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1.  Adult B lymphoblastic leukaemia/lymphoma with hypodiploidy (-9) and a novel chromosomal translocation t(7;12)(q22;p13) presenting with severe eosinophilia – case report and review of literature 
Patients suffering from adult acute lymphoblastic leukemia are acutely ill and present most commonly with fever, pallor, bleeding, lymphadenopathy, hepatosplenomegaly and presence of lymphoblasts in the peripheral blood and bone marrow. We describe a rare presentation of acute lymphoblastic leukemia, in a young adult male who had vague and minimal symptoms with mild splenomegaly. There was severe eosinophilia along with absence of blasts in the peripheral blood, and 40% blasts with increase in eosinophils in the bone marrow. The blasts were positive for common precursor B cell markers on flow cytometry. The patient had a unique cytogenetic abnormality t(7;12)(q22;p13),-9, not previously described in acute lymphoblastic leukemia. He was categorized as poor risk due to failure to achieve complete remission after induction with UK ALL XII chemotherapy.
PMCID: PMC2706857  PMID: 19545391
2.  High-Risk Childhood Acute Lymphoblastic Leukemia 
Clinical lymphoma & myeloma  2009;9(Suppl 3):S222.
Although most children with acute lymphoblastic leukemia (ALL) are cured, certain subsets have a high risk of relapse. Relapse risk can be predicted by early response to therapy, clinical and pharmacogenetic features of the host, and genetic characteristics of leukemic cells. Though early treatment response can be assessed by the peripheral blast cell count after 1 week of single-agent glucocorticoid treatment or percent of bone marrow blasts by morphology after 1 or 2 weeks of multiagent induction treatment, determination of minimal residual disease by polymerase chain reaction (PCR) or flow cytometry after 2 to 6 weeks of induction is the most precise and useful measure. Augmented therapy has improved outcome for the poor responders to initial treatment. Infants with mixed-lineage leukemia (MLL)–rearranged ALL comprise a very poor-risk group wherein further intensification of chemotherapy causes significant toxicity. Hybrid protocols incorporating drugs effective for acute myeloid leukemia could improve survival, a strategy being tested in international trials. Studies on the biology of MLL-induced leukemogenesis have prompted the development of novel targeted agents, currently under evaluation in clinical trials. Short-term outcomes of patients with Philadelphia chromosome (Ph)–positive ALL have improved significantly by adding tyrosine kinase inhibitors to standard chemotherapy regimens. New agents and methods to overcome resistance are under investigation, and allogeneic stem cell transplantation is recommended for certain subsets of patients, for example those with Ph+ and T-cell ALL with poor early response. Genome-wide interrogation of leukemic cell genetic abnormalities and germline genetic variations promise to identify new molecular targets for therapy.
PMCID: PMC2814411  PMID: 19778845
Childhood cancer; Dasatinib; Imatinib; Infant ALL; Pediatric disease; Philadelphia chromosome; positive disease; Slow early response
3.  Imatinib Treatment Alone in Philadelphia-Positive Acute Lymphoblastic Leukemia: Is It Enough? 
Case Reports in Oncology  2010;4(2):323-326.
BCR-ABL fusion gene t(9;22)(q34;q11) occurs in only 3% of pediatric acute lymphoblastic leukemia (ALL) cases. Previously, less than 40% of Philadelphia-positive ALL patients were cured with intensive chemotherapy. The use of imatinib (340 mg/m2/day) added to an intensive chemotherapy regimen has improved the outcome in this population at 3 years to an event-free survival of 80%. Imatinib treatment alone was administered after remission induction chemotherapy to a patient with Philadelphia-positive ALL who presented with serious chemotherapy toxicity, so that intensive chemotherapy could not be maintained. This is the only patient in the literature who survived remission for more than 2.5 years with imatinib treatment only.
PMCID: PMC3130983  PMID: 21738503
Imatinib; Pediatrics; Philadelphia-positive acute lymphoblastic leukemia
4.  Correlation of oral health of children with acute leukemia during the induction phase 
Treatment of acute leukemia's- a common childhood malignancy, involves intensive and powerful multi-drug chemotherapeutic regime. Oral lesions are a common complication in these patients affecting oral health status.
This study was conducted to evaluate and assess the oral health status of newly diagnosed leukemic pediatric patients during induction phase and its correlation to outcome of induction therapy.
Material Methods:
Oral examinations was done in 33 children between the age group of 5-15 years with acute lymphoblastic leukemia (ALL) and acute myloblastic leukemia (AML), who were undergoing chemotherapy. Oral Hygiene Index- Simplified, (OHI-S) decayed missing filled teeth index (def/DMFT), Loe and Sillness index for gingiva, and complete blood count at first and fourth week of induction phase were recorded for each patient. The changes in the oral health status were analyzed with Wilcoxon signed rank test.
During an induction phase it was observed that level of OHI-S (P = 0.002), Loe and Sillness index (P = 0.003), def/DMFT index (P = 0.076), platelet count (P = 0.00) increased significantly and no significant difference was noted in hemoglobin (P = 0.4) and total leucocytes count (P = 0.11).
It was observed that, although oral health status had significantly worsened, the induction outcome was not affected.
PMCID: PMC4080661
Induction phase; leukemia; oral hygiene; oral lesions
5.  Absence of Biallelic TCRγ Deletion Predicts Early Treatment Failure in Pediatric T-Cell Acute Lymphoblastic Leukemia 
Journal of Clinical Oncology  2010;28(24):3816-3823.
To identify children with T-cell acute lymphoblastic leukemia (T-ALL) at high risk of induction chemotherapy failure by using DNA copy number analysis of leukemic cells collected at diagnosis.
Patients and Methods
Array comparative genomic hybridization (CGH) was performed on genomic DNA extracted from diagnostic lymphoblasts from 47 children with T-ALL treated on Children's Oncology Group Study P9404 or Dana-Farber Cancer Institute Protocol 00-01. These samples represented nine patients who did not achieve an initial complete remission, 13 who relapsed, and 25 who became long-term, event-free survivors. The findings were confirmed in an independent cohort of patients by quantitative DNA polymerase chain reaction (DNA-PCR), an assay that is well suited for clinical application.
Analysis of the CGH findings in patients in whom induction chemotherapy failed compared with those in whom induction chemotherapy was successful identified the absence of biallelic TCRγ locus deletion (ABD), a characteristic of early thymocyte precursors before V(D)J recombination, as the most robust predictor of induction failure (P < .001). This feature was also associated with markedly inferior event-free (P = .002) and overall survival (P < .001) rates: 25% versus 58% and 25% versus 72%, respectively. Using a rapid and inexpensive quantitative DNA-PCR assay, we validated ABD as a predictor of a poor response to induction chemotherapy in an independent series of patients.
Lymphoblasts from children with T-ALL should be evaluated at diagnosis for deletion within the TCRγ locus. Patients lacking biallelic deletion, which confers a high probability of induction failure with contemporary therapy, should be assigned to alternative therapy in the context of a prospective clinical trial.
PMCID: PMC2940399  PMID: 20644084
6.  Targeting survivin and p53 in pediatric acute lymphoblastic leukemia 
Leukemia  2011;26(4):623-632.
Despite advances in treatment and outcomes for patients with pediatric acute lymphoblastic leukemia (ALL), there continue to be subsets of patients who are refractory to standard chemotherapy and hematopoietic stem cell transplant. Therefore, novel gene targets for therapy are needed to further advance treatment for this disease. RNA interference technology has identified survivin as a potential therapeutic target. Survivin, a member of the inhibitor of apoptosis (IAP) proteins and chromosome passenger complex, is expressed in hematologic malignancies and overexpressed in relapsed pediatric ALL. Our studies show that survivin is uniformly expressed at high levels in multiple pediatric ALL cell lines. Furthermore, silencing of survivin expression in pediatric ALL cell lines as well as primary leukemic blasts reduces viability of these cells. This includes cell lines derived from patients with relapsed disease featuring cytogenetic anomalies such as t(12;21), Philadelphia chromosome t(9;22), t(1;19) as well as a cell line carrying t(17;19) from a patient with de novo ALL. Furthermore, inhibition of survivin increases p53-dependent apoptosis that can be rescued by inhibition of p53. Finally, a screen of randomly selected primary patient samples confirms that survivin-specific small interfering RNA and survivin-targeted drug, YM155, effectively reduce viability of leukemic blasts.
PMCID: PMC3364442  PMID: 21960246
RNAi; targeted therapy; IAP
7.  Emerging Pharmacotherapies for Adult Patients with Acute Lymphoblastic Leukemia 
Acute lymphoblastic leukemia (ALL) treatment regimes are amongst the longest, most intensive and complex used in hematooncology. Despite this, while treatment of pediatric ALL is a success story, we are far from being able to ensure a durable response in adult ALL. This is not due to failure of induction therapy as a complete remission (CR) is achieved in over 90% of patients. However the challenge remains in ensuring a sustained remission. Furthermore in the face of relapsed disease, salvage therapies currently offer a poor chance of a good outcome. This article reviews the novel agents which show the most promise in the treatment of adult ALL.
PMCID: PMC3273927  PMID: 22346368
acute lymphoblastic leukemia; therapy; developments
8.  Specificity of Heteroantisera to Human Acute Leukemia-Associated Antigens 
Journal of Clinical Investigation  1974;54(6):1273-1278.
Antisera have been raised to human leukemic blast cells from individual patients in mice rendered tolerant with cyclophosphamide to remission leukocytes from the same individual. 10 antisera were raised against acute myelogenous leukemia (AML) cells and 5 antisera were raised against acute lymphoblastic leukemia (ALL) cells. Antisera to AML cells were absorbed with ALL cells, and antisera to ALL cells were absorbed with AML cells. Unabsorbed and absorbed antisera as well as antisera raised in nontolerant mice were tested for cytotoxicity against various cells of a panel containing myeloblasts from 35 patients with AML, lymphoblasts from 7 patients with ALL, myeloblasts from 7 patients with chronic myelogenous leukemia (CML) in blast crisis, peripheral blood leukocytes from 12 patients with acute leukemia in remission and 30 nonleukemic patients, and nucleated bone marrow cells from 10 nonleukemic patients. Unabsorbed antisera to AML or ALL cells raised in tolerant mice were highly cytotoxic to leukemic blasts cells but significantly less cytotoxic to remission and control cells. Antisera to AML cells absorbed with ALL cells retained measurable cytotoxicity against AML cells but were not cytotoxic to ALL cells or control cells. Similarly, antisera to ALL cells absorbed with AML cells retained significant cytotoxicity only to ALL cells. Control antisera raised in nontolerant mice were cytotoxic to all cells tested. Although species specific, histocompatibility, differentiation, maturation, and cell cycle-associated antigens may be responsible in part for the cytotoxic activity of the unabsorbed antisera, the absorbed antisera are probably detecting antigens specific for their leukemic cell type.
PMCID: PMC301680  PMID: 4140196
9.  Clinical consequences of hyperglycemia during remission induction therapy for pediatric acute lymphoblastic leukemia 
Hyperglycemia adversely affects outcomes in adult patients with acute lymphoblastic leukemia (ALL), but its impact on children with this disease is unknown. We evaluated the relationship between hyperglycemia during remission induction therapy and clinical outcomes among pediatric patients with ALL. We reviewed the records of patients enrolled on four consecutive ALL protocols (Total Therapy protocols XIIIA, XIIIB, XIV, and XV) at St. Jude Children's Research Hospital from 1991 to 2007 and identified those who experienced hyperglycemia (glucose ≥200 mg/dL) during remission induction. Complete remission rates at the end of induction, event free survival, overall survival, cumulative incidence of relapse, and occurrence of infections were compared between those who did and did not experience hyperglycemia. Of 871 patients analyzed, 141 (16%) experienced hyperglycemia during remission induction. Patients with hyperglycemia were significantly older than the other patients (p<0.0001). There was no significant difference in complete remission rate (p=0.92), event-free survival (p=0.80), overall survival (p=0.28), cumulative incidence of relapse (p=0.59), or in the probability or types of infection between patients who did and did not experience hyperglycemia. Pediatric patients with or without hyperglycemia during remission induction for ALL have similar clinical outcome. Occurrence of hyperglycemia does not warrant alteration of the antileukemic regimen.
PMCID: PMC2706830  PMID: 18923438
Pediatric Oncology; Acute lymphoblastic leukemia; Infections; Hyperglycemia; Supportive care
10.  Acute leukemia in adults: assessment of remission induction with combination chemotherapy by clinical and cell-culture criteria. 
Remission induction was assessed by clinical and cell-culture criteria for 65 patients with acute myelogenous leukemia (AML), 11 patients with chronic myelogenous leukemia (CML) in blast crisis and 19 patients with acute lymphoblastic leukemia (ALL). Cyclophosphamide, cytosine arabinoside and vincristine (CAV) therapy resulted in complete remission in 23 of 50 previously untreated patients with AML and in 3 of the 11 patients with CML. Fourteen patients with ALL responded to vincristine-prednisone induction therapy and two to induction therapy with CAV. The median duration of survival of the responding patients was 2.2 years, compared with 4 months for the patients who did not respond to treatment. Granulopoietic colony formation, assessed by assay of colony-forming units dependent on colony-stimulating activity in culture (CFU-C), was abnormal in 37 of 42 bone marrow aspirates from patients with AML before treatement. CFU-C concentration increased when leukocyte-conditioned medium (LCM) was added to the cultures; 13 cultures had normal or elevated CFU-C concentration with LCM. Marrow cells of patients with ALL or CML in blast crisis demonstrated a similar pattern. Serial studies of marrow CFU-C concentration of 31 patients with AML demonstrated a change to a normal pattern with successful remission induction. Results of this study suggest that administration of purified LCM to leukemic patients might increase granulocyte production from potential but unstimulated granulopoietic precursors. This therapy would lessen the probability of death from infection during remission induction.
PMCID: PMC1956383  PMID: 1056807
11.  Novel agents and biomarkers for acute lymphoid leukemia 
New genetic markers for adult acute lymphoblastic leukemia (ALL) have been found to have prognostic impact, such as the lymphoid transcription factor gene IKZF1 alterations, which are associated with a high rate of leukemic relapse in B-ALL. Although complete remission rates by induction chemotherapy in ALL are now high, the long-term survival is still disappointing. Improvements in the survival outcome of ALL have been observed in young adults as a result of the use of pediatric inspired regimens and the broadening of the number of patients who are eligible for allogeneic SCT. Development of new and less toxic agents also provide promise to improve the outcome in adult ALL, such as tyrosine kinase inhibitors in Ph-positive ALL, rituximab in CD20-positive disease, blinatumomab in precursor B-ALL and nelarabine in T-lineage ALL. Challenges for the future are to implement genomic profiling into the clinical setting to guide risk stratification and providing novel targets for tailored therapies.
PMCID: PMC3718656  PMID: 23773228
Acute lymphoblastic leukemia; Genetic alteration; Philadelphia chromosome; Tyrosine kinase inhibitor; Monoclonal antibodies; Stem cell transplantation
12.  Flow Cytometric Chemosensitivity Assay As A Predictive Tool of Early Clinical Response in Acute Lymphoblastic Leukemia 
Pediatric blood & cancer  2009;53(4):543-550.
Residual disease or rapidity of response to induction therapy is among the most powerful predictors of outcome in pediatric Acute Lymphoblastic Leukemia (ALL).
Utilizing a multiparameter flow cytometric chemosensitivity assay (FCCA), we studied the relationship between in vitro drug sensitivity of diagnostic leukemic blasts from 30 children with ALL and rapidity of response to induction therapy. We also analyzed the in vitro drug sensitivity of de novo leukemic blasts among various clinical subsets.
Compared to rapid early responders (RER), slow early responders (SER) had a significantly greater in vitro drug resistance to Dexamethasone (DEX) (P = 0.04) and Prednisone (P = 0.05). The studies with all other drugs showed a non-significant trend with the SER having a higher in vitro drug resistance compared to the RER. Risk group stratified analyses indicated that in vitro resistance to Asparaginase (ASP), DEX, and Vincristine (VCR) were each significantly related to having very high risk ALL. Additionally, a significantly higher in vitro drug resistance to ASP and VCR was associated with unfavorable lymphoblast genetics and ultimate relapse.
Our data indicate that this FCCA is a potentially simple and rapid method to detect inherent resistance to initial ALL therapy very early in induction, thus allowing for treatment modification shortly thereafter.
PMCID: PMC2775428  PMID: 19499583
Acute Lymphoblastic Leukemia; childhood; in vitro drug resistance; flow cytometry; chemosensitivity assay; response to induction
13.  Vitamin D levels in patients of acute leukemia before and after remission-induction therapy 
Objectives: To determine the levels of 25-hydroxyvitamin [25(OH)D3] in patients with acute leukemia and the effect of remission-induction chemotherapy.
Methodology: This study was case control, all newly diagnosed patients of acute leukemia between the age of one to sixty years and residents of Pakistan were enrolled and evaluated. Those who were unwilling or unable to provide written informed consent were excluded. All selected patients (n=86) were grouped in to acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). AML was further categorized as A1 before remission-induction (n=17) and B1 after remission induction (n=13), ALL was further categorized as A2 before remission-induction (n=31) and B2 after remission induction (n=25). The 25-hydroxyvitamin [25(OH)D3] levels were measured in the sera of all patients (before and after remission-induction) by one step delayed chemiluminescent micro particle immunoassay (CMIA).We compared 25(OH)D3 levels in all patients before and after the remission-induction chemotherapy.
Results: A total of 86 patients were analyzed, in which 60 patients were male. Mean age was 24.39 years (range, 1 to 60 years); the mean levels of 25(OH)D in group A1 (n=17) was 17.70±3.2 ng/ml, in group B1 (n=13) 14.06±2.4 ng/ml, 19.07±7.08 ng/ml in group A2 (n=31), while 10.59±3.9 ng/ml found in group B2 (n=25).
Conclusion: 25(OH)D3 insufficiency was evident subnormal in majority of patients with acute leukemia and 25(OH)D3 were further reduced after remission-induction as compared to untreated group, difference was statistically significant when compared with each group.
PMCID: PMC3809206  PMID: 24353499
AL: Acute Leukemia; ALL: Acute Lymphoblastic Leukemia; AML: Acute Myeloid Leukemia; Vitamin D
14.  Cannabis Extract Treatment for Terminal Acute Lymphoblastic Leukemia with a Philadelphia Chromosome Mutation 
Case Reports in Oncology  2013;6(3):585-592.
Acute lymphoblastic leukemia (ALL) is a cancer of the white blood cells and is typically well treated with combination chemotherapy, with a remission state after 5 years of 94% in children and 30–40% in adults. To establish how aggressive the disease is, further chromosome testing is required to determine whether the cancer is myeloblastic and involves neutrophils, eosinophils or basophils, or lymphoblastic involving B or T lymphocytes. This case study is on a 14-year-old patient diagnosed with a very aggressive form of ALL (positive for the Philadelphia chromosome mutation). A standard bone marrow transplant, aggressive chemotherapy and radiation therapy were revoked, with treatment being deemed a failure after 34 months. Without any other solutions provided by conventional approaches aside from palliation, the family administered cannabinoid extracts orally to the patient. Cannabinoid resin extract is used as an effective treatment for ALL with a positive Philadelphia chromosome mutation and indications of dose-dependent disease control. The clinical observation in this study revealed a rapid dose-dependent correlation.
PMCID: PMC3901602  PMID: 24474921
Acute lymphoblastic leukemia; Philadelphia chromosome; Cannabinoids; Hemp oil
15.  Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia 
Pediatric acute lymphoblastic leukemia (ALL) is the prototype for a drug-responsive malignancy. Although cure rates exceed 80%, considerable unexplained interindividual variability exists in treatment response.
Using a genome-wide approach, to assess the contribution of inherited genetic variation to therapy response and to identify germline single nucleotide polymorphisms (SNPs) associated with risk of minimal residual disease (MRD) after remission induction chemotherapy.
Design, Setting, and Patients
We performed a genome-wide interrogation of 476,796 germline SNPs to identify genotypes that predicted MRD in two independent cohorts of children with newly diagnosed ALL: 318 patients on St. Jude trials Total XIIIB and XV and 169 patients on a Children’s Oncology Group (COG) trial P9906.
Main Outcome Measures
MRD at the end of induction therapy, measured by flow cytometry.
There were 102 SNPs associated with MRD in both cohorts (P≤0.0125), including 5 SNPs in the interleukin 15 (IL15) gene. A high proportion, 21 of these 102 SNPs, also predicted hematologic relapse (P<0.05). Of 102 SNPs, 21 were also associated with antileukemic drug disposition, generally linking MRD eradication with greater drug exposure. In total, 63 of 102 SNPs were also associated with early response, relapse, or with drug disposition.
Host genetic variability affected treatment response for childhood ALL, and germline variants may exert their effects on MRD by effects on leukemic cell biology and on host disposition of antileukemic drugs.
PMCID: PMC2664534  PMID: 19176441
16.  Improvement of Induction Remission Rate by Modifying the Dose of Idarubicin for Relapsed Childhood Acute Lymphoblastic Leukemia 
Journal of Korean Medical Science  2009;24(2):281-288.
Relapse is the major cause of treatment failure in acute lymphoblastic leukemia (ALL), yet there is no established treatment for relapsed ALL. To improve the induction remission rate, we modified the dose of idarubicin in the original Children's Cancer Group (CCG)-1884 protocol, and retrospectively compared the results. Twenty-eight patients diagnosed with relapsed ALL received induction chemotherapy according to the CCG-1884 protocol. Complete remission (CR) rate in all patients after induction chemotherapy was 57%. The idarubicin 10 mg/m2/week group showed CR rate of 74%, compared with the 22% CR rate of the idarubicin 12.5 mg/m2/week group (p=0.010). Remission failure due to treatment-related mortality (TRM) was 44% and 5.2% in the idarubicin 12.5 mg/m2/week and 10 mg/m2/week groups, respectively (p=0.011). Overall survival (OS) and 4-yr event-free survival (EFS) were 12.8% and 10.3%, respectively. OS and 4-yr EFS were higher in the idarubicin 10 mg/m2/week group (19.3% and 15.6%) than in the 12.5 mg/m2/week group (0% and 0%). In conclusion, a modified dose of idarubicin from 12.5 mg/m2/week to 10 mg/m2/week resulted in an improved CR rate in the treatment of relapsed ALL, which was due to lower TRM. However, despite improved CR rate with modified dose of idarubicin, survival rates were unsatisfactory.
PMCID: PMC2672129  PMID: 19399271
Idarubicin; Remission Induction; Recurrence; Precursor Cell Lymphoblastic Leukemia-Lymphoma
17.  Constitutive Function of the Ikaros Transcription Factor in Primary Leukemia Cells from Pediatric Newly Diagnosed High-Risk and Relapsed B-precursor ALL Patients 
PLoS ONE  2013;8(11):e80732.
We examined the constitutive function of the Ikaros (IK) transcription factor in blast cells from pediatric B-precursor acute lymphoblastic leukemia (BPL) patients using multiple assay platforms and bioinformatics tools. We found no evidence of diminished IK expression or function for primary cells from high-risk BPL patients including a Philadelphia chromosome (Ph)+ subset. Relapse clones as well as very aggressive in vivo clonogenic leukemic B-cell precursors isolated from spleens of xenografted NOD/SCID mice that developed overt leukemia after inoculation with primary leukemic cells of patients with BPL invariably and abundantly expressed intact IK protein. These results demonstrate that a lost or diminished IK function is not a characteristic feature of leukemic cells in Ph+ or Ph- high-risk BPL.
PMCID: PMC3835424  PMID: 24278314
18.  Transplant-Related Mortality Following Allogeneic Hematopoeitic Stem Cell Transplantation for Pediatric Acute Lymphoblastic Leukemia: 25-Year Retrospective Review 
Pediatric Blood & Cancer  2013;60(9):1520-1527.
Over the last 25 years, donor source, conditioning, graft-versus-host disease prevention and supportive care for children undergoing hematopoeitic stem cell transplantation (HSCT) have changed dramatically. HSCT indications for acute lymphoblastic leukemia (ALL) now include high-risk patients in first and subsequent remission. There is a large burden of infectious and pre-HSCT morbidities, due to myelosuppressive therapy required for remission induction. We hypothesized that, despite these trends, overall survival (OS) had increased.
A retrospective audit of allogeneic pediatric HSCT for ALL was performed in our institution over 25 years. Outcomes for 136 HSCTs were analyzed in three consecutive 8-year periods (Period 1: 1/1/1984–31/8/1992, Period 2: 1/9/1992–30/4/2001, Period 3: 1/5/2001–31/12/2009).
Despite a significant increase in unrelated donor HSCT, event-free and OS over 25 years improved significantly. (EFS 31.6–64.8%, P = 0.0027; OS 41.8–78.9%, P < 0.0001) Concurrently, TRM dropped from 33% to 5% (P = 0.0004) whilst relapse rate was static (P = 0.07). TRM reduced significantly for matched sibling and unrelated cord blood transplantation (UCT) in Period 3 compared with earlier periods (P = 0.036, P = 0.0098, respectively). Factors leading to improved survival in patients undergoing UCT include better matching, higher total nucleated cell doses, and significantly faster neutrophil engraftment. Length of initial HSCT admission was similar over time.
EFS and OS have increased significantly despite heightened HSCT complexity. This survival gain was due to TRM reduction. Contemporary patients have benefited from refined donor selection and improved supportive care. Overall rates of leukemic relapse post-HSCT are unchanged, and remain the focus for improvement.
PMCID: PMC3798104  PMID: 23733511
hematopoeitic stem cell transplant; lymphoblastic leukemia; outcomes; pediatric acute survival; transplant-related mortality
19.  Philadelphia chromosome-positive acute lymphoblastic leukemia with extramedullary and meningeal relapse after allogeneic hematopoietic stem cell transplantation that was successfully treated with dasatinib 
SpringerPlus  2014;3:177.
Central nervous system (CNS) relapse is a critical issue while treating Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). A 58-year-old woman with Ph-positive ALL who relapsed after bone marrow transplantation for meningeal leukemia was treated with high-dose methotrexate, which resulted in remission. She underwent allogeneic cord blood transplantation followed by reduced intensity conditioning chemotherapy with imatinib; however, she experienced CNS relapse and developed an extramedullary mass on the right side of the temporal region. We treated 40 mg of dasatinib once daily, which had to be temporarily discontinued because she developed grade 2 pleural effusion and grade 2 hematemesis. After reinitiation of dasatinib, the extramedullary mass disappeared and meningeal leukemia ameliorated almost immediately. With 40 mg dasatinib administered once daily, its trough level and cerebrospinal fluid (CSF) concentration were 32 ng/mL and below the sensitivity threshold of 1 ng/mL, respectively. Treatment was continued, and the patient remained in complete remission until she died of pneumonia 7 years after the initial diagnosis of ALL. Dasatinib can be an effective treatment for Ph-positive ALL with CNS relapse. Although the concentration in the CSF seems low, it may be sufficient to exert anti-leukemic effects in the human CNS.
PMCID: PMC4000600  PMID: 24790822
Philadelphia chromosome-positive acute lymphoblastic leukemia; Meningeal leukemia; Extramedullary relapse; Hematopoietic stem cell transplantation; Dasatinib
20.  Effect of Allopurinol versus Urate Oxidase on Methotrexate Pharmacokinetics in Children with Newly Diagnosed Acute Lymphoblastic Leukemia 
Cancer  2010;116(1):227-232.
Allopurinol and urate oxidase are both effective in preventing or treating hyperuricemia during remission induction therapy for lymphoid malignancies, but their effect on concomitant anticancer drug therapy has not been compared.
We compared plasma methotrexate pharmacokinetics in pediatric patients with newly diagnosed acute lymphoblastic leukemia who received concomitant allopurinol (n=20) versus non-recombinant or recombinant urate oxidase (n=96) during high-dose methotrexate administration before conventional remission induction therapy.
The minimum plasma concentration of uric acid was significantly (p<0.0001) lower after treatment with urate oxidase as compared to allopurinol treatment. Methotrexate clearance was significantly higher (median, 117.1 vs. 91.1ml/min/m2, p=0.019) in patients receiving urate oxidase. A higher proportion of patients in the allopurinol group had elevated methotrexate plasma concentrations (36% vs. 7%, p=0.003), and experienced mucositis (45% vs. 16%, p=0.003) after methotrexate treatment than those in the rasburicase group.
The lower rate of methotrexate clearance in patients receiving allopurinol likely reflects a less potent hypouricemic effect of allopurinol, leading to precipitation of uric acid in renal tubules. Hence, during remission induction therapy for lymphoid malignancies, renally-excreted drugs should be monitored closely, especially in patients receiving allopurinol.
PMCID: PMC2846832  PMID: 19834958
methotrexate; acute lymphoblastic leukemia; hyperuricemia; allopurinol; urate oxidase
21.  Blast cell methotrexate-polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia. 
Journal of Clinical Investigation  1994;94(5):1996-2001.
High-dose methotrexate (HDMTX) is a component of most treatment protocols for childhood acute lymphoblastic leukemia (ALL), yet recent studies of receptor-mediated transport and saturable polyglutamylation have questioned its rationale. To investigate this in vivo, methotrexate and its active polyglutamated metabolites (MTX-PG) were measured in bone marrow blasts obtained from 101 children randomized to single-agent therapy with either HDMTX (1 g/m2 per 24 h i.v., n = 47) or low-dose MTX (LDMTX, 30 mg/m2 by mouth every 6 h x 6, n = 54), before remission induction therapy. Blast concentrations of total MTX-PGs (median 460 vs 1380 pmol/10(9) cells) and of long-chain MTX-glu4-6 were both significantly higher after HDMTX (P < 0.001). With either treatment, MTX-PGs were significantly higher in B-lineage blasts than in T-lineage blasts (LDMTX P = 0.001, HDMTX P = 0.03). In a multiple regression analysis of B-lineage ALL, blast MTX-PG was significantly related to MTX dose (or plasma MTX concentration), lymphoblast ploidy (hyperdiploid > nonhyperdiploid), and percentage S-phase. This is the first evidence that HDMTX achieves higher MTX-PG concentrations in ALL blasts in vivo, establishing a rationale for HDMTX in the treatment of childhood ALL, especially T-lineage or nonhyperdiploid B-lineage ALL, disease characteristics associated with a poor prognosis on conventional therapy.
PMCID: PMC294625  PMID: 7525652
22.  Monitoring of minimal residual disease (MRD) is useful to predict prognosis of adult patients with Ph-negative ALL: results of a prospective study (ALL MRD2002 Study) 
Allogeneic hematopoietic stem cell transplantation (HSCT) for patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1) is much more intensive than multi-agent combined chemotherapy, although allogeneic HSCT is associated with increased morbidity and mortality when compared with such chemotherapy. Minimal residual disease (MRD) status has been proven to be a strong prognostic factor for adult patients with Ph-negative ALL.
We investigated whether MRD status in adult patients with ALL is useful to decide clinical indications for allogeneic HSCT. We prospectively monitored MRD after induction and consolidation therapy in adult patients with Ph-negative ALL.
Of 110 adult ALL patients enrolled between July 2002 and August 2008, 101 were eligible, including 59 Ph-negative patients. MRD status was assessed in 43 patients by the detection of major rearrangements in TCR and Ig and the presence of chimeric mRNA. Thirty-nine patients achieved CR1, and their probabilities of 3-year overall survival and disease-free survival (DFS) were 74% and 56%, respectively. Patients who were MRD-negative after induction therapy (n = 26) had a significantly better 3-year DFS compared with those who were MRD-positive (n = 13; 69% vs. 31%, p = 0.004). All of 3 patients who were MRD-positive following consolidation chemotherapy and did not undergo allogeneic HSCT, relapsed and died within 3 years after CR.
These results indicate that MRD monitoring is useful for determining the clinical indications for allogeneic HSCT in the treatment of ALL in CR1.
PMCID: PMC3574830  PMID: 23388549
Acute lymphoblastic leukemia; Minimal residual disease; Hematopoietic stem cell transplantation; Adult
23.  Unrelated Donor Bone Marrow Transplantation for Children With Acute Myeloid Leukemia Beyond First Remission or Refractory to Chemotherapy 
Journal of Clinical Oncology  2008;26(26):4326-4332.
Identify prognostic factors that influence outcome after unrelated donor bone marrow transplantation in children with acute myeloid leukemia (AML).
Patients and Methods
Included are 268 patients (age ≤ 18 years) with AML in second complete remission (n = 142), relapse (n = 90), or primary induction failure (n = 36) at transplantation. All patients received bone marrow grafts from an unrelated donor and a myeloablative conditioning regimen. Cox regression models were constructed to identify risk factors that influence outcome after transplantation.
In this analysis, the only risk factor that predicted leukemia recurrence and overall and leukemia-free survival was disease status at transplantation. The 5-year probabilities of leukemia-free survival were 45%, 20%, and 12% for patients who underwent transplantation at second complete remission, relapse, and primary induction failure, respectively. As expected, risk of acute but not chronic graft-versus-host disease (GVHD) was lower with T-cell–depleted bone marrow grafts; T-cell–depleted grafts were not associated with higher risks of leukemia recurrence. We observed similar risks of leukemia relapse in patients with and without acute and chronic GVHD.
Children who underwent transplantation in remission had a superior outcome compared with children who underwent transplantation during relapse or persistent disease. Nevertheless, 20% of children who underwent transplantation in relapse are long-term survivors, suggesting that unrelated donor bone marrow transplantation is an effective therapy in a significant proportion of children with recurrent or primary refractory AML.
PMCID: PMC2653120  PMID: 18779619
24.  Treatment Outcome of Acute Promyelocytic Leukemia with Modified Aida Protocol 
Advances in Hematology  2010;2010:672137.
We analyzed the outcome of a series of 19 newly diagnosed patients with acute promyelocytic leukemia treated with AIDA modified protocol, using mitoxantrone in place of idarubicin. Eleven patients achieved morphologic CR (58%). The remaining 8 patients had induction failure due to death during induction. Ten of eleven patients in CR achieved molecular remission after induction therapy and all the 8 patients had molecular remission after consolidation. Eight patients completed the three consolidation courses as scheduled and then proceeded to maintenance therapy. After a median follow up of 52 months, no molecular or hematological relapse has occurred. The 4-year disease-free survival is 82%. The study showed the antileukemic efficacy of mitoxantrone and that it could be used as a reasonable option in anthracycline-based strategies in APL.
PMCID: PMC2871550  PMID: 20490274
25.  Long-term follow-up of the United Kingdom Medical Research Council protocols for childhood acute Lymphoblastic leukaemia, 1980–2001 
Leukemia  2009;24(2):406-418.
Between 1980 and 2001, the United Kingdom Medical Research Council Childhood Leukemia Working Party has conducted 4 clinical trial in acute lymphoblastic leukemia, which have recruited a total of 6516 patients. UKALL VIII examined the role of daunorubicin in induction chemotherapy, and UKALL X examined the role of post-induction intensification. Both resulted in major improvement in the outcomes. UKALL XI examined the efficacy of different methods of CNS-directed therapy and the effects of an additional intensification. ALL97, which was initially based on the UKALL X D template (two intensification phases), examined the role of different steroids in induction and different thiopurines through continuing chemotherapy. A reappraisal of results from UKALL XI compared to other cooperative group results led to a redesign in 1999, which subsequently resulted in a major improvement in outcomes. Additionally, ALL97 and 97/99 demonstrated a significant advantage for the use of dexamethasone rather than prednisolone; although the use of 6-thioguanine resulted in fewer relapses, this advantage was offset by an increased incidence of deaths in remission. Over the era encompassed by these four trials there has been a major improvement in both event-free and overall survival for children in the UK with ALL.
PMCID: PMC2820452  PMID: 20010621
acute leukemia; therapy; clinical trial

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