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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.

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.

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.

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

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.

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.

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

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

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 ...

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.

During the past 30 years, survival rates after allogeneic stem cell transplantation (SCT) have been improved substantially. These improvements have mostly been due to better graft matching using genomic HLA typing, GVHD prophylaxis, infection management, and supportive care [1-3]. The incidence of leukemia relapse and death rates after relapse, however, have not been significantly decreased [4]. This makes relapse still a major obstacle to successful SCT.

Leukemia was the first malignant condition in which cancer stem cells were described. Leukemia stem cells (LSCs) have now been described in a number of different types of leukemia and are currently a major focus of research interest. LSCs are an important target for treatment of leukemia, and failure to eradicate these very primitive cancer cells is a common cause of leukemia relapse. Therefore, improved understanding of the biology of LSCs and the differences between normal hematopoietic and leukemic stem cells is likely to lead to the development of novel therapeutic strategies and improvements in leukemia therapy and patient survival.

Autotransplants in leukemia are controversial; their rationale and results have been questioned. Here we consider several issues central to this debate: (1) Are there convincing data to suggest that more intensive therapy increases cures? (2) Are results post-autotransplant a consequence of the transplant, or do they reflect subject-selection and time-to-treatment (time censoring) biases? (3) Does leukemia relapse after an autotransplant develop from persisting leukemia cells in the subject or the graft? (4) Do autotransplants using hematopoietic stem cells from different sources have distinct outcomes? (5) Are immune-mediated anti-leukemia mechanisms likely to prevent relapse after autotransplants? and (6) Can comparably intensive therapy be given without an autotransplant?

HLA-matched sibling donor (MSD) stem cell transplantation can cure >60% of pediatric patients with acute lymphoblastic leukemia (ALL), but

Recurrent or residual leukemia found in extramedullary sites after intensive treatments adversely affects prognosis. To summarize the sites and outcomes when extramedullary relapses have been reported after stem cell transplants, and to elucidate when long survival has been achieved, 207 cases were analysed. Authors were contacted for follow-up information. The most commonly reported sites are soft tissue in acute leukemias and bone in CML. Extramedullary relapse occurred typically within 2 years in ALL, but later in one-third of myeloid leukemias. Most testicular relapses reported in AML followed non-TBI conditioning. Marrow relapse was not inevitable if aggressive treatment was begun early. Local therapy alone was generally inadequate. Intensive therapy has produced lengthy remissions in cases of acute leukemias involving various sites, whereas CML cases, particularly involving bone, were most resistant to treatment. Heightened awareness and aggressive treatment should improve the prospect for cure after extramedullary relapse.

Recent studies suggest that components of the prosurvival signal transduction pathways involving the Ras-mitogen-activated protein kinase (MAPK) can confer an aggressive, apoptosis-resistant phenotype to leukemia cells. In this study, we report that acute promyelocytic leukemia (APL) cells exploit the Ras-MAPK activation pathway to phosphorylate at Ser112 and to inactivate the proapoptotic protein Bad, delaying arsenic trioxide (ATO)-induced apoptosis. Both in APL cell line NB4 and in APL primary blasts, the inhibition of extracellular signal-regulated kinases 1/2 (ERK1/2) and Bad phosphorylation by MEK1 inhibitors enhanced apoptosis in ATO-treated cells. We isolated an arsenic-resistant NB4 subline (NB4-As(R)), which showed stronger ERK1/2 activity (2.7-fold increase) and Bad phosphorylation (2.4-fold increase) compared to parental NB4 cells in response to ATO treatment. Upon ATO exposure, both NB4 and NB4-As(R) cell lines doubled protein levels of the death antagonist Bcl-xL, but the amount of free Bcl-xL that did not heterodimerize with Bad was 1.8-fold greater in NB4-As(R) than in the parental line. MEK1 inhibitors dephosphorylated Bad and inhibited the ATO-induced increase of Bcl-xL, overcoming ATO resistance in NB4-As(R). These results may provide a rationale to develop combined or sequential MEK1 inhibitors plus ATO therapy in this clinical setting.

Aims of this study were to verify whether reduction in transplant-related mortality (TRM) of children with acute lymphoblastic leukemia (ALL) in second complete remission (CR) given allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated volunteers has occurred over time and to investigate the role of other variables on the probabilities of relapse, TRM and event-free survival (EFS). We compared results obtained in 26 children given HSCT before January 1998 with those of 37 patients transplanted beyond that date. In all donor-recipient pairs, histocompatibility was determined by serology for HLA-A and -B antigens and by high-resolution DNA typing for DRB1 antigen. High-resolution molecular typing of HLA class I antigens was employed in 20 of the 37 children transplanted more recently. Probability of both acute and chronic GVHD was comparable in the two groups of patients. In multivariate analysis, children transplanted before January 1998, those with T-lineage ALL and those experiencing grade II-IV acute GVHD had a higher relative risk of TRM at 6 months after transplantation. Relapse rate was unfavorably affected by a time interval between diagnosis and relapse

We report here a preliminary experience with gemtuzumab ozogamicin (GO) used at low dosage (3 mg/m2) in 3 elderly patients with acute promyelocytic leukaemia (APL) who presented molecular relapse and were unfit for intensive chemotherapy.

Tumor relapse remains a major obstacle to the success of allogeneic bone marrow transplantation (BMT) as a treatment for leukemia. Due to limited treatment options, the outlook for most patients that relapse following allogeneic BMT has been poor. The infusion of normal immunocompetent leukocytes from the original marrow donor has become a promising new option for treating/preventing leukemia relapse in allogeneic BMT recipients. This form of treatment has often been referred to as donor leukocyte infusion (DLI) therapy. Our laboratory is using murine models of allogeneic BMT to address important unresolved issues regarding DLI therapy in an effort to make the treatment more effective. These include identification of the antileukemic effector cells, augmentation of the antileukemic effect, and understanding why graft-versus-host-disease (GVHD) is less severe than anticipated. This article reviews our work in murine models of DLI and introduces our current working hypotheses concerning DLI therapy.

T cell-depletion of the donor bone marrow prevents GvHD in matched BMT recipients, but this benefit is offset by an increased risk of graft failure and leukemia relapse. One approach 10 improving disease-free survival of TCD transplants recipients is to employ intensified conditioning regimens. More intensive pre-transplant immunosuppression and myeloablation should compensate for the loss of the anti-host and anti-leukemic effect, mediated by donor T cells and thereby overcome resistance to engraftment and provide a greater anti-leukemic activity. To this end, we desisned in 1989, a new conditioning regimen that added ATG and thiotepa (IT) to Cy and 1440 cGy hyperfractionated TBI, to enhance both immunosuppression and myeloablation. From June 1989, 54 patients (33 M, 21 F; median age 29 years, range 6–53) with acute leukemia (30 AML, 24 ALL) in hematological remission (22 CR L 14 CR II) or relapse (N = 18) received HLA-identical BMI depleted of T cells by the soybean agglutinin and E-rosetting technique. No additional post-transplant immunosuppressive treatment was given. All patients engrafted with a full-donor type chimerism. Neither acute nor chronic GvHD occurred in any evaluable patient of the 36 patients in remission at transplant, 24, survive event-tree at a median follow-up of 50 months (range 26.78) with a PS 100%. 6 relapsed (2AML, 4 ALL) and 6 died from TRM Of the 18 in relapse at transplant, 4 survive event-free at a median follow-up of 44 months (range 30–46), 7 relapsed (2AML.5ALL) and 6 died from TRM. We believe that TT enhances the cytoreductive elfect of the conventional conditioning regimens in T-depleted BMTs and that there is a GvL effect mediated by the expansion of immunocompetent lymphocytes in the absence of GvHD when no cyclosporine is given.

ABLATIVE chemotherapy with allogeneic bone-marrow transplantation has become an accepted means of therapy for acute leukemia.1 It is the only treatment capable of producing long-term unmaintained remissions in patients with acute lymphoblastic leukemia who have had relapses during the course of conventional chemotherapy, and it has been advocated for acute myeloblastic leukemia in first remission.1 An initially unforeseen and rare form of failure of such therapy has been the relapse of leukemia in donor cells.2 3 4 5 We report here our experience with a patient with acute lymphoblastic leukemia who had a relapse after therapy with high-dose cyclophosphamide, total-body irradiation, and bone-marrow . . .

Modern intensive induction chemotherapy produces remissions in > 90% of individuals with acute lymphoblastic leukemia (ALL) and > 60–80% of those with acute myelogenous leukemia (AML). If these individuals receive no further therapy two distinct outcomes will occur. A small proportion, probably substantially < 10%, will remain in remission, for a prolonged period; probably most of these individuals are cured. A more frequent outcome is for leukemia to recur. Leukemia relapse also occurs in a substantial proportion of adults with ALL and children and adults with AML despite intensive post-remission chemotherapy.