lung diseases (ILD) complicated with polymyositis/dermatomyositis (PM/DM) or systemic sclerosis (SSc) are the most severe conditions with poor prognosis. Because of the rarity and severity of the disease status, and of variety in evaluation methods, randomized clinical trials tend to be difficult in recruiting patients, in designing protocols, and in meeting primary endpoints. In such tough conditions, superiority of IVCY over corticosteroids alone for LN has been established, which is now going to be replaced by mycophenolate mofetil (MMF). Moreover, non-inferiority of tacrolimus to MMF is reported and efficacy of biologics such as Rituximab and Abatacept for LN is under investigation. In contrast, PM/DM-ILD is not suitable for randomized controlled trial because of the severity/acute progression in some patients. Intensive immunosuppressive regimen is recommended for those with poor prognostic factor(s). Cyclophosphamide has limited efficacy in SSc-ILD. Hematopoietic stem cell transplantation elongated patient survival and improved ILD, but with high treatment-related mortality rate. Efficacy of rituximab and MMF has been reported in small-sized trials. In this review, previously established treatment as well as emerging immunotherapies for organ involvements will be discussed. Our experiences in autoimmune settings also will be introduced.

Comparable Leukemia-Free Survival after Autologous Hematopoietic Cell Transplantation Versus HLA-Identical Sibling Hematopoietic Cell Transplantation for Adult Acute Myeloid Leukemia in First Complete Remission: A Registry Study By the Adult AML Working Group of the Japan Society for Hematopoietic Cell Transplantation

Allogeneic hematopoietic cell transplantation (HCT) from a matched sibling donor (MSD) may provide a cure for acute myeloid leukemia in first complete remission (AML/CR1), although the procedure is associated with a higher rate of treatment-related mortality (TRM) than autologous HCT, and it remains uncertain which modality is preferable as post-remission treatment. We therefore conducted a retrospective registry-based analysis to compare the outcomes of patients with AML/CR1 receiving autologous peripheral blood (PB) grafts (n=398, median age: 47, range: 17-80) and those receiving allogeneic MSD bone marrow (BM) grafts (n=633, median age: 38, range: 16-73) or allogeneic MSD PB grafts (n=475, median age: 42, range: 16-74) between 1995 and 2011. Consequently, the 5-year overall survival (OS) rates for the autologous PB, allogeneic BM and allogeneic PB recipients were 62% (95% confidence interval [CI], 57-67%), 61% (95% CI, 57-65%; P=0.90) and 54% (95% CI, 49-59%; P=0.07), respectively (Fig. 1-A), and the 5-year leukemia-free survival (LFS) rates were 57% (95% CI, 52-62%), 58% (95% CI, 54-63%; P=0.49) and 51% (95% CI, 46-56%; P=0.12), respectively(Fig. 1-B). Meanwhile, the 5-year cumulative incidence of TRM was 8% (95% CI, 5-11%), 16% (95% CI, 13-19%; P=0.009) and 19% (95% CI, 15-23%; P=0.0001), respectively, while that of relapse was 35% (95% CI, 30-40%), 26% (95% CI, 22-29%; P=0.003) and 30% (95% CI, 26-35%; P=0.08), respectively. A multivariate analysis performed with autologous PB HCT as the reference showed a hazard ratio (HR) for OS of 0.93 (95% CI, 0.73-1.18; P=0.53) for allogeneic BM HCT and 1.08 (95% CI, 0.83-1.39; P=0.57) for allogeneic PB HCT and an HR for LFS of 0.86 (95% CI, 0.69-1.09; P=0.21) and 0.98 (95% CI, 0.77-1.24; P=0.85), respectively. Stratifying the patients according to cytogenetics (favorable, intermediate and poor) and age (<50 years and ≥ 50 years) did not influence the results. Accordingly, autologous PB HCT may be a viable alternative as post-remission therapy in patients with AML/CR1 in the absence of MSD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Conditioning Intensity Does Not Influence the Outcome of Allogeneic Stem Cell Transplantation in Myelodysplastic Syndrome. a Joint Study By the Polish Adult Leukemia Group and the Polish Pediatric Group for Hematopoietic Stem Cell Transplantation

Background: Allogeneic stem cell transplantation (alloSCT) is a potential curative treatment for patients (pts) with myelodysplastic syndrome (MDS), with reported long-term survival of 27% to 54% depending on risk group. Myeloablative conditioning (MAC) considered as standard therapy is associated with substantial treatment related mortality (TRM), especially in older pts or those with therapy related disease (tMDS); on the other hand, high rate of relapse have been reported after reduced intensity conditioning (RIC). Therefore, Polish Adult Leukemia Group (PALG) in cooperation with Polish Pediatric Group for Hematopoietic Stem Cell Transplantation analyzed the outcome of MDS pts transplanted between 2000 and 2013 with respect to conditioning intensity.Material and methods. Three hundred and four pediatric and adult patients with median age of 38 years (range: 1-69) were retrospectively analyzed. The study cohort included pts with intermediate-2/high risk according to IPSS (136), unfavorable cytogenetics (86), secondary AML (43) and tMDS (35). Among adult pts (216), 74 (34%) were older than 50. The median time between diagnosis and transplant was 8 months (range:1-117). Before transplantation 202 pts had <5% bone marrow blasts, while 48 pts underwent alloSCT with blasts >10%. For conditioning, RIC protocols based on fludarabine were used in 180 pts and 102 pts were treated with myeloablative therapy based on busulphan. Stem cells from related (144) or unrelated (160) donors were grafted in median dose 4.75 (1.3-27.4)x106 of CD34+ cells/kg. Peripheral blood (PB) stem cells were transplanted in 222 pts. Thirty nine pts received allograft from HLA mismatched donors.Results: Engraftment occurred in 285 (94%) pts and 8 pts died before +21 day after transplantation. Infectious complications were observed in 252 (82%) pts during neutropenia (febrile of unknown origin 163, bacterial 53, fungal 24, bacterial and fungal 12). Late infections, assessed in those who survived 100 days, occurred in 130 (50%) pts, and were related mainly to CMV infection. Severe toxic complications (CTCAE grade 3-4) developed in 67 (22%) pts. Acute graft versus host disease (GVHD) grade 2-4 occurred in 77 (27%) pts, while chronic extensive GVHD in 37 (14.5%) pts. Forty seven pts experienced disease relapse after treatment.Over a median follow-up of 43 months (range: 15-70) 156 (51%) pts were alive. In 44 cases deaths were related to relapse, 36 pts died due to GVHD, 43 due to infection and 25 because of organ toxicity. Probability of 3-years overall survival (OS), disease free survival (DFS), relapse incidence (RI) and TRM were 0.51±0.03, 0.50±0.03, 0.18±0.03 and 0.47±0.03, respectively. OS (0.56±0.04 vs 0.44±0.04, p=0.036) and TRM (0.31±0.04 vs 0.43±0.04, p=0.040) were statistically better for pts transplanted after 2007 (Figure 1).In multivariate analysis the only factors associated with lower OS were bone marrow blasts before alloSCT >10% (p=0.05, HR 1.5), mismatched donor (p=0.015, HR 1.8), PB as source of stem cells (p=0.048, HR 1.5) and alloSCT performed after 2007 (p=0.029, HR 1.6). There were no statistically significant differences in OS, DFS, RI and TRM between pts conditioned with RIC or MAC when analyzed in whole study cohort or with respect to age group, IPSS risk group, cytogenetics, interval from diagnosis to alloSCT.Conclusions: Allogeneic SCT is an option for MDS patients in different age groups. Disease status at time of transplant, mismatched donor and PB source of stem cells, but not conditioning intensity are the most important determinant for the outcome. High rate of TRM remains a concern, despite improvement over time. [Display omitted] DisclosuresJedrzejczak:Amgen, Novartis : Consultancy, Research Funding.

Expanding Clinical Trial Networks in Pediatric Acute Lymphoblastic Leukemia

Expanding Clinical Trial Networks in Pediatric Acute Lymphoblastic Leukemia