Issue 03 November 2015

Table of Contents

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Section 1. General Hematology, Thrombosis & Transfusion Medicine

Inhibitor recurrence after immune tolerance induction: a multicenter retrospective cohort study

IL-1β, in contrast to TNFα, is pivotal in blood-induced cartilage damage and is a potential target for therapy

Hydroxyurea with AKT2 inhibition decreases vaso-occlusive events in sickle cell disease mice

Erythropoietin Stimulates Tumor Growth via EphB4

Free hemoglobin increases von Willebrand factor–mediated platelet adhesion in vitro: implications for circulatory devices

Hypoxia-reperfusion affects osteogenic lineage and promotes sickle cell bone disease

Review: Complement in hemolytic anemia

Section 2. Leukemia and Lymphoma & Bone Marrow Transplantation

A Heritable Missense Polymorphism in CDKN2A Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution

Intravenous pegylated asparaginase versus intramuscular native Escherichia coli l-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial

Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: a systematic genetic study

Treatment of Young Children With CNS-Positive Acute Lymphoblastic Leukemia Without Cranial Radiotherapy

Treatment of Acute Graft-versus-Host Disease in Childhood with Extracorporeal Photochemotherapy/Photopheresis: The Padova Experience

Second allogeneic stem cell transplant for aplastic anaemia: a retrospective study by the severe aplastic anaemia working party of the European society for blood and marrow transplantation

Recursive partitioning analysis of prognostic factors in post-transplant lymphoproliferative disorders (PTLD): a 120 case single institution series

Review: How I treat posttransplant lymphoproliferative disorders

Review: Hodgkin lymphoma in children and adolescents: improving the therapeutic index

Section 3. Oncology: Solid Tumors and Neuro-Oncology

Relapse After Localized Rhabdomyosarcoma: Evaluation of the Efficacy of Second-Line Chemotherapy

RNA-Seq of Tumor-Educated Platelets Enables Blood-Based Pan-Cancer, Multiclass, and Molecular Pathway Cancer Diagnostics

Equivalence Ratio for Daunorubicin to Doxorubicin in Relation to Late Heart Failure in Survivors of Childhood Cancer

 

 


Inhibitor recurrence after immune tolerance induction: a multicenter retrospective cohort study.

Antun A (2015), Hemostasis and Thrombosis (Link to Abstract)

Immune tolerance induction (ITI) is successful in about 70% of cases in patients with Hemophilia A who develops inhibitors, but little is known about the rate and predictors of recurrence. This is a retrospective, multicenter (12 US center) cohort study of patients with Hemophilia A (levels 1% or less) after successful ITI. Sixty-four patients were included with a median follow up of 3.4 years. Probability of recurrence was 12.8% at 1 year, 26% at 3 years, and; 32% at 5 years.  Amongst them, 10 restarted ITI and 10 used bypassing agents.  Predictors of recurrence were: use of concurrent immune therapy during ITI (4/5 recurred), and recovery less than 85% (3 fold increase in risk). Lack of adherence to post ITI prophylaxis was not predictive of recurrence.

* There is a high rate of recurrence after successful ITI. Immune therapy and incomplete recovery are predictive of recurrence, but lack of adherence is not.

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IL-1β, in contrast to TNFα, is pivotal in blood-induced cartilage damage and is a potential target for therapy

Van Vulpen LFD, (2015), Blood (Link to Abstract)                                                          

Joint bleeds from various causes can induce cartilage remodeling and apoptosis after a single event. In this article, the authors used in vitro analyses to study the effect of cytokine inhibition on cartilage damage. Postmortem human cartilage was extracted and cells were cultured. IL-1β inhibition within 24hrs from blood exposure led to dose-dependent recovery of cartilage dysfunction markers. TNFα inhibition did not show the same effect.

*IL-1β inhibition might be a target for prevention of blood-induced cartilage damage in joint bleeds. 

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Hydroxyurea with AKT2 inhibition decreases vaso-occlusive events in sickle cell disease mice.

Barazia A, (2015), Blood (Link to Abstract)              

Hydroxyurea (HU) is the established mainstay of chronic treatment in sickle cell disease (SCD). HU was shown to stimulate HbF production, serve as an NO donor, and inhibit tissue factor expression in leukocytes. HU was also effective as acute vaso-occlusive crisis (VOC) treatment in SCD mouse models. The authors of this manuscript showed that co-administration of hydroxyurea and Akti XII, an AKT2 inhibitor, did have beneficial effect and prolonged survival in SCD mice with VOC. AKT2 plays an important role in neutrophil-erythrocyte and neutrophil-platelet interaction and its inhibition led to increased blood flow in affected areas of VOC.

* AKT2 inhibition might be a novel target in the acute VOC of SCD patients improving perfusion of affected tissues.

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Erythropoietin Stimulates Tumor Growth via EphB4.

Pradeep S, 2015, Cancer Cell ((Link to abstract)

In the adult world, recombinant erythropoietin had been used to treat anemia associated with cancer until several studies showed an association with poorer survival. However, this association has been tenuous without a clear mechanism (the Epo receptor isn’t present in many tumor cells). This group hypothesized that Epo binds to another receptor and found one using an in-silico analysis – EphB4. They then showed in vitro and in vivo that this ligand-receptor interaction leads to cell proliferation and migration. Finally, they found that women with ovarian or breast carcinoma treated with Epo whose tumors expressed EphB4 had worse survival than those whose tumors had low expression.

* Now that there’s a mechanism it seems pretty solid that Epo is not a good choice for treating anemia associated with cancer. We hadn’t used it before in pediatrics but now we probably never will (pending better evidence).

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Free hemoglobin increases von Willebrand factor–mediated platelet adhesion in vitro: implications for circulatory devices.

Da Q, 2015, Blood ((Link to abstract)   

Patients on extra-corporeal life support (ECMO) are prone to hemolysis. This report analyzed the effect of free hemoglobin on thrombus formation in vitro. The authors found that free hemoglobin ≥50mg/dl induces thrombus-formation through GPIbα-vWF interaction. GPIbαantibodies inhibited platelet deposition.  Heparin insufficiently inhibited thrombus formation in this setting.

* Hemolysis and resulting free hemoglobin ≥50mg/dl are involved in thrombus formation in an ECMO model through GPIbα-vWF interaction. Inhibition of this process might decrease thrombus formation.

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Hypoxia-reperfusion affects osteogenic lineage and promotes sickle cell bone disease

Dalle Carbonare L, 2015, Blood (Link to abstract)                                                          

Using a SCD mouse model, the authors showed that these mice [JB1] have reduced osteoblasts while osteoclasts were increased compared to healthy mice. Simulating vaso-occlusive crises with hypoxia-reperfusion events, osteoclast recruitement was seen and osteoblast activity was reduced. Zolendronic acid, a bisphosphonate, reduced bone loss in SCD mice with hypoxia-reperfusion damage.

* This study on SCD mice supports further evaluation of bisphosphonates in SCD patients to reduce sickle cell bone disease.

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Review: Complement in hemolytic anemia

Brodsky RA, 2015, Blood (Link to Abstract)

A Heritable Missense Polymorphism in CDKN2A Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution.

Walsh,K (2015) Cancer Research   (Link to abstract)                                                     

There is an increased interest in heritable genetic variants and their association with cancer. Recent GWAS studies identified SNPs that modify ALL risk; in this study, the authors identify a CDKN2A missense variant that confers 3-fold increase in ALL risk in children of different ethnic backgrounds. The risk was even higher for CDKN2A-deleted ALL. Their findings show that leukemia cells preferentially retain the germline heritable genetic variation, suggesting that it confers a growth advantage. Further somatic loss of the protective CDKN2A allele is commonly observed, demonstrating a direct interaction between heritable and somatic genetic variation in CDKN2A in leukemogenesis.

* This is supportive evidence that there are hereditable genetic changes that raise the risk for developing ALL – another puzzle piece when trying to understand the etiology of this disease. Heritable and somatic alterations in CDKN2A are important for ALL etiology and progression.

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Intravenous pegylated asparaginase versus intramuscular native Escherichia coli l-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial.

Place A, (2015) (Link to abstract)

The authors report the findings of the Dana-Farber Cancer Institute Acute Lymphoblastic Leukaemia Consortium Protocol 05-001 (DFCI 05-001) which compared the relative toxicity and efficacy of intravenous PEG-asparaginase and intramuscular native E coli l-asparaginase in children with newly diagnosed acute lymphoblastic leukaemia who achieved CR after 32 days of induction.  They describe that the overall frequency of asparaginase-related toxicities does not differ significantly between the 2 groups: 65 [28%] of 232 patients in the intravenous PEG-asparaginase group vs 59 [26%] of 231 patients in the intramuscular native E coli l-asparaginase group, p=0•60.  In particular they found no difference in the individual frequency of allergy (p=0•36), pancreatitis (p=0•55), or thrombotic or bleeding complications (p=0•26).

* Intravenous PEG-asparaginase is not more toxic than, and is similarly efficacious to intramuscular native E coli l-asparaginase.  This adds to previous reports showing that PEG-asparaginase is a useful alternative to other asparaginase products – now if only we could do something about the cost.

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Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: a systematic genetic study.

Moriyama T (2015) Lancet Oncology (Link to abstract)

This study looked to identify ALL predisposition variants in ETV6 and to determine how these contribute to the overall risk of childhood ALL.  The authors undertook targeted sequencing of ETV6 in 4405 children from COG and St Jude Children's Research Hospital front-line ALL trials with available germline DNA.  They compared ETV6 variant genotypes with non-ALL controls to define ALL-related germline risk.  They  identified 31 exonic variants (four non-sense, 21 missense, one splice site, and five frameshift variants) that were potentially related to ALL risk in 35 cases (1%). These children were significantly older at diagnosis and more likely to be hyperdiploid.  48% of the variants clustered in the erythroblast transformation specific domain and were predicted to be highly deleterious.

* Germline ETV6 variations can predispose to childhood ALL and should be looked for in families with several cases of ALL; recommendations for treatment and surveillance need to be developed.

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Treatment of Young Children With CNS-Positive Acute Lymphoblastic Leukemia Without Cranial Radiotherapy.

Wilejto M, (2015) Pediatr Blood Cancer  (Link to abstract)       

Retrospective analysis of 19 children aged 1-5 with CNS-positive ALL (precursor B-ALL n=16, T-ALL n=3). These children were treated between 2000 and 2013 at The Hospital for Sick Children in Toronto with different treatment regimens. None of the children were treated with routine Cranial radiation therapy (CRT) although 2 received total body irradiation (TBI) as part of the conditioning regimen for HSCT. When CRT was omitted intensification of systemic and intrathecal therapy was used and was at the discretion of treating physicians (intensification included high dose MTX, triple intrathecal chemotherapy and dexamethasone instead of prednisone). OS was 84.2%, EFS was 79%.

* Although this study has a small number of patients overall and children with T-ALL are under represented, it suggests that at least in children with B-ALL between the ages of 1 and 5, the omission of CRT does not result in inferior outcomes when intensification of systemic therapy and triple ITs are used.

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Treatment of Acute Graft-versus-Host Disease in Childhood with Extracorporeal Photochemotherapy/Photopheresis: The Padova Experience.

Calore E. (2015), Biology of Blood and Marrow Transplantation  (Link to abstract)                                                        

This is a retrospective study of 72 consecutive pediatric patients treated with extracorporeal photopheresis (ECP) for acute graft-versus-host disease (aGVHD). Twenty one patients were steroid-refractory, 42 were steroid-dependent, and 9 patients had no steroids given before ECP due to infectious complications. The outcomes at the end of ECP were 72% complete remission, 11% partial remission and only 17% with no response to treatment. The transplant related mortality at day +180 was only 4%.  The 5-year overall survival was 71%, time to progression of 81%, and progression-free survival of 72%.

* This study suggests that ECP is effective in treating aGVHD, without a negative impact on the primary disease. Prospective data likely would be further illuminating.

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Second allogeneic stem cell transplant for aplastic anaemia: a retrospective study by the severe aplastic anaemia working party of the European society for blood and marrow transplantation.

Cesaro S (2015), British Journal of Haematology (Link to abstract)                                        

This retrospective study assesses the outcomes and risk factors of a second allogeneic haematopoietic stem cell transplant in patients with acquired SAA and subsequent graft failure. A total of 162 patients were analyzed, as reported to the registry of the European Society for Blood and Marrow Transplantation between 1998 and 2009. After a median follow-up of 3.5 years, the 5-year overall survival was 60.7%. The only factor significantly associated with a better outcome in multivariate analysis was a Karnofsky/Lansky score ≥80.

* A second allogeneic HSCT is a feasible rescue option for graft failure in SAA but the need for a second HSCT significantly reduces the overall survival from 80-90% to 60%.

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Recursive partitioning analysis of prognostic factors in post-transplant lymphoproliferative disorders (PTLD): a 120 case single institution series.

Montanari F. (2015), British Journal of Haematology (Link to abstract)

This is a large single center retrospective analysis of 120 patients with PTLD treated at Columbia University Medical Center between 1990 and 2009. Based on recursive partitioning of this data, a new prognostic score model is suggested using three clinical-pathologic features: Eastern Cooperative Oncology Group (ECOG) score, age and CD20 expression. Using these parameters patients were allocated into 4 risk categories with overall survival as the main outcome. A subgroup of CD20 negative pediatric patients with ECOG scores of 2–4 was identified with particularly low survival. Interestingly, no benefit in overall survival was observed in CD20 positive adults post rituximab treatment compared to a homogeneous group from the pre rituximab era.

* A new prognostic score model for PTLD is suggested but has not yet been validated in a second unrelated cohort.

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Review: How I treat posttransplant lymphoproliferative disorders

                               

Relapse After Localized Rhabdomyosarcoma: Evaluation of the Efficacy of Second-Line Chemotherapy.  

Winter, S (2015), Pediatric Blood & Cancer (Link to abstract)

This is a retrospective multi-centre analysis performed in France, analyzing the efficacy of various second line regimens in children with relapsed locoregional RMS. 49 children were included who were treated between 1995 and 2013. At relapse, the chemotherapy regimen was at the physician’s discretion.  Overall response rate to second line chemo was 39.1%, 5 year OS was 49%. Response rates to various regimens are as follows: CEV/IVE: 11/15 patients: 73.3%, VI[T]: given to 7 patients: 42.9%, IVA/VAC: 0%.  Receipt of doxorubicin upfront is associated with poorer outcomes at relapse.  Local control was the most important factor in survival.

* It is important to note that salvage rates in Europe may appear higher than in North America because radiotherapy is sometimes used as salvage treatment rather than upfront. Alternatives like oral etoposide can also be used, and in practice sometimes patients receive maintenance chemotherapy with cyclophosphamide/vinorelbine after initial therapy. There is still no standard and local control remains vital.

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RNA-Seq of Tumor-Educated Platelets Enables Blood-Based Pan-Cancer, Multiclass, and Molecular Pathway Cancer Diagnostics.

Best J, 2015, Cancer Cell (Link to abstract)        

It has been previously established that mRNA expression and splicing in platelets is affected by their interactions with other cells. This group hypothesized that they could detect cancer by examining platelet mRNA. Using next generation sequencing they found a high (>97%) sensitivity and specificity for detecting cancer in general using platelet mRNA. With less accuracy they were also able to discriminate between different carcinoma types. There is also some ability to detect canonical mutations using this method such as KRAS mutations in colorectal cancer.

* “Liquid biopsies” are going to be a clinical thing in the near future. Whether they come in the form of plasma “cell free DNA” tests, circulating tumor cells, or this technique using platelet mRNA, you will see likely see them in your practice soon.

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Equivalence Ratio for Daunorubicin to Doxorubicin in Relation to Late Heart Failure in Survivors of Childhood Cancer.                                                                                               

Feijin A (2015), Journal of Clinical Oncology (Link to abstract)

The differential risk for cardiotoxicity between daunorubicin and doxorubicin has not been rigorously evaluated among childhood cancer survivors but based on hematologic toxicity has been assumed to be approximately equivalent.  Here the authors report data from 7,387 survivors; 5,144 who received doxorubicin and 2,243 who received daunorubicin, with a median follow up of 17.3 years and a cumulative incidence of heart failure at age 40 years of 3.2 %.  They found the average ratio of HRs for daunorubicin to doxorubicin to be 0.45 (95% CI, 0.23 to 0.73).

* Compared with doxorubicin, daunorubicin is less cardiotoxic among childhhod cancer survivors than most current guidelines suggest. This has implications for treatment protocols in terms of reducing cardiotoxicity as well as follow up guidelines

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