Genomic profiling of B-progenitor acute lymphoblastic leukemia

Childhood acute lymphoblastic leukemia (ALL) is comprised of multiple subtypes defined by recurring chromosomal alterations that are important events in leukemogenesis and are widely used in diagnosis and risk stratification, yet fail to fully explain the biology of this disease. In the last 5 years, genome-wide profiling of gene expression, structural DNA alterations and sequence variations has yielded important insights into the nature of submicroscopic genetic alterations that define novel subgroups of acute lymphoblastic leukemia and cooperate with known cytogenetic alterations in leukemogenesis. Importantly, several of these alterations are important determinants of risk of relapse and are potential targets for therapeutic intervention. Here, these advances and future directions in the genomic analysis of ALL are discussed.     

A phase 1/2 trial of lenalidomide and dexamethasone in adult patients with refractory/relapsed acute lymphoblastic leukemia

Objectives: Adult patients with refractory/relapsed ALL have poor survival outcomes with current chemotherapies. We aimed to determine safety and efficacy of lenalidomide, an oral immunomodulator, in these patients.

Methods: This phase 1/2 trial (EUDRACT # 2009-009372-13) included 10 patients who received 28-day cycles of oral lenalidomide 25?mg/day, days 1 through 21, in combination with oral dexamethasone 40?mg/day on days 1, 8, 15, 22. Primary endpoints were tolerance and the overall response rate (ORR). Secondary endpoints included overall survival (OS) and quality of life.

Results: The most common grade 3 or 4 adverse events were myelosuppression. The ORR among the participants who could be evaluated was 28.6% (95% confidence interval [CI], 0–62.2%). The median OS was 92 days (range, 43–133 days). All patients have died because of progressive disease. Quality of life remains stable during treatment cycles.

Discussion and conclusion: The safety of combination therapy consisting of lenalidomide plus dexamethasone is consistent with ambulatory administration. Efficacy should be reevaluated in a larger series including patients less intensively previously treated.     

Hypergranular acute lymphoblastic leukemia (ALL)

Summary We report a case of adult acute lymphoblastic leukemia (ALL) with myeloid-like hypergranulation of blast cells. Like most of the granular ALLs described in the literature, the blast cells had L2 morphology and exhibited a common-ALL immunologic phenotype. The clinical findings at diagnosis were unremarkable. Cytogenetic analysis showed a 46XY karyotype. Molecular genetic analysis revealed T-cell receptor (TCR) and immunoglobulin heavy chain rearrangements; no rearrangement was found at the TCR gene locus. The polymerase chain reaction (PCR) for the BCR-ABL translocation was negative. The clinical course of the patient was uncomplicated. On standard ALL treatment protocol he achieved complete remission (CR) within 4 weeks, and he is currently disease free 8 months after diagnosis. The case contributes well-documented data to the characterization of adult granular ALL, with special regard to changes at the molecular genetic level.     

Detection of clonality by polymerase chain reaction in childhood B-lineage acute lymphoblastic leukemia

Summary DNA-based PCR with various sets of primers for TCR /, and Ig heavy chain (IgH) genes were used to study clonality in childhood B-lineage acute lymphoblastic leukemia. Amplification of the IgH CDR-III was observed in 75 of 120 analyzed cases (62.5%). From all analyzed groups, the IgH gene rearrangement was most often observed in pre-B ALL (85.7%) and was rather rare in null-ALL (34.5%). TCR delta gene rearrangement was the most common, and was observed in 77 patients (64.2%). The typical pattern of rearrangements was defined as anincomplete V2 to D3, V2 to D2, or D3 to D3 to D2 recombination product. Rearrangements of TCR gamma gene we observed in 61 cases (50.8%). TCR gamma gene rearrangements were detected predominantly in null-ALL and early B-ALL (55.2% and 60%, respectively) and were rather rare in other groups. Of all eight V segments of VI group, the most frequent gene usage concerns regions V2, V4, and V7. We have confirmed that IgH gene amplification, together with TCR gamma and delta gene amplification, provides a rapid, sensitive approach to assessing clonality in ALL almost in 100% of cases.This work was financed by KBN grants 4.0551.91.01 and 6.6346.92.03     

急性淋巴细胞白血病用甲氨喋啶治疗的动力学研究

目的 :根据不同年龄 ,采用两种不同大剂量甲氨喋啶 2 4h持续静滴下的稳态血药浓度及毒性反应。方法 :分别于甲氨喋啶静滴开始后 1、6、2 3、44、6 8h点采集静脉血 2 ml及 1、2 4h点脑脊液 2 m l,应用免疫偏振荧光法检测血清与脑脊液 MTX浓度。结果 :9例老年组采用 2 g· M- 2 剂量 ,在 1、6、2 3、44、6 8h点血清 MTX浓度分别为 5 6 .97± 4.7μmol/ L、40 .46± 7.0 6μmol/ L、17.31± 9.76μm ol/ L、0 .91± 1.34μm ol/ L、0 .2 5± 0 .2 2μmol/L ;在 1、2 4h点脑脊液 MTX浓度分别为 0 .38± 0 .2 4μm ol/ L、2 .0 7± 0 .76μmol/ L。 16例中青年组采用 3 g· M- 2剂量 ,各小时点血清 MTX浓度分别为 82 .15± 12 .13μmol/ L、6 2 .33± 10 .0 6μm ol/ L、14.75± 7.0 6μm ol/ L、1.71± 1.6 8μm ol/ L、0 .45± 0 .44 μmol/ L;脑脊液 MTX浓度分别为 0 .5 4± 0 .35 μmol/ L、1.96± 0 .5 2 μm ol/ L。结论 :此两种剂量能达到急性淋巴细胞白血病 (AL L)细胞聚谷氨酸盐 MTX饱和所需的剂量 ,毒性反应是可以接受的。     

Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia

Pediatric de novo acute myeloid leukemia (AML) is an aggressive malignancy with current therapy resulting in cure rates of only 60%. To better understand the cause of the marked heterogeneity in therapeutic response and to identify new prognostic markers and therapeutic targets a comprehensive list of the genetic mutations that underlie the pathogenesis of AML is needed. To approach this goal, we examined diagnostic leukemic samples from a cohort of 111 children with de novo AML using single-nucleotide-polymorphism microarrays and candidate gene resequencing. Our data demonstrate that, in contrast to pediatric acute lymphoblastic leukemia (ALL), de novo AML is characterized by a very low burden of genomic alterations, with a mean of only 2.38 somatic copy-number alterations per leukemia, and less than 1 nonsynonymous point mutation per leukemia in the 25 genes analyzed. Even more surprising was the observation that 34% of the leukemias lacked any identifiable copy-number alterations, and 28% of the leukemias with recurrent translocations lacked any identifiable sequence or numerical abnormalities. The only exception to the presence of few mutations was acute megakaryocytic leukemias, with the majority of these leukemias being characterized by a high number of copy-number alterations but rare point mutations. Despite the low overall number of lesions across the patient cohort, novel recurring regions of genetic alteration were identified that harbor known, and potential new cancer genes. These data reflect a remarkably low burden of genomic alterations within pediatric de novo AML, which is in stark contrast to most other human malignancies.     

Recent progress in acute leukemia and myelodysplasia

The advances and progress in the understanding and management of acute leukemia and myelodysplasia continue to occur at an exponential rate. While this has led to more therapy options, clinicians and researchers are now facing more challenges in terms of clinical decision-making and more unanswered questions. This paper has outlined some conundrums in acute leukemia and myelodysplasia, and the efforts that are underway to address these.     

Replication analysis confirms the association of ARID5B with childhood B-cell acute lymphoblastic leukemia

Although childhood acute lymphoblastic leukemia is the most common pediatric cancer, its etiology remains poorly understood. In an attempt to replicate the findings of 2 recent genome-wide association studies in a French-Canadian cohort, we confirmed the association of 5 SNPs [rs7073837 (P=4.2 × 10⁻⁴), rs10994982 (P=3.8 × 10⁻⁴), rs10740055 (P=1.6 × 10⁻⁵), rs10821936 (P=1.7 × 10⁻⁷) and rs7089424 (P=3.6 × 10⁻⁷)] in the ARID5B gene with childhood acute lymphoblastic leukemia. We also confirmed a selective effect for B-cell acute lymphoblastic leukemia with hyperdiploidy and report a putative gender-specific effect of ARID5B SNPs on acute lymphoblastic leukemia risk in males. This study provides a strong rationale for more detailed analysis to identify the causal variants at this locus and to better understand the overall functional contribution of ARID5B to childhood acute lymphoblastic leukemia susceptibility.     

Acute Sciatica: An Unusual Presentation of Extramedullary Relapse of Acute Lymphoblastic Leukemia

A 10-year-old boy who had been treated for acute lymphoblastic leukemia presented with persistent numbness of the left big toe and progressive pain of the ipsilateral lower leg. He had received allogeneic bone marrow transplantation 3 months after a testicular relapse. He was in hematologic remission at admission but as progressive swelling of his left leg continued, bone marrow relapse developed. A muscle biopsy revealed leukemic infiltrates in the surrounding muscles of the left sciatic nerve, and swelling of the nerve was found on a magnetic resonance imaging scan. His symptoms/signs subsided soon after reinduction chemotherapy. Unfortunately, he didn't survive because of a fungal sepsis that developed during the neutropenic state. This case represents a rare neurologic complication of what is currently an uncommon presentation for relapse of acute lymphoblastic leukemia, with acute sciatica and without coexisting epidural or leptomeningeal leukemia.     

Antibody based therapy in relapsed acute lymphoblastic leukemia

Outcomes for relapsed and refractory acute lymphoblastic leukemia (ALL) remain poor. With the advent of targeted monoclonal antibodies and antibody constructs, these outcomes have been significantly improved both in the frontline and salvage setting. These targets include a bispecific antibody that targets both CD3 and CD19, known as blinatumomab, as well as a conjugated antibody that targets CD22, known as inotuzumab ozogamicin. These agents have been thoroughly studied and successively approved for use as monotherapy, however, more recently they have been incorporated in combination or sequentially with cytotoxic chemotherapy. In this chapter, we will discuss the role that these monoclonal antibodies play as monotherapy and in combination in the treatment of ALL in the salvage setting, and how they continue to transform the treatment management of relapsed and refractory ALL.     

Transient complete remission of acute lymphoblastic leukemia in relapse after allogeneic bone marrow transplantation induced by donor leukocyte transfusions

We report the case of a young patient with refractory acute lymphoblastic leukemia relapse, after allogeneic bone marrow transplantation, who was treated by donor leukocyte infusions. We observed potent adoptive immunotherapy which produced a cytologic complete remission and total chimeric state. This was of short duration and the patient died of severe graft-versus-host disease. We present a short summary of the literature concerning acute lymphoblastic leukemia and donor leukocyte infusions.     

Granular acute lymphoblastic leukemia with hypereosinophilic syndrome

9 /l), features of hypereosinophilic syndrome, and acute lymphoblastic leukemia (ALL-L2), the latter characterized by the presence of granular blasts. Blasts were negative for myeloperoxidase, non-specific esterase, acid phosphatase, periodic-acid Schiff stain, and toluidine blue. They exhibited an early pre-B immunophenotype (TdT, CD19, CD10, CD20 and CD22 positive) and stained negative for T (CD7, CD2, CD5 and CD3) and myeloid markers (MPO, CD33 and CD13). Chromosomal analysis revealed a normal karyotype. To the best of our knowledge, this case represents the first report of the coexistence of granular ALL and hypereosinophilic syndrome. Received: 11 May 1999 / Accepted: 20 October 1999     

L-asparaginase induced fatal cortical venous thrombosis in acute lymphoblastic leukemia

L-asparaginase has become an integral part in the treatment of acute lymphoblastic leukemia. The major worry of using L-asparaginase is thromboembolism. The case presented here is a 21-year-old lady who developed fatal cortical venous thrombosis during induction phase of treatment for ALL. Early recognition is very important to treat this potentially catastrophic yet treatable complication.     

Predictive value of multidrug resistance proteins and cellular drug resistance in childhood relapsed acute lymphoblastic leukemia

Purpose Cellular resistance in childhood acute leukemias might be related to profile and function of multidrug resistance proteins and apoptosis regulating proteins. The aims of the study were: (1) analysis of expression of MRP1, PGP1, LRP, BCL-2 and p53 proteins; (2) correlation with ex vivo drug resistance, and (3) analysis of their prognostic impact on clinical outcome in childhood acute lymphoblastic (ALL) and acute myeloid (AML) leukemia. Methods Total number of 787 children diagnosed for initial ALL (n = 527), relapsed ALL (n = 104), initial AML (n = 133) and relapsed AML (n = 23) were included into the study. Mean follow-up period was 3.5 years. Drug resistance for up to 30 anticancer agents was performed by the MTT assay. Expression of all proteins was tested by flow cytometry. Results Both initial AML and relapsed ALL samples showed higher drug resistance than initial ALL samples. No significant differences were found in drug resistance between initial and relapsed AML samples. The presence of multidrug resistance and apoptosis proteins had no impact on pDFS in iALL and iAML, however strong trend towards adverse prognostic impact of MRP1, PGP and LRP on pDFS in rALL was observed. The same trend was observed for each of analyzed co-expressions of tested multidrug resistance proteins. Conclusions The phenomenon of cellular drug resistance in childhood acute leukemias is multifactorial and plays an important role in response to therapy. Expression of MRP1, PGP and LRP proteins, as well as their co-expression play possible role in childhood relapsed ALL. An erratum to this article can be found at     

The use of venetoclax-based salvage therapy for post-hematopoietic cell transplantation relapse of acute myeloid leukemia

For patients with high risk myeloid disease, allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy. Unfortunately, many of these patients relapse after HCT and have a limited survival. The recent approval of venetoclax, an orally bioavailable BCL-2 inhibitor, resulted in significant responses in treatment naïve acute myeloid leukemia (AML), and off-label use in the relapsed/refractory setting is increasing. We report the outcomes of 21 patients who underwent allogeneic HCT for myeloid disease, relapsed with AML, and were treated with venetoclax. Several patients had poor risk features including antecedent hematologic malignancy (6/21), complex karyotype (6/21), and TP53 mutations (5/21). The median age was 64.5 years and time from HCT to relapse was 5.7 months (range: 0.9 to 44.9 months). Of the 19 patients who were assessed for response, there were meaningful treatment responses seen in eight patients: five CR, three CRi, zero PR, for an ORR of 42.1%. Treatment effect was seen in six additional patients, including four in the morphologic leukemia-free state. Nine patients maintained their response for ≥3 months and eight were receiving therapy at data cut. Post-HCT AML relapse has an exceedingly poor outcome, and venetoclax-based therapy is a potent therapy option that should be studied prospectively in this setting.     

FLAG-IDA in the treatment of refractory/relapsed adult acute lymphoblastic leukemia

Relapsed or refractory adult acute lymphoblastic leukemias (ALL) have poor prognosis. The strategy for treating these patients is through reinduction chemotherapy followed by allogeneic stem cell transplantation, provided that the toxicity of the salvage regimen is acceptable. Twenty three patients with relapsed/refractory adult ALL were treated with fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA). Five patients had primary refractory disease, and 18 were in first relapse. Nine (39.1%) patients achieved complete remission (CR) following salvage therapy, whereas 13 (56.5%) patients were refractory, and one patient died in aplasia due to infection. In patients achieving remission, the median time to reach absolute neutrophil count (ANC) more than 0.5×10⁹/l and 1×10⁹/l was 20 (range 16–25) and 24 (range 20–28) days from the start of chemotherapy, respectively. Platelet levels of more than 20×10⁹/l and 100×10⁹/l were achieved in a median time of 23 (range 19–25) and 33 (range 28–39) days, respectively. Fever more than 38.5°C was observed in 18 of 23 patients (78.2%), 13 had fever of unknown origin, and 5 had documented infections. Nonhematological side effects, consisting mainly of mucositis (18/23 or 78.2%) and transient liver toxicity increase (10/23 or 43.4%), were generally tolerated. All nine patients who achieved CR received a second course with FLAG-IDA, and seven patients underwent allogeneic stem cell transplantation (four from a matched donor, one from a mismatched donor, and two from an unrelated donor), while two did not reach that stage due to early relapse from CR. The median overall survival (OS) for all 23 patients was 4.5 (range 1–38) months; for the nine responders, the disease-free survival (DFS) and the OS were 6 (range 3–38) and 9 (7–38) months, respectively; the seven patients who received allogeneic stem cell transplantation had a DFS of 10 (range 7–38) months. In our experience, FLAG-IDA is a well-tolerated regimen in relapsed/refractory ALL patients; the toxicity is acceptable, enabling patients who have achieved CR to receive allogeneic transplantation.