Recurrent Acute Leukemia Research Articles

CAR T-cell bridging to allo-HSCT for relapsed/refractory B-cell acute lymphoblastic leukemia: the follow-up outcomes

目的研究嵌合抗原受体T细胞（CAR-T）细胞治疗桥接异基因造血干细胞移植（allo-HSCT）治疗复发/难治急性B淋巴细胞白血病（R/R B-ALL）的疗效及安全性。方法回顾性分析2017年1月至2019年5月于苏州大学附属第一医院行CAR-T细胞治疗桥接allo-HSCT的50例R/R B-ALL患者的临床资料，分析CAR-T细胞治疗前、后及allo-HSCT前不同骨髓微小残留病（MRD）水平患者总生存（OS）率、无事件生存（EFS）率、累积复发率（CIR）、移植相关死亡率（TRM）。结果全部患者共行55例次CAR-T细胞治疗，CAR-T细胞治疗反应率、严重细胞因子释放综合征（CRS）发生率分别为92％、28％。未发生治疗相关死亡。CAR-T细胞输注至allo-HSCT的中位时间为54（26～232）d。CAR-T细胞输注后中位随访637（117～1097）d，1年OS、EFS率分别为（80.0±5.7）％、（60.0±6.9）％。移植后1年CIR、TRM分别为（28.0±0.4）％、（8.0±0.2）％。CAR-T细胞输注后及allo-HSCT前骨髓MRD<0.01％患者1年EFS率更高［（70.0±7.2）％、（20.0±12.6）％，P<0.001；（66.7±7.5）％对（36.4±14.5）％，P＝0.008］，CIR更低［（25.0±0.5）％、（70.0±2.6）％，P<0.001；（23.1±0.5）％、（45.4±2.6）％，P＝0.038］。结论CAR-T细胞治疗桥接allo-HCT对于复发/难治B-ALL是一种安全有效的治疗策略。

Posttransplant maintenance therapy for acute leukemias.

Allogeneic hematopoietic stem cell transplantation cures a significant proportion of patients with hematological malignancies. Unfortunately, leukemia recurrence is the main cause of transplant failure. Risk factors for relapse include presence of minimal residual disease and a variety of well-recognized leukemia prognostic factors. Posttransplant therapy could decrease the risk of leukemia relapse and is under investigation. In this review, we summarize the current research in maintenance therapy for the prevention of acute leukemia recurrence after allogeneic transplant. Epigenetic modifiers, tyrosine kinase inhibitors, and antibody-drug conjugates are among potential maintenance therapies given their side-effect profile and many are currently under investigation. In the posttransplant setting, the phase I/II data are maturing and have been encouraging enough to lead to the initiation of multicenter phase III randomized clinical trials. Currently, there is no standard of care for posttransplant maintenance for acute leukemias. Further investigation into the efficacy and safety of posttransplant maintenance is warranted given phase I/II clinical trials results. Beyond chemo-immunotherapy, the use of targeted cellular therapy, such as chimeric antigen receptor T cells, is a potential therapy as well.

Clinical analysis of donor-derived CD19 chimeric antigen receptor T lymphocytes for the treatment of recu-rrent acute B-cell leukemia after allogeneic hematopoietic stem cell transplantation

Objective To discuss the cure effect and side effects of donor anti-CD19 chimeric antigen receptor T lymphocytes(CD19 CAR-T)for treating recurrent acute B-cell leukemia after allogeneic hematopoietic stem-cell transplantation(Allo-HSCT), and to analyze the influencing factors for this therapy. Methods The clinical data of 5 acute B-cell leukemia patients were analyzed retrospectively who relapsed after Allo-HSCT and received donor CD19 CAR-T therapy at Beijing Children′s Hospital from July 2015 to October 2017.Disease status before infusion, conditioning regimen, reinfusion cell dose, and side-effect of CAR-T infusion, changes in the related immunological indicators, and follow-up treatment results were investigated. Results One patient had no effect, other patients got remission or minimal residual disease(MRD) negative within 4 weeks after CAR-T infusion, and the middle time was 14 days.Peripheral CAR-T peak happened 2 weeks after CAR-T infusion.By the last follow, 2 patients died of leukemia, 3 patients were alive, and 1 case of them lived with tumor after CD19 negative relapse, others lived with disease-free condition.Cytokine release syndrome(CRS) was the most common side effect, happening in 1 to 2 weeks after infusion, 1 patient had neurologic toxicities, and 2 patients had suspicious graft-versus-host disease. Conclusions Donor CD19 CAR-T therapy has a good short-term effect for relapsed B-cell leukemia patients after Allo-HSCT, but long-term effect requires further observation; CRS is the most common side-effect.Off-target and cell exhaustion are the main reasons for defeat. Key words: Donor chimeric antigen receptor T cell; CD19; Relapse acute leukemia; Allogeneic hematopoietic stem cell transplantation

A Phase I/Pilot Study of CPX-351 [Daunorubicin and Cytarabine Liposome for Injection (Vyxeos®)] for Children, Adolescents and Young Adults with Recurrent or Refractory Acute Leukemia

▪Background: CPX-351 (Vyxeos®) is a liposomal nanoparticle of cytarabine and daunorubicin in a 5:1 molar ratio currently FDA approved for treatment of adults with newly-diagnosed therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes. The agent also has potent activity against acute lymphoblastic leukemia (ALL) in murine xenograft models [H. Carol et al. Pediatr Blood Cancer 2015;62: 65-71]. We conducted the first phase I/pilot study to evaluate the safety and describe the efficacy of CPX-351 in children and adolescents with relapsed or refractory (R/R) acute leukemia (NCT01943682).Methods: In the Dose Exploration Phase participants age 12 months to 21 years were eligible to receive a single course of CPX-351 administered once daily on Days 1, 3, and 5. Enrollment was initiated at the recommended dose for study in adults (Dose Level 1: 100 Units/m2/dose= cytarabine 100 mg/m2 and daunorubicin 44 mg/m2 per dose) with provisions to explore either a single dose escalation to 134 Units/m2/dose (Dose Level 2) or de-escalation to 67 Units/m2/dose. Response was determined after Day 28. The upper age for eligibility was increased to 30 years and an additional 18 subjects were enrolled into the Expanded Phase of the study.Results: Nine children and adolescents with R/R AML (n=6) or ALL (n=3) were enrolled and evaluable for toxicity in the Dose Exploration Phase. All 9 experienced Grade 3 or 4 hematologic toxicity including 8 with fever with neutropenia or infection. Dose Limiting Toxicity (DLT) was not observed in the 4 patients enrolled at Level 1 but Grade 3 pain/headache lasting greater than 48 hours did occur in 2 of the 5 patients treated at Dose Level 2. One patient with AML was unevaluable for response in this phase due to removal from protocol therapy to receive bone marrow transplantation while in aplasia. All others were evaluable for response. One patient with ALL had stable disease, 2 with AML achieved a complete remission (CR), and 1 with AML achieved a CR in blood and marrow but developed low level disease in the cerebral spinal fluid (CSF).One patient with mixed phenotype acute leukemia and 17 with R/R AML were subsequently enrolled into the Expanded Phase of the study to receive CPX-351 at Dose Level 1. CPX-351 treatment was well tolerated in this population with a similar toxicity profile observed in the Dose Exploration Phase. Dose limiting prolonged aplasia occurred in one patient but no other DLTs were observed. The response has yet to be determined in one patient. To date, seven patients with AML (41%) achieved a CR or complete remission with incomplete blood recovery (CRi). Another patient achieved a CR in marrow but with low level disease detected in the CSF similar to the patient described in the Dose Exploration phase. The remaining 9 patients failed to achieve a clinical response. Pharmacokinetic (PK) parameters of total cytarabine and daunorubicin were analyzed for 21 of these pediatric patients and the results were similar to those observed in adults. However, due to the small sample size of each age group, these interim PK results will need to be validated as data in pediatric patients become available from future clinical studies.Conclusions: CPX-351 100 Units/m2/dose on Days 1, 3, and 5 was well tolerated in this pediatric population and has promising activity in children and young adults with R/R AML. Additional CNS directed therapy is recommended for pediatric patients at high risk for failure in the CNS. DisclosuresPhillips:Novartis AG: Consultancy. An:Jazz Pharmaceuticals: Employment.

Clinical characteristics and outcome of invasive fungal infections in pediatric acute myeloid leukemia patients in a medical center in Taiwan.

Invasive fungal infection (IFI) causes significant morbidity and mortality in patients with hematological malignancies, especially those with acute myeloid leukemia (AML), recurrent acute leukemia, high-risk acute lymphoblastic leukemia, and after allogeneic hematopoietic stem cell transplantation. The study aimed to investigate the clinical characteristics and outcome of IFIs in pediatric AML patients in a medical center in Taiwan. We performed retrospective chart reviews. We enrolled pediatric AML patients who were admitted to National Taiwan University Hospital between January 2005 and December 2014. IFI was defined according to the European Organization for Research and Treatment of Cancer/Mycosis Study Group 2008 consensus criteria. In total, 78 patients were included for analysis. Twenty two episodes of IFIs were identified in 16 patients. The incidence for IFIs was 20.5% (16/78), and no specific trend of increase or decrease was observed through the study period (p=0.374). Candida species caused the majority (59.1%) of IFIs. Prolonged neutropenia and elevated alanine aminotransferase and creatinine values were factors associated with IFIs (p<0.001, p<0.001, and p=0.001, respectively). Patients with endotracheal intubation or inotropes usage had a higher probability of developing IFIs (p<0.001 and p=0.001, respectively). The overall mortality of IFIs was 53% (8/15) over 10 years, and patients with pulmonary aspergillosis had the highest mortality (80%). IFIs continue to pose significant morbidity and mortality in pediatric AML patients, and patients with other hematology-oncology cancers. Recognition of factors associated with IFIs may help us early identify IFIs and promptly initiate antifungal therapy.

Decreased Hemolysis of Red Cells Washed with Plasma-Lyte As Compared with 0.9% Sodium Chloride

Introduction -Washed red blood cell (RBC) and platelet transfusions have been a valuable therapeutic option for patients with repeated or severe allergic or febrile reactions. Recent data from randomized and observational clinical trials demonstrate that washed transfusions reduce inflammatory and immunologic complications, including recurrence of acute leukemia, death after coronary surgery, elevations of IL-6 and C-reactive protein after pediatric cardiac surgery, and transfusion related acute lung injury and transfusion associated cardiac overload. However, washing of RBCs may not be completely benign. Increased hemolysis may occur in vitro. Washing of RBCs stored for longer periods (>28 days) is associated with increased morbidity in pediatric cardiac surgery patients receiving massive transfusions of older RBCs. Current washing techniques and dilution of RBCs for transfusion employ 0.9% normal saline (NS) which is both hypertonic and acidic. We evaluated whether use of a more physiologic solution, Plasma-Lyte, causes less damage to RBCs than use of NS.Methods -We employed RBC units (n=15) collected for, but not suitable for clinical transfusion. Median storage age was 19 days (range 10-39 days). Each donor unit (11 AS-1, 3 AS-3 and 1 CPD-A1) was split in two using aseptic technique, and washed with either a liter of NS or Plasma-Lyte employing a standard clinical protocol on a Terumo 2991. Each half was resuspended in 20 ml of washing solution. Aliquots (12 ml) were removed prior to and immediately after washing, and after 24, 48 and 72 hours of storage at 1-6¡ C. These aliquots were immediately centrifuged (15 min at 4,300 x g) and the supernatant stored at -80¡ C. Hemoglobin and heme in the supernatant were quantitated using QuantiChrom kits. All comparisons were by Wilcoxon matched pairs non-parametric tests.Results -Supernatants immediately after washing had similar mean free hemoglobin (pre = 160 mg/dl ± 80 [SEM]; post = 66 ± 12 for NS and 58 ± 10 for Plasma-Lyte) and heme (pre = 92 µM ± 46; post = 36 ± 8 for NS and 33 ± 7 for Plasma-Lyte ). However, by 24 hours of storage after washing (the current limit for clinical use), supernatant heme and hemoglobin were significantly greater by about 50% in RBCs stored in NS (87 µM ± 22 and 151 mg/dl ± 36) as compared to Plasma-Lyte (59 µM ± 21 and 108 mg/dl ± 36; p = 0.014 and 0.02). These changes accelerated during subsequent storage (see figure for heme levels-differences in hemoglobin were comparable). Prolonged storage after NS washing predisposed to greater hemolysis than did Plasma-Lyte washing. Supernatant heme levels at 72 hours post washing increased from early (10-18 days; n=5) to late (31-39 days; n=5) storage by a mean of 61% in Plasma-Lyte washed RBCs (p=0.26) compared with 200% in NS washed RBCs (p=0.016)Conclusions -RBCs stored for 10-39 days and then washed with Plasma-Lyte experience strikingly less hemolysis. Whether such differences would occur in vivo is not known, and the clinical implications are yet to be determined. Circulating free heme and hemoglobin levels have been associated with thrombosis in animal models, transfused patients and patients with sickle cell disease. NS, as opposed to Plasma-Lyte, has been linked to increased renal injury and mortality in animal models and patients. We speculate that hemolysis may be a contributing cause. Our results indicate that RBC washing with Plasma-Lyte is a superior approach and potentially safer than NS. These findings also suggest the hypothesis for further investigation of whether NS is truly a suitable diluent for RBC transfusion, and whether NS is the safest choice when crystalloid is indicated for volume replacement or apheresis. Plasma-Lyte washing might also facilitate increasing the storage period of washed RBCs. [Display omitted] DisclosuresOff Label Use: See Dr. Blumberg's disclosure. Blumberg:Biomet: Consultancy; Terumo: Consultancy.

Usefulness and pitfalls of F-18-FDG PET/CT for diagnosing extramedullary acute leukemia

PurposeIt is very important to identify whether there is extramedullary involvement in acute leukemia (AL), especially in those with recurrent disease. This retrospective study aimed to assess the role of 18F-FDG PET/CT for diagnosing extramedullary AL. Materials and methodsPET/CT examinations were performed in 9 patients with newly diagnosed AL, and 70 patients suspected to have recurrent AL. All the patients were diagnosed with AL by bone marrow biopsy. The diagnosis of extramedullary lesions was established according to the combination of pathology, physical examination, and imaging techniques including magnetic resonance imaging (MRI) and PET/CT, and/or cerebrospinal fluid (CSF) cytologic testing, and clinical follow-up. ResultsOf the 79 patients, including 34 acute lymphocytic leukemia (ALL) and 45 acute myeloid leukemia (AML) cases, 30 patients were diagnosed with extramedullary AL. 18F-FDG PET/CT demonstrated 18F-FDG positive lesions in the extramedullary regions in 42 patients. Among them, 28 patients were diagnosed to have extramedullary AL and the other 14 were diagnosed with non-hematological malignancies (false positive disease). The sensitivity, specificity, and accuracy of 18F-FDG PET/CT in diagnosing extramedullary involvement of AL were 93.3% (28/30), 71.4% (35/49), and 79.7%, respectively. The 18F-FDG uptake of lesions was not significantly different between extramedullary AL and false positive cases (SUVmax: 6.66±2.65 vs. 5.85±1.88, t=1.275, P=0.206). The FDG uptake of extramedullary AL between ALL and AML were also not significantly different (SUVmax: 7.01±2.82 vs. 6.10±2.29, t=1.332, P=0.188). The predominant locations of extramedullary AL were the spleen, soft tissue, lymph nodes, central nerve system, liver, testis, and kidney. A total of 48.2% (27/56) of extramedullary AL lesions presented as diffuse FDG uptake compared with 6.25% (1/16) in the false positive lesions (χ2=9.221, P=0.002). Conclusion18F-FDG PET/CT is a sensitive, but not specific imaging modality for diagnosing extramedullary AL. Diffuse 18F-FDG uptake in extramedullary lesions may indicate leukemia involvement.

Expression of HMGB1 and NF-κB in Patients with Acute Leukemia and Its Significance

To explore the expression of high mobility group box protein 1 (HMGB1) and nuclear factor-kappa B (NF-κB) in patients with acute leukemia and its significance. 20 samples of bone marrow and peripheral blood from each acute leukemia groups (newly diagnozed, relapsed and complete remission groups) and 20 samples as control from patients with no-hematologic malignancies were collected. The expression level of HMGB1 in peripheral blood plasma was determined by ELISA; HMGB1 and NF-κB level in mononuclear cells were examined by RT-PCR. Western blot was used to determine HMGB1 and NF-κB protein levels. HMGB1 and NF-κB in bone marrow smears were determined by immnohistochemistry method (IHC). The expression level of HMGB1 obviously increased in patients of newly diagnosed and relapsed groups, as compared with control group there was statistical significance (P < 0.05), but there was no obvious difference in expression level of HMGB1 between complete remission group and control group (P > 0.05). The expression level of HMGB1 and NF-kB in monnuclear cells of bone marrow in newly-diagnosed group and relapsed group was significantly higher than that in control group (P < 0.05), but the expression levels of HMGB1 and NF-kB in complete remisson group did not change (P > 0.05). The results of immnohistochemistry method indicated that the possitive expression of HMGB1 and NF-kB maily was found in bone marrow smears of newly diagnosed and relapsed groups. HMGB1 is overexpressed in acute leukemia, which may be involved in the occurrence and development of acute leukemia by activating the NF-κB signaling pathway, HMGB1 may be a important index for observing therapeutic effectiveness and predicting recurrence of acute leukemia.

歯肉腫瘤を伴って再発した急性骨髄性白血病の1例

歯肉腫瘤を伴って再発した急性骨髄性白血病の1例

Late onset graft versus host disease requiring lung transplantation following bone marrow transplant

A spectrum of clinic-pathologic pulmonary manifestations of graft versus host disease following bone marrow transplant has been reported. These manifestations are usually underdiagnosed. Lung transplantation to manage end stage lung disease following the development of this entity is extremely rare. Herein, we present the diagnosis and management of a patient who presented with severe lung disease following graft versus host disease in the setting of previous bone marrow transplant. A 29-year-old male underwent allogeneic bone marrow transplantation two years ago for recurrent acute lymphocytic leukaemia. The patient developed graft versus host disease with cutaneous, pulmonary and hepatic involvement. His pulmonary disease included interstitial pulmonary fibrosis, obliterative bronchiolitis and recurrent pneumothoraces, requiring admission to the intensive care unit for the management of adult respiratory distress syndrome. The patient underwent left sided lung transplant for the treatment of respiratory failure. Except for an episode of post-operative pneumonia, he had an uneventful recovery. The patient was discharged home in satisfactory clinical condition one month post-operatively. The features of pulmonary disease following graft versus host disease will be discussed along with a brief review of the relevant literature.

Leukocytapheresis for the treatment of hyperleukocytosis secondary to acute leukemia.

Patients presenting with new or recurrent acute leukemia, particularly of the myeloid lineage, with WBC counts exceeding 100 × 10(9)/L are often considered for leukocytapheresis, especially if they are experiencing symptoms of leukostasis. These symptoms are thought to occur because of blast aggregates and WBC thrombi in the circulation, which reduce blood flow. Leukostasis may cause various complications, including hyperviscosity syndrome, vascular occlusion resulting in intracranial hemorrhages and respiratory failure, and perivascular leukemic infiltrates. Leukostasis occurs more commonly with a high WBC count and with leukemias of monocytoid lineage such as acute myelomonocytic leukemia, which is a reflection of the nature of the leukemic blasts. Leukocytapheresis is used in an effort to quickly decrease a patient's circulating blast count, which can both prevent the development of leukostasis and provide symptomatic relief of leukostasis. However, the impact of leukocytapheresis on early- and long-term mortality is controversial, with several studies producing conflicting results. In this chapter, the pathophysiology of leukostasis, performance of leukocytapheresis, and efficacy of this treatment are reviewed.

Inactivation of PTEN increases ABCG2 expression and the side population through the PI3K/Akt pathway in adult acute leukemia

Both the occurrence and recurrence of acute leukemia (AL) might suggest the presence of leukemia stem cells. Side population (SP) cells, exhibiting stem cell-like properties, express ABCG2 (breast cancer resistance protein [BCRP]). This study revealed that over-expression of ABCG2 in Jurkat and HL60 cells led to an increased SP fraction, up-regulated levels of phosphorylated-PI3K and phosphorylated-Akt, and enhanced drug resistance, all of which could be attenuated by treatment with either the PI3K inhibitor LY294002 or the mTOR inhibitor rapamycin. ABCG2 expression and SP cell counts were further characterized in 222 adult AL patients at three disease stages: upon diagnosis, at remission and at refractory/relapse (R/R), while 10 healthy donors served as the normal controls. Only a small fraction of the ABCG2+population (0.05–12.3%) and SP cells (0.02–1.60%) were observed in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients. In the normal control population, the SP cell fraction represented a statistically higher percentage of total cells compared to the fraction of SP cells upon diagnosis or relapse in both AML and ALL. In addition, we demonstrated that ABCG2 expression and SP cell ratios can be upregulated by the inactivation of phosphatase and tensin homolog (PTEN) protein, achieved in this study by removing inhibition of the PI3K/Akt pathway. Collectively, this study suggests that the PTEN/PI3K/Akt pathway up-regulates ABCG2 expression and the SP cell population and is a potential AL-specific treatment target worth investigating further.

Differential diagnosis of pericardial effusion after stem cell transplantation in acute myeloic leukemia

The pathology underlying a pericardial effusion in a 24-year-old patient, who had suffered from acute myeloic leukemia 5 years previously and undergone chemotherapy followed by whole body radiation prior to allogeneic stem cell transplantation, could be identified by the careful analysis of pericardial cytology and epicardial biopsy guided by flexible pericardioscopy. Molecular, histological, cytochemical and immunological examination of the effusion and the epicardial biopsy for a viral or bacterial infection despite known CMV reactivation, or an effusion induced by radiation or graft-versus-host reaction, could be ruled out as possible causes of pericardial tamponade. The infiltration of CD 117-positive cells in the biopsied cardiac tissue revealed recurrent acute myeloic leukemia now also affecting the heart and the pericardium. An intrapericardial instillation of 1000 mg triamcinolone acetate at day 1 and 50 mg/m(2) cisplatin at day 3 effectively prevented the recurrence of tamponade, but could not prevent a lethal outcome 3 weeks later.

A Case of Type B Lactic Acidosis in Acute Leukemia

Type B lactic acidosis is a rare condition in patients with solid tumors or hematological malignancies. Although there have been several theories to explain its mechanism, the exact cause of lactic acidosis remains to be discovered. Lactic acidosis is usually related to increased tumor burden in patients with malignancy. We experienced a case of lactic acidosis in a 39-year-old man who visited an emergency room because of dyspnea, and the cause of lactic acidosis turned out to be recurrent acute leukemia. Chemotherapy relieved the degree of lactic acidosis initially, but as the disease progressed, lactic acidosis became aggravated. Type B lactic acidosis can be a clinical presentation of acute exacerbation of acute leukemia.

Detection and clinical significance of multidrug resistance-1 mRNA in bone marrow cells in children with acute lymphoblastic leukemia by real-time fluorescence quantitative RT-PCR

Objective Multidrug resistance(MDR) is one of the most important reasons for treatment failure and recurrence of acute leukemia. Its manifestations are different in children with acute lymphoblastic leukemia(ALL) which may be due to different detection methods. This study was to detect the expression of MDR1 mRNA in bone marrow cells of children with ALL by real-time fluorescence-quantitative reverse transcription polymerase-chain reaction(FQ-RT-PCR), and combine minimal residual desease(MRD) detection by flow cytometry(FCM) and to study their relationship with treatment response and prognosis of ALL. Methods The MDR1 mRNA levels in bone marrow cells from 67 children with ALL[28 had newly diagnosed disease, 27 had achieved complete remission(CR), 12 recurrent] and 22 children without leukemia were detected by FQ-RT-PCR. MRD was detected by FCM. The patients were observed for 9∼101 months, with a median of 64 months. Results Standard curves of human MDR1 and GAPDH genes were constructed successfully. MDR1 mRNA was detected in all children with a positive rate of 100%. The mRNA level of MDR1 was similar among the newly diagnosed ALL group, CR group, and control group( P > 0.05), but significantly higher in the recurrence group than that in newly diagnosed disease group and control group(0.50 ±0.55 vs. 0.09 ±0.26 and 0.12 ±0.23, P < 0.05). 54 ALL patients were followed up, and it was found that MDR1 mRNA level was significantly higher in ALL patients within 3 years duration than that of ALL patients with 3∼6 years and over 6 years duration(0.63 ±0.56 vs. 0.11 ±0.12 and 0.04 ±0.06, P < 0.01). For the 28 children with newly diagnosed disease, the MDR1 mRNA level was similar between WBC > 50×10 9 group and WBC<50×10 9 group( P > 0.05). In the 33 CR patients, the MDR1 mRNA level was significantly higher in MRD>10 3 group than that in MRD<10 3 group(0.39 ±0.47 vs. 0.03 ±0.03, P < 0.05). Conclusion The sensitivity and specificity of FQ-RT-PCR in detecting MDR1 mRNA in bone marrow cells of children with ALL patients are high. MDR1 mRNA is expressed in children with and without leukemia. MDR1 mRNA is highly expressed in the CR ALL patients with high MRD, recurrence and short duration(within 3 years). Monitoring MRD and the MDR1 mRNA level might be helpful for individual treatment.

Outcomes among Patients with Recurrent High-Risk Hematologic Malignancies after Allogeneic Hematopoietic Cell Transplantation

We retrospectively analyzed outcomes among 307 consecutive patients who had recurrent or persistent acute leukemia (n = 244), chronic myelogenous leukemia in blast phase (CML; n = 28), or advanced myelodysplastic syndromes (MDS; n = 35) after allogeneic hematopoietic cell transplantation and who received at least 1 relapse-directed intervention: withdrawal of immunosuppression, chemotherapy, or donor lymphocyte infusion (DLI). Transplants were performed at a single institution between 1995 and 2004, and outcomes were analyzed according to time intervals from transplantation to detection of malignancy: “early,” <100 days (n = 111); “intermediate,” 100-200 days (n = 73); and “late,” >200 days (n = 123). The overall remission rate was 30%. Compared to early recurrence, intermediate recurrence and late recurrence were associated with increasing probabilities of remission (hazard ratios, 1.89 and 2.16; P = .05 and .02) and decreasing risks of overall mortality (hazard ratios, 0.73 and 0.33; P = .05 and <.0001). The 2-year overall survival (OS) estimates for patients with early, intermediate, and late recurrence were 3%, 9%, and 19%, respectively. Remission was associated with a median survival prolongation of 9.5 months. Individual types or combinations of these nonrandomly assigned relapse-directed interventions were not associated with higher or lower probabilities of remission or survival. More effective intervention strategies are needed for treatment of recurrent high-risk hematologic malignancies after hematopoietic cell transplantation. In the absence of innovative clinical trials, patients with early recurrence might wish to forego further interventions in favor of palliative care.

Do Parents Have the Right to Refuse Standard Treatment for Their Child With Favorable-Prognosis Cancer? Ethical and Legal Concerns

A 7-year-old boy presenting with bone pain and fever was found to have standard-risk pre–B-cell precursor acute lymphoblastic leukemia (ALL). Parental written consent was obtained to begin a standard 3.5-year chemotherapy treatment regimen with an estimated 85% chance of long-term survival. Induction chemotherapy was successful in producing remission; however, after 3 months of chemotherapy, the parents opposed continuation of the standardtreatment,citingconcerns thatchemotherapy would damage their son’s immune system and cause other long-term problems. As a replacement for standard treatment, the parents elected to pursue alternative holistic approaches including nutritional supplements, dietary changes, and stress reduction techniques. The parents transferred the care of their child to a licensed family medicine physician who was board certified in holistic medicine. The new physician agreed to monitor the patient’s blood counts to monitor the leukemia, and if the patient’s blood counts suggested relapse, he would refer him back to a pediatric oncologist. The Department of Job and Family Services in the patient’s county of residence was notified, and a hearing was held in the county Court of Common Pleas (family court division) to determine whether the parents were guilty of neglect and whether standard therapy should be mandated. The pediatric oncologist involved with this case testified that he believed that stopping standard therapy at this point would almost certainly result in a return of the leukemia. Furthermore, he testified that the child’s likelihood of being cured would be significantly less on relapse. The court dismissed the case stating that the parents’ “concerns about long-term effects of chemotherapy” did not qualify as neglect. Furthermore, the court recognized that the patient was under the care of a licensed physician and refused to judge the relative merits of the two different treatment options recommended by two different physicians licensed to practice medicine in the state. After the hearing, the holistic physician was reported to the State Medical Board to determine whether he had “departed from or failed to conform to minimal standards of care.” After an investigation, the Secretary and Supervising Member of the State Medical Board determined that formal disciplinary charges were not warranted. Approximately 4 months after the court’s decision, the patient experienced a recurrence of acute leukemia.

Activity of alemtuzumab in patients with CD52‐positive acute leukemia

Alemtuzumab is a humanized monoclonal antibody directed against the cell surface antigen CD52 and has demonstrated activity in chronic lymphocytic leukemia and other CD52-positive lymphoproliferative disorders. Because CD52 also is expressed on acute leukemic blasts, the authors investigated the safety and efficacy of alemtuzumab in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Fifteen patients with CD52-positive (> or = 20%), recurrent or refractory acute leukemia (9 patients with AML and 6 patients with ALL) received alemtuzumab at a dose of 30 mg intravenously given 3 times a week (dose escalation during Week 1) for a total of 4 to 12 weeks. The median age of the patients was 39 years (range, 18-71 years). Patients had received a median of 3 prior therapies (range, 1-5 prior therapies). Two patients (13%) achieved a bone marrow complete response and 1 patient achieved a substantial reduction in bone marrow blasts. No complete remissions were observed. Ten patients developed disease progression while on study. Alemtuzumab was myelosuppressive in nearly all patients. Infusion-related toxicities were common, but usually did not exceed Grade 2 (according to the National Cancer Institute Common Toxicity Criteria). Infectious episodes occurred in 13 patients (87%) and included pneumonia (6 patients), bacteremia (11 patients), fungemia (2 patients), and cytomegalovirus reactivation (2 patients). Single-agent alemtuzumab was found to have limited activity in recurrent or refractory acute leukemia. An evaluation in patients with a better prognosis, in combination with other agents or as part of consolidation therapy, is warranted.

Granulocytic sarcoma and subsequent acute leukemia recurrence with different biologic characteristics 5 years after allogeneic bone marrow transplantation for acute myeloid leukemia

Granulocytic sarcoma and subsequent acute leukemia recurrence with different biologic characteristics 5 years after allogeneic bone marrow transplantation for acute myeloid leukemia

Transient encephalopathy after intrathekal methotrexate chemotherapy: diffusion-weighted MRI

Methotrexate (MTX) is an indispensable antimetabolite for the treatment of oncological and immunological disorders in all age groups. Chronic leukoencephalopathy is a well know side effect of MTX, especially in conjunction with intrathecal administration and whole brain radio therapy. However, acute neurotoxicity with confusion, disorientation, seizures and focal deficits has also been reported. Because acute neurological symptoms in patients under chemotherapy for neoplastic disorders may have many reasons, MR-imaging is usually necessary to identify the underlying pathology. Apart from conventional sequences, diffusion-weighted imaging (DW-MRI) is frequently performed. We report on clinical and imaging findings of reversibly restricted diffusion in a patient with transient encephalopathy after intrathecal administration of MTX for recurrent acute lymphatic leukaemia.