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Leukemia relapse rarely presents with ophthalmic manifestations. We report on a 62-year-old woman with relapse of Philadelphia chromosome–positive acute lymphoblastic leukemia who presented with ocular infiltration as the sole presentation. The diagnostic difficulties are also discussed.

Cytomegalovirus (CMV) reactivation in cord blood transplantation (CBT) may result in the proliferation and maturation of natural killer (NK) cells. Similarly, a mismatch of the killer cell immunoglobulin-like receptor (KIR)-ligand induces NK cell activation. Therefore, if CMV reactivation occurs in the presence of KIR-ligand mismatch, it might improve CBT outcomes. We assessed the difference in the effect of CMV reactivation in the presence of KIR-ligand mismatch on disease relapse in the graft-versus-host direction. A total of 2840 patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, and chronic myeloid leukemia were analyzed. Among those with a HLA-Bw4/A3/A11 (KIR3DL-ligand) mismatch, CMV reactivation up to 100 days following CBT had a favorable impact on relapse (18.9% vs. 32.9%, P = 0.0149). However, this effect was not observed in cases without the KIR3DL-ligand mismatch or in those with or without a HLA-C1/C2 (KIR2DL-ligand) mismatch. The multivariate analysis suggested that CMV reactivation had a favorable effect on relapse only in cases with a KIR3DL-ligand mismatch (hazard ratio 0.54, P = 0.032). Moreover, the interaction effect between CMV reactivation and KIR3DL-ligand mismatch on relapse was significant (P = 0.039). Thus, our study reveals the association between KIR-ligand mismatches and CMV reactivation, which will enhance CBT outcomes.

Acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy. The bone marrow (BM) microenvironment in AML plays an important role in leukemogenesis, drug resistance and leukemia relapse. In this study, we aimed to identify reliable immune-related biomarkers for AML prognosis by multiomics analysis. We obtained expression profiles from The Cancer Genome Atlas (TCGA) database and constructed a LASSO-Cox regression model to predict the prognosis of AML using multiomics bioinformatic analysis data. This was followed by independent validation of the model in the GSE106291 (n=251), GSE12417 (n=163) and GSE37642 (n=137) datasets and mutated genes in clinical samples for predicting overall survival (OS). Molecular docking was performed to predict the most optimal ligands to these hub genes. The single-cell RNA sequence dataset GSE116256 was used to clarify the expression of the hub genes in different immune cell types. According to their significant differences in immune gene signatures and survival trends, we concluded that the immune infiltration-lacking subtype (IL type) is associated with better prognosis than the immune infiltration-rich subtype (IR type). Using the LASSO model, we built a classifier based on 5 hub genes to predict the prognosis of AML (risk score = −0.086×ADAMTS3 + 0.180×CD52 + 0.472×CLCN5 - 0.356×HAL + 0.368×ICAM3). In summary, we constructed a prognostic model of AML using integrated multiomics bioinformatic analysis that could serve as a therapeutic classifier.

Background Infiltration of the breast by leukemic cells is uncommon but may manifest as an oncological emergency requiring prompt management. Extramedullary relapse of T-cell acute lymphoblastic leukemia (T-ALL) within the breast is exceedingly rare and there is paucity of data in the literature regarding this entity. No consensus exists on management of isolated extramedullary breast relapses of T-ALL. Herein, we report a case of isolated extramedullary breast relapse of T-ALL treated with breathing adapted radiation therapy (BART) using the active breathing control (ABC) system. Case summary The patient was a 33-year-old female with diagnosis of T-ALL. She received intensive systemic chemotherapy that resulted in complete remission of her disease, and then underwent allogeneic hematopoietic stem cell transplantation. After a 15 mo period without symptoms and signs of progression, the patient presented with palpable masses in both breasts. She complained from severe pain and swelling of the breasts. Imaging workup showed bilateral breast lesions, and diagnosis of breast infiltration by leukemic cells was confirmed after immunohistopathological evaluation. The patient suffering from severe pain, discomfort, and swelling of both breasts due to leukemic infiltration was referred to the Radiation Oncology Department for symptomatic palliation. Whole breast irradiation was delivered to both breasts of the patient with BART using the ABC system. The patient had complete resolution of her symptoms after treatment with BART. Conclusion BART with the ABC system resulted in complete resolution of the patient's symptoms due to leukemic infiltration of both breasts with T-ALL. This contemporary treatment technique should be preferred for radiotherapeutic management of patients with leukemic infiltration of the breasts to achieve effective symptomatic palliation.

Chimeric antigen receptor T cell therapy (CART) has achieved excellent results in the past 10 years for treating of leukemia. Treatment of B cell acute lymphoblastic leukemia by anti-CD19 CART can reach a complete remission rate of 90%. Although CART has greatly improved the treatment of patients with leukemia and lymphoma, as many as one-third of the patients can suffer disease relapse after CART. The tumor surface marker CD19 is negative in most the patients who relapse, and these patients display high expression of CD19 before treatment. In this review, the current causes of CD19-negative relapses after CD19 CART against leukemia, and the mechanisms of target escape are briefly summarized. Also, methods and strategies for treating relapse to provide references for the treatment of leukemia relapse are also discussed.

Background: Total body irradiation (TBI) is a mandatory step for patients with acute lymphoblastic leukemia (ALL), undergoing allogeneic hematopoietic stem cell transplantation (HSCT). In the past, amylases have been reported to be a possible sign of TBI toxicity. We investigated the relationship between total amylases (TA) and transplant-related outcomes in pediatric recipients. Methods: We retrospectively analyzed the medical records of all the patients who underwent allogeneic HSCT between January 2000 and November 2019. The inclusion criteria were the following: recipient’s age between 2 and 18, diagnosis of ALL, no previous transplantation, and use of TBI-based conditioning. The serum total amylase and pancreatic amylase were evaluated before, during, and after transplantation. Cytokines and chemokines assays were retrospectively performed. Results: 78 patients fulfilled the inclusion criteria. Fifty-seven patients were treated with fractionated TBI, and 21 with a single-dose regimen. The overall survival (OS) was 62.8%. Elevated values of TA were detected in 71 patients (91%). The TA were excellent in predicting the OS (AUC = 0.773, 95% CI = 0.66–0.86, p &lt, 0.001). TA values below 374 U/L were correlated with a higher OS. The highest mean TA values (673 U/L) were associated with a high disease-progression mortality rate. The TA showed a high predictive performance for disease progression-related death (AUC = 0.865, 95% CI = 0.77–0.93, 0.0001). Elevated TA values were also connected with significantly higher levels of proinflammatory cytokines, such as TNF-α, IL-6, and RANTES (p &lt, 0.001). Conclusions: this study shows that TA is a valuable predictor of post-transplant OS and increased risk of leukemia relapse.

Venetoclax is a selective B-cell lymphoma 2 (BCL2) inhibitor, which is approved to treat elderly patients with newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). A total of 60 patients with a median age of 67 years from different centers were included in the final analysis. Our real-life data support the use of venetoclax in patients with both newly diagnosed and relapsed high-risk MDS and AML. Introduction: Venetoclax is a selective B-cell lymphoma 2 (BCL2) inhibitor, which is approved to treat elderly patients with newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) in combination with either low-dose cytarabine (ARA-C) or hypomethylating agents. We aimed to collect and share data among the efficacy and safety of venetoclax both as a monotherapy or in combination with other drugs used to treat high-risk MDS or AML. Materials and Methods: A total of 60 patients with a median age of 67 (30-83) years from 14 different centers were included in the final analysis. Thirty (50%) of the patients were women; 6 (10%) of the 60 patients were diagnosed with high-risk MDS and the remaining were diagnosed with AML. Results: The best objective response rate (complete remission [CR], complete remission with incomplete hematological recovery (CRi), morphological leukemia-free state [MLFS], partial response [PR]) was 35% in the entire cohort. Best responses achieved during venetoclax per patient number were as follows: 7 CR, 1 CRi, 8 MLFS, 5 PR, and stable disease. Median overall survival achieved with venetoclax was 5 months in patients who relapsed and not achieved in patients who were initially treated with venetoclax. Nearly all patients (86.7%) had experienced a grade 2 or more hematologic toxicity. Some 36.7% of these patients had received granulocyte colony stimulating factor (GCSF) support. Infection, mainly pneumonia (26.7%), was the leading nonhematologic toxicity, and fatigue, diarrhea, and skin reactions were the others reported. Conclusion: Our real-life data support the use of venetoclax in patients with both newly diagnosed and relapsed high-risk MDS and AML.

Leukemia relapse 5 years after achieving first complete remission (CR1) is uncommon in patients with acute myeloid leukemia (AML). In this study, we evaluated the outcomes of AML patients with late relapse at our institution and reviewed the literature for these patients. The study cohort consisted of nine AML patients with late relapse. The median interval between CR1 and AML relapse was 6.1 years (range: 5.116.2 years). At relapse, the karyotype was different from the initial AML diagnosis in 50% of patients. At the time of AML relapse, seven patients received induction chemotherapy and two patients received hypomethylating agents with an overall CR rate of 66%. The median time to relapse after achieving second CR (CR2) was 16.5 months [95% confidence interval (CI): 9.4, NA]. The median overall survival after first relapse was 28.6 months (95% CI: 7.3, 3.466.5 months). Despite initial CR after reinduction therapy, relapse rates are still high, suggesting that alternative strategies for postremission therapies are warranted in CR2. These approaches include the use of allogeneic hematogenic cell transplantation and the use of newly approved AML agents as maintenance therapy in nontransplant eligible patients.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a curable strategy for acute lymphoblastic leukemia (ALL), especially for adult cases. However, leukemia relapse after allograft restricts the improvement of transplant outcomes. Measurable residual disease (MRD) has been the strongest predictor for relapse after allo-HSCT, allowing MRD-directed preemptive therapy.This manuscript summarizes the detection of MRD in patients with ALL who undergo allo-HSCT, focusing the effects of positive pre-HSCT MRD and post-HSCT MRD on outcomes as well as MRD-directed interventions.Except for MFC and RQ-PCR, other strategies, such as next-generation sequencing and RNAseq, have been developed for MRD determination. Negative effects of positive MRD peri-transplantation on outcomes of ALL patients were observed both in human leukocyte antigen (HLA)-matched sibling donor transplantation and in alternative donor transplantation. Advances have been made in determining the need for transplant according to MRD evaluation after induction or consolidation therapy. A number of approaches, including CAR-T-cell therapy, antibodies (blinatumomab, etc), targeted therapy (imatinib, etc), transplant donor selection, as well as donor lymphocyte infusion and interferon-α, have been successfully used or are promising for peri-transplantation MRD interventions. This progress could lead to the significant improvement of transplant outcomes for ALL patients.

Leukemia relapse occurring in donor cells, so called donor cell leukemia (DCL) after allogeneic hematopoietic stem cell transplantation has been previously reported [1–3]. Some authors have suggest...

Recipient chimerism increase has been used to predict leukemia relapse in post-hematopoietic cell transplant (HCT) patients with conventional GVHD prophylaxis. However, the value of recipient chimerism increase in patients with post-transplant cyclophosphamide (PTCy) is not clear. We compared PTCy to conventional GVHD prophylaxis (non-PTCy) patients regarding engraftment kinetics and the clinical significance of the 2 chimerism parameters, increasing mixed chimerism (IMC) and degree of recipient chimerism increase at the first event (Δ increase). We studied both total and T-cell-specific chimerism. While leukemia relapse is manifested by an increase in total cell recipient chimerism, an increase in T-cell-specific recipient chimerism may be more impactful in predicting relapse because of the effect of increased T-cell-specific chimerism on the graft-versus-leukemia effect. A total of 220 patients (PTCy: 44, non-PTCy: 176) with AML, MDS, and ALL underwent HCT at our institution from January 2014 to September 2020 and were included in this study (Table). Chimerism was tested at least monthly for the first 3 months, followed by every 3 months up until 1-year post-HCT, and then every 6-12 months thereafter. Short tandem repeat or quantitative PCR were used when percent recipient chimerism was ≥5% and PTCy patients achieved complete donor chimerism (CC) in total cells earlier at a deeper level (>99%) as compared to non-PTCy patients. Deeper total cell CC (>99%) was achieved in 79.5% of PTCy vs. 51% of non-PTCy patients at day 250, while CC (>95%) was achieved in almost 90% of patients in both groups within 100 days (Figure 1A and B). In comparison, the percentage of PTCy patients achieving T-cell-specific CC was significantly higher at day 250 post-HCT: CC (>95%/>99%) was 79.7%/68.4% in PTCy patients vs. 56.1%/37.5% in non-PTCy patients (Figure 1C and D). To evaluate their impact in predicting relapse, IMC was stratified into no IMC, 1 IMC (≥1 nonconsecutive IMC), and 2 IMC (≥2 consecutive IMC), and degree of recipient chimerism increase at the first event (Δ increase) was stratified into Two IMC (total), 1 IMC (T-cell), and 2 IMC (T-cell) groups were associated with shorter DFS in non-PTCy patients but not in PTCy patients (Figure 2). One and 2 IMC groups (both total and T-cell) were associated with relapse risk in non-PTCy patients. Furthermore, 1 IMC (T-cell) in non-PTCy patients showed a strong association in relapse risk (HR 7.0 (95%CI 2.83-17.8) p Δ increase ≥1% (total and T-cell) and Δ increase ≥0.1% (T-cell) were associated with shorter DFS in non-PTCy patients, while only Δ increase ≥1% (T-cell) only showed a trend towards shorter DFS in PTCy patients (Figure 3). The Cox regression model showed Δ increase ≥1% in both total, and T-cell chimerism was associated with relapse risk in non-PTCy patients (HR 6.4 (95%CI 2.9-14.2) p This is one of the most extensive studies investigating engraftment kinetics and the association of total and T-cell recipient chimerism increase to predict leukemia relapse in PTCy and non-PTCy HCT recipients. We found that PTCy HCT recipients achieved deeper engraftment earlier as compared to non-PTCy recipients. In addition, the two chimerism parameters (IMC and Δ increase) are less reliable in predicting relapse in PTCy than non-PTCy recipients. However, other factors, such as disease type, conditioning regimen, and donor HLA disparity, may have affected engraftment kinetics and the significance of chimerism parameters. Further investigations are warranted to elucidate the impact of the engraftment kinetics and recipient chimerism increase to predict relapse, especially in the PTCy setting. Figure 1 Figure 1. Disclosures Rakszawski: SeaGen: Speakers Bureau. Naik: Takeda: Other: Virtual Advisory Board Member ; Sanofi: Other: Virtual Advisory Board Member ; Kite: Other: Virtual Advisory Board Member. Rybka: Spark Therapeutics: Consultancy; Merck: Consultancy. Claxton: Astellas: Other: Clinical Trial; Novartis: Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Daiichi Sankyo: Research Funding; Incyte: Research Funding.

Mass cytometry of acute B cell lymphoblastic leukemias at diagnosis reveals intrapatient phenotypic heterogeneity and specific signatures that mimic cell developmental stage and predict future relapse.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curable strategy for the treatment of hematological malignancies and nonmalignant diseases. However, graft-versus-host disease (GVHD) and relapse are still two major causes of morbidity and mortality after allo-HSCT, and both restrict the improvement of transplant outcomes. Regulatory T cells (Tregs) has been successfully used in allo-SCT settings. In this review, we summarize recent advances in experimental studies that have evaluated the roles played by Tregs in the establishment of novel transplant modalities, the prevention of GVHD and the enhancement of immune reconstitution. We also discuss the application of Tregs in clinical to prevent acute GVHD, treat chronic GVHD, as well as enhance immune reconstitution and decrease leukemia relapse, all of which lead to improving transplant outcomes.

Mismatched HLA loss is a cause of leukemia relapse after HLA-haploidentical stem cell transplantation (haplo-SCT). We report a patient with a history of 2 occurrences of leukemia relapse due to mismatched HLA loss after haplo-SCT. He received haplo-SCT from his father but showed leukemia relapse with loss of the maternal HLA haplotype. He then underwent haplo-SCT from his mother, and developed relapse with loss of the paternal HLA haplotype. Both donors had killer cell immunoglobulin-like receptor-ligand mismatch but alloreactive natural killer cells could not prevent relapse. Second haplo-SCT should be conducted carefully for patients with relapse due to mismatched HLA loss.

Background As information on incidence, risk factors, and outcome of acute leukemia (AL) relapse after unmanipulated haploidentical stem cell transplantation (haplo-SCT) is scarce, a retrospective registry study was performed by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Methods Among 1652 transplants performed for lymphoblastic and myeloid AL between 2007 and 2014, 587 patients (acute lymphoblastic leukemia (ALL) 131, acute myeloid leukemia (AML) 456) with detailed information were analyzed aiming to identify risk factors for post-transplant relapse and for overall survival (OS) after relapse. Results The cumulative incidence of relapse at 3 years was 44% (35–53%) for ALL and 32% (27–36%) for AML (p = 0.023). In ALL, risk factors for relapse were disease status different from the first complete remission (CR1) at haplo-SCT (CR2 vs CR1: HR 2.85, p = 0.011; advanced vs CR1: HR 14.28, p < 0.0001) and male donor gender (HR 3.64, p = 0.0002), while in AML, risk factors were advanced disease at haplo-SCT (advanced vs CR1: HR 3.95, p < 0.0001) and comorbidities (HCT-CI) ≥ 3 (HR 1.75, p = 0.014). Transplants performed in more recent years were associated with lower relapse incidence (RI) in AML, but not in ALL (HR 0.91, p = 0.042). After relapse, median follow-up was 13 months (mos). OS at 1-year post relapse was 18%. Prognostic factors for superior OS after relapse were remission at time of haplo-SCT (CR vs advanced: HR 0.71, p = 0.028), time from transplant to relapse (≥ 5 mos vs < 5 mos: HR 0.530, p < 0.0001), and bone marrow as a stem cell source (peripheral blood (PB) vs bone marrow (BM): HR 1.473, p = 0.016). Conclusions Risk factors for relapse after haploidentical transplantation were disease specific. Longer OS after relapse was achieved in particular by patients both in CR at haplo-SCT and relapsing more than 5 months after transplant (1-year OS 33%). Electronic supplementary material The online version of this article (10.1186/s13045-019-0751-4) contains supplementary material, which is available to authorized users.

Background Chronic myeloid leukaemia (CML) is very rare in children. The aim of the study is to report the experience within the I-CML-Ped study in children and adolescents presenting at diagnosis with advanced phase disease and to describe their characteristics and outcomes. Methods Of 479 children and adolescents enrolled in the international registry for childhood chronic myeloid leukaemia (I-CML-Ped Study; www.clinicaltrials.gov NCT01281735 ), 36 children (7.5%) presented at initial diagnosis with CML in advanced phase according to the European LeukemiaNet criteria. Results Nineteen (4%) patients were diagnosed in accelerated phase (CML-AP), and among the 17 patients (3.5%) diagnosed in blastic phase (CML-BP), 70% presented with lymphoid immunophenotype. Initial treatment of CML-AP/CML-BP consisted of tyrosine kinase inhibitors (TKIs) with or without chemotherapy, leading to complete haematologic response in 33 of 36 (92%) patients. Seventeen patients proceeded to haematopoietic stem cell transplantation. At the last follow-up, 18 of 19 patients with de novo CML-AP are alive in at least major molecular response (MMR) (n = 16), in progression (n = 1) or in molecular relapse (n = 1) and 13 of 17 patients with de novo CML-BP are alive in at least MMR. Five-year overall survival rates are 94% (95% confidence interval [CI]: 66%–99%) and 74% (95% CI: 44%–89%) for patients diagnosed in CML-AP and CML-BP, respectively. Conclusion Children with advanced phase at diagnosis of CML seem to have a better survival rate than that reported for advanced phases evolving under TKI treatment.

Resistance of extramedullary leukemia growth post-transplant prevents cure. Review of its behavior detailed in 585 published cases should lead to better treatment. Leukemic tumors were found up to 13 years after transplant, most in sites inaccessible to physical exam. In 83%, marrow was not in morphologic relapse; next relapse was most often extramedullary. Induction protocols alone produced few durable responses in acute leukemias and fatal marrow aplasia in 17 %. Overall, 120 patients survived over 2 years, 43 relapse-free up to 18 years, the majority after combined tumor-directed and systemic therapy. Overall median survival was 9 months. This review highlights how results can improve: by defining extent of leukemia involvement with scans before transplant, and emergently when leukemic tumor is found after, ablating tumor directly to abort metastasis, and determining dosing of systemic chemotherapy that protects, without ablating, donor marrow. Monitoring total body remission with body scans should increase transplant cures.

Autologous Hematopoietic Stem Cell Transplantation (auto-HSCT) has become a therapeutic option for first-line consolidation in Acute Myeloid Leukemia (AML) patients with favorable and intermediate risk features. A total of 101 AML patients in first complete remission, who were not eligible for allogeneic HSCT, were randomized to receive intensive cytarabine-based chemotherapy or to undergo auto-HSCT. The probability of LFS was significantly better in auto-HSCT recipients compared to chemotherapy arm (43% vs. 4.8%, p = 0.008). At the end of 915 (30–4470) days of followup, the probability of overall survival was better in auto-HSCT group compared to chemotherapy, without statistical significance (79.2% vs. 38.8%, p = 0.054). Multivariate analysis revealed a significant predictive impact of cytogenetic risk status on OS (p = 0.002, HR: 2.824, 95% CI: 1.445–5.521). Auto-HSCT is considered as an effective consolidation approach in favorable and intermadiate risk AML patients.

Persons with acute leukemia relapsing after allotransplant and who respond to anti-leukemia interventions are at high risk of a second relapse. We studied the impact of minimal residual disease (MRD)- and graft-vs.-host disease (GvHD)-guided multiple consolidation chemotherapy and donor lymphocyte infusions (DLIs) to prevent second relapse in patients with acute leukemia relapsing post-transplant and who achieved complete remission after induction chemotherapy and DLI. Forty-seven subjects with acute leukemia relapsing after an allotransplant and who achieved complete remission after post-relapse induction chemotherapy and DLI were eligible. The use of consolidation chemotherapy and DLI was guided by the results of MRD testing and whether or not DLI caused acute and/or chronic GvHD. Outcomes were compared with those of 34 similar historical controls who did not receive consolidation chemotherapy and DLIs after induction chemotherapy and DLI. One-year cumulative incidence of relapse (CIR; 22 % 95 % confidence interval (10, 35 %) vs. 56 % (39, 73 %); P

αβ-T-cell depleted donor lymphocyte infusion for leukemia relapse after allogeneic stem cell transplantation

As a malignant hematopoietic stem cell disease, leukemia remains life-threatening due to its increasing incidence rate and mortality rate. Therefore, its early diagnosis and treatment play a very important role. In the present work, we systematically reviewed the current applications and future directions of positron emission tomography (PET) in patients with leukemia, especially 18F-FDG PET/CT. As a useful imaging approach, PET significantly contributes to the diagnosis and treatment of different types of leukemia, especially in the evaluation of extramedullary infiltration, monitoring of leukemia relapse, detection of Richter’s transformation (RT), and assessment of the inflammatory activity associated with acute graft versus host disease. Future investigations should be focused on the potential of PET/CT in the prediction of clinical outcomes in patients with leukemia and the utility of novel radiotracers.

In recent years, the human leukocyte antigen-haploidentical stem cell transplantation (haplo-SCT) approach is an attractive option for patients who require transplantation, but relapse is still the main reason that affects the curative effect of transplantation. Some studies have shown that haplo-SCT is superior to sibling or unrelated matching donor transplantation in preventing leukemia relapse after transplantation. In this review, we discussed the known and unknown aspects of relapse post haplo-SCT. Encouragingly, haplo-SCT experienced lower or similar incidence of relapse. But there is currently a lack of multicenter prospective studies evaluating the outcomes of different haplo-SCT strategies. The combination of common prophylactic strategies and pre-emptive interventions might help prevent relapse after transplantation. Novel methods such as target drugs therapy and chimeric antigen receptor T cell therapy may be useful in treatment of relapse.

Dismal outcomes of acute myeloid leukemia (AML), especially in the elderly, are mainly associated with leukemia relapse and primary no response to initial therapy. This review will focus on AML relapse, and how a better understanding of the evolutionary stages that lead to relapse might help us improve disease outcome. The fact that the relapse rate for some AMLs is so high indicates that we do not truly understand the biology of relapse or possibly that we are not implementing our current understanding into, clinical practice. Therefore, this review will also aim to explore some of the current understanding of AML relapse biology in order to identify the gaps in our knowledge and translation. Accumulating evidence suggests that the root of relapse evolves even before the time of diagnosis, meaning that the complex clonal structure of AML is created before patients present to the clinic. Some of the clones that exist at diagnosis can survive chemotherapy and give rise to relapse. Accordingly, in order to better understand the mechanisms of relapse, we must consider both early and late steps in AML evolution.

Double umbilical cord blood transplantation (UCBT) was developed as a strategy to circumvent the cell dose limitation of single UCBT with a concomitant potential benefit of lowering the rate of leukemia relapse. Sustained hematopoiesis after double UCBT usually is derived from a single donor unit, as only a few patients have been reported to display stable mixed-unit chimerism for varying periods of time. Explanations for the 1 unit dominance, predictors for identifying unit superiority, and persistence of long-term mixed-unit chimerism remain elusive. Review of published literature revealed only 11 of 280 patients (4%) with mixed-unit chimerism for at least 1 year after transplantation, with 3 patients receiving reduced-intensity conditioning regimens. Mixed-unit chimerism was more likely if both units were closely HLA matched to each other. Outcome data for patients with stable mixed-unit chimerism, for the most part, were scarcely reported. Analysis of the small sample size revealed a potential advantage of stable mixed-unit chimerism on enhancing the graft-versus-leukemia effect; however, definitive conclusions cannot be made on the effect of mixed-unit chimerism on the rates of graft-versus-host disease. Therefore, gathering outcome data prospectively in larger clinical series will help answer the question of whether stable mixed-unit chimerism is either beneficial and, therefore, should be strived for, detrimental and, thus, needs to be eliminated, or if it is of no clinical consequence.

The significance of patient and donor ethnicity on risk of acute graft-versus-host disease (GVHD) and disease relapse after unrelated donor hematopoietic cell transplantation (HCT) is not known. A total of 4335 patient–donor pairs from the International Histocompatibility Working Group in HCT met the following 3 criteria: (1) HLA-A, -B, -C, -DRB1, and -DQB1 allele matched donor, (2) diagnosis of leukemia, and (3) non–T cell depleted GVHD prophylaxis. Posttransplantation risks of acute GVHD and leukemia relapse were defined in Asian/Pacific Islander, white, African American, Hispanic, and Native American patients that underwent transplantation from donors with the same self-described background. Asian patients had a significantly lower incidence of acute GVHD (Japanese patients: 40.0% grades II to IV and 15.3% grades III to IV; non-Japanese Asian patients: 42.1% grades II to IV and 15.7% grades III to IV) compared with white patients (56.5% grades II to IV and 22.6% grades III to IV) (P

Despite marked clinical successes in the treatment of childhood T-ALL, leukemia relapse, refractory disease and induction failure (around 30% of patients) remain significant clinical problems. New insights in the molecular alterations of ALL have revealed new molecular targets, such as activating mutations of Notch1 (N1), identified in more than 50% of T-ALL patients. However, disruption of N1 signaling by gamma-secretase inhibitors failed to fulfill its clinical promise. Furthermore, little is known about N1 downstream mediators that can be potential therapeutic targets in T-ALL.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for patients with relapsed acute myeloid leukemia. In this retrospective, multicenter study, we analyzed the outcome of 63 children (median age, 7 y; range, 0.2 to 17) who received unmanipulated allo-HSCT in second complete remission. Either a matched family donor or an unrelated donor was used in 29 (46%) and 34 (54%) patients, respectively. The stem cell source was bone marrow in 53 children (84%), peripheral blood in 7 (11%), and cord blood in 3 patients (5%). Preparative regimen included total body irradiation in 25 patients (40%). The 5-year estimates of overall survival and leukemia-free survival were 53% [95% confidence interval (CI) 39-66] and 49% (95% CI 35-63), respectively, whereas the cumulative incidence of relapse and transplant-related mortality (TRM) were 26% (95% CI 16-41) and 25% (95% CI 15-40), respectively. In multivariate analysis, the use of a matched family donor predicted a better probability of LFS [relative risk (RR) 2.29, P=0.05]. Both chronic graft-versus-host disease occurrence and age at diagnosis greater than 11 years were associated with an increased TRM (RR 8.08, P=0.04 and RR 4.38, P=0.05, respectively). These results indicate that allo-HSCT is a procedure able to rescue a significant proportion of children with acute myeloid leukemia in second complete remission, especially if an human leukocyte antigen-compatible relative is employed as donor. Both leukemia recurrence and TRM contributed to treatment failure. Optimization of donor selection and of strategies for both prophylaxis and treatment of graft-versus-host disease may improve the results of unrelated donor allo-HSCT.

We have established a novel immunotherapeutic approach involving dendritic cells (DCs) with potent immunoregulatory property (designated as regulatory DCs [rDCs]) for acute graft-versus-host disease (GVHD) and leukemia relapse in allogeneic bone marrow (BM) transplantation (BMT) in mice bearing leukemia. rDCs displayed high levels of MHC molecules and extremely low levels of costimulatory molecules. A single injection of rDCs following allogeneic BMT controlled the ability of the transplanted T cells to induce acute GVHD and graft-versus-leukemia (GVL) effect in the recipients bearing leukemia, and that resulted in protection from the lethality caused by acute GVHD and tumor burden. Thus, the use of rDCs may be therapeutically useful for the treatment of acute GVHD and leukemia relapse in allogeneic BMT.

A low thymic function is associated with leukemia relapse in children given T-cell-depleted HLA-haploidentical stem cell transplantation

PURPOSE To investigate the use of spectral domain optical coherence tomography (SD-OCT) findings in pediatric acute lymphoblastic leukemia (ALL) patients. METHODS Children that were diagnosed with precursor B-cell ALL and classified as belonging to the medium-risk group for relapse were selected for this study. Individuals who were in. continuous remission and on maintenance therapy were included in the study group. Cases that had central nervous system involvement were excluded. Age-matched, otherwise healthy children were selected for the control group. Each study participant underwent a comprehensive eye examination and SD-OCT evaluation. Thickness measurements were made within the retinal nerve fiber layer (RNFL), central macula, posterior polar, and peripapillary choroid. RESULTS A total of 112 eyes of 56 children were included: 54 eyes in the study group and 58 in the control group. Compared to the control group, subfoveal and temporal choroidal thicknesses of the posterior pole were significantly thinner in the study group (P < 0.005). Similarly, peripapillary choroidal thicknesses were significantly thinner in most sectors of the study group (P < 0.005). There were no major differences between groups in terms of central macular thicknesses and overall RNFL thicknesses. CONCLUSIONS Evidence of choroidal attenuation was found in this subgroup of pediatric ALL patients. Further studies are warranted to clarify the utility of SD-OCT in detecting subclinical ocular involvement and monitoring treatment response and risk of relapse in patients with pediatric leukemia.

Chronic graft-versus-host disease is a frequent complication of allogeneic hematopoietic cell transplantation and plays an important role in posttransplant morbidity and mortality, yet is correlated with the graft-versus-tumor effect in some studies. New approaches to separate the graft-versus-tumor from the graft-versus-host effect are urgently needed. Clin Cancer Res; 21(9); 1981–3. ©2015 AACR. See related article by Boyiadzis et al., p. 2020

Loss of mismatched HLA is a cause of relapse following HLA-mismatched allo-SCT. We directly detected the loss of mismatched HLA alleles in relapsed leukemic cells at a MRD level using HLA typing by multicolor FACS (HLA-Flow) in combination with FISH in the BM of two patients with MLL-AF9-positive AML, at 6 and 10 months after mismatched allo-SCT. HLA-Flow with FISH analysis detected relapsed leukemic cells not expressing a mismatched HLA allele and harboring the MLL rearrangement. Simultaneously, real-time quantitative RT-PCR detected a low copy number of MLL-AF9 transcripts, consistent with MRD detection. HLA-Flow with FISH is a powerful method for detecting molecular relapse after mismatched allo-SCT and provides important information on the HLA expression status of the relapsed leukemic cells to help determine the next intervention.

PURPOSE To report a case of leukemia relapse in the subretinal space that was diagnosed by transvitreal subretinal biopsy. METHODS Case report and literature review. RESULTS A 5-year-old girl with prior history of acute lymphocytic leukemia who was in clinical remission was examined for a unilateral subretinal mass. Her systemic evaluation was negative for recurrence of the acute lymphocytic leukemia. Pars plana vitrectomy with a subretinal biopsy showed leukemic cells confirmed by flow cytometric immunophenotyping. The patient subsequently underwent bone marrow transplantation with regression of the subretinal mass. CONCLUSION Leukemia relapse may occur in the subretinal space. A relapse may be successfully diagnosed with a subretinal biopsy through a pars plana vitrectomy.

Leukemia relapse occurring in donor cells, so called donor cell leukemia (DCL) after allogeneic hematopoietic stem-cell transplantation has been reported infrequently; less than 50 cases have been ...

Acute myelocytic leukemia (AML) is a relapsing and deadly disease. Thus, it is important to early predict leukemia relapse. Recent studies have demonstrated strong correlations of relapse with abnormal localization of immature precursors (ALIP). However, there is no related research on automated detection of ALIP so far. To this end, we have proposed an ALIP detection method to investigate the relevance with AML relapse. Kernelized fuzzy C-means clustering is applied first to separate the foreground (with cells) and background (without cells). Image repairing is then used to wipe out noises to mark region of interest. Then, image partition is introduced to separate the overlapping cells. After that, a set of features are extracted for the classification. Thereafter, support vector machine is applied to classify precursors. At last, filtering operations are applied to obtain the binary-precursor detection results. Thirty-seven patients with AML are examined. The results show that ALIP is efficiently detected in a high sensitivity and positive predictive value by our proposed method. The investigation also demonstrates the strong correlations of AML relapse with ALIP.

In recent years, significant progress has been achieved in the monitoring of treatment effectiveness in hematological malignancies through the detection of so-called minimal residual disease (MRD). In this chapter, we present the methodological principles of MRD monitoring and its clinical application using acute lymphoblastic leukemia as a model disease. Detection of MRD kinetics during the first months of treatment has high prognostic value and it is currently employed for patient stratification in many treatment protocols. In high-risk patients and relapsed patients the MRD clearance is a prerequisite for effective stem cell transplantation. Therefore, MRD monitoring forms the basis for subsequent treatment intervention.

Obesity increases the risk of developing all four common subtypes of leukemia. In addition, children and adults who are obese when they are diagnosed with acute lymphoblastic leukemia (ALL), have a higher risk of relapse. While a number of potential mechanisms linking obesity and cancer have been postulated, none can convincingly explain the links between obesity and leukemia incidence or relapse. In the present chapter, we review the evidence that obesity increases leukemia relapse, and explore some mechanisms that might contribute to this observation.

In total, 17 pediatric patients with hematologic malignancies (n=14) and Fanconi anemia (FA) (n=3) underwent haploidentical SCT with T-cell depletion. The patients were conditioned with reduced-intensity regimens, and CYA was used for GVHD prophylaxis. Successful engraftment occurred in 16 patients (94%). One patient failed to achieve a primary engraftment. Another patient rejected the first SCT after 10 weeks and had a successful second transplant. Of all engrafted patients, only one developed severe acute GVHD. Ten patients were alive at a median follow-up of 18 months (range, 5–62 months). The 5-years’ OS was 53.8%. The three patients with FA are currently well with full-donor chimerism at 16, 6 and 5 months post transplant, respectively. The OS of 14 patients with high-risk hematologic malignancies was 47.6%. Three patients died as a result of post transplant leukemia relapse. CMV infection, GVHD and organ injury were other causes of mortality. Haploidentical SCT was found to be an alternative feasible treatment in Uruguay for patients who need allogenic transplantation but lack an HLA-identical family donor. It should be considered as an early option in FA patients before transformation or significant exposure to blood products.