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.

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%.

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.

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.

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.

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.

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.

Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey

Zeiser R, 2015, Leukemia  (Link to abstract)                                            

Ruxolitinib is a JAK 1 /2 inhibitor for treating myelofibrosis, which was also reported to be effective for treatment of GVHD in mouse models. This study is a retrospective survey of the outcomes of patients who received ruxolitinib as salvage therapy for corticosteroid refractory GVHD. Data was collected from 19 centers in Europe and the USA. A total of 95 patients were included for analysis (acute GVHD n=54, chronic GVHD n=41). Overall response rate was 81.5% and 85.4%, for aGVHD and for cGVHD, respectively. 6 month survival rates [NW5] were 79% and 97.4%for aGVHD and cGVHD, respectively. Adverse events observed included increased risk of CMV reactivation, and cytopenias.

* Ruxolitinib appears to be a promising new agent for steroid resistant acute and chronic GVHD in a retrospective review.

Stem cell transplantation in severe congenital neutropenia: an analysis from the European Society for Blood and Marrow Transplantation

Fioredda, F. Blood. 2015 (Link to abstract)                                 

This multicenter, retrospective study included patients from the EBMT and SCETIDE registries. 136 Severe Congenital Neutropenia (SCN) patients underwent HSCT between 1990-2012 at European and Middle Eastern centers. Indications leading to transplant included: HD-GCSF requirements (79%), severe infection (37%), transformation to MDS before HSCT (16%).

The following complications were seen: Graft failure: Probability after 90 days from HSCT was 10%, probability of engraftment was 92% in HLA-matched, and 72% in mismatched donor. GVHD: Cumulative incidence at 90 days (grade 2-4) was 21%. 2 factors associated with a significant lower rate of GVHD: HLA-matched related donor and double prophylaxis with CSA and MTX. Peripheral blood as sources of HSCT was associated with higher cGvHD incidence.

Overall Survival: 3-year OS after HSCT 82%. Median time from transplant to death: 3 months, with 80% of the deaths occurring within 12 months after transplant. [NW4] Transplants undertaken in later years had better survival (OS-3ys 66% in 1990-2000, 79% 2001-2007 and 91% in 2008-2012). No secondary malignancies were reported.

* HSCT is an option for treatment of SCN with an acceptable 3 year OS and EFS (82% and 71%, respectively). TRM is 17% and therefore appropriate selection of patients and SC sources as well as GVHD prophylaxis are important factors.

Pediatric T-cell lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation

Kunz JB, Oct 2015, Haematologica (Link to abstract)

This study aimed to understand the genetic basis for relapse in T-cell ALL. Matched samples of T-cell ALL patients at diagnosis, remission and relapse where analyzed by various deep sequencing methods and DNA methylation array. The investigators found 2 mutation patterns at relapse. Type 1 was derived from major leukemic clones at diagnosis, with additional mutations. Type 2 arose from a common pre-leukemic ancestor, with the relapse clone having new mutations not similar to the major diagnostic clone. Overall there is significant increase in mutational load at relapse compared to first diagnosis. NT5C2 was identified as a recurrently mutated gene and may confer resistance to therapy. Relapse specific genetic changes tend to activate general mechanisms of carcinogenesis rather than known leukemia specific drivers. 

* This paper implies that there are at least two evolutionary pathways through which T-ALL can relapse.

Results of a Multicenter Phase II Trial of Brentuximab Vedotin as Second-Line Therapy before Autologous Transplantation in Relapsed/Refractory Hodgkin Lymphoma

Chen R  (2015), Biology of Blood and Marrow Transplantation (Link to abstract)                                                          

Brentuximab vendolin (BV, anti CD30 antibody conjugated to monomethyl auristatin E) is currently used in Hodgkin Lymphoma (HL) patients as a third-line treatment usually to bridge to autologous hematopoietic stem cell transplantation (HSCT). In this multicenter prospective phase II trial the activity and toxicity of BV were examined for relapsed/ refractory HL as a second-line treatment, bridging for autologous HSCT. Of 37 patients, the overall response rate was 68%, and the drug was well tolerated, with 32 (86%) of the patients proceeding to autologous HSCT. 

* This study demonstrated that brentuximab vedotin as second-line therapy for patients with HL is active, well tolerated, and does not hinder stem cell collection or engraftment.

Similar outcome of upfront-unrelated and matched sibling stem cell transplantation in idiopathic paediatric aplastic anaemia. A study on behalf of the UK Paediatric BMT Working Party, Paediatric Diseases Working Party/Severe Aplastic Anaemia Working..

Similar outcome of upfront-unrelated and matched sibling stem cell transplantation in idiopathic paediatric aplastic anaemia. A study on behalf of the UK Paediatric BMT Working Party, Paediatric Diseases Working Party and Severe Aplastic Anaemia Working Party of EBMT

Dufour C  (2015), British Journal of Haematology (Link to abstract)            

The current first-line treatment for patients with SAA without a matched sibling donor is immune suppressive therapy. This study shows very good results with upfront unrelated donor hematopoietic stem cell transplantation (HSCT)[NW3]  for these patients. In a cohort of 29 patients, the 2 year overall survival was 96% and event free survival was 92%, These outcomes were similar to the matched historical sibling donor control group and superior to the matched historical immune suppressive therapy control group.

* In a very small cohort using a different conditioning regimen than used in most centres, HSCT unrelated donors appeared to have similar outcomes to historical sibling-related donors.

Incidence of breast cancer among female survivors of Hodgkin lymphoma: a US-population–based trend analysis from 1973 to 2011

Giri S (2015) Blood  (Link to abstract)                                             

The NCI database of cancer patient follow up SEER 9 was used to analyze a total of 5776 women with Hodgkin lymphoma followed up for a median duration of 229 months. The authors found an excess risk of breast cancer with diagnosis at a median age of 46 years and a latency of 231 months since HL diagnosis. In contrast the median age for a breast cancer diagnosis in the general population is 61 years (data from the same database). The age-adjusted incidence ratios steadily declined over the study time. The authors speculate that this might be due to advances in radiation techniques (involved field vs. extended field), less radiation, differences in chemotherapies or combinations.

* This report confirms the excess risk of breast cancer in HL survivors and highlights that these women develop breast cancer at an earlier age. The good news is that the age-adjusted incidence declines.


Targeting casein kinase II restores Ikaros tumor suppressor activity and demonstrates therapeutic efficacy in high-risk leukemia

Song, C, 2015, Blood (Link to abstract)

Inactivating tumor suppressor Ikaros mutations are associated in humans with high-risk B-cell leukemia resistant to treatment. The authors assessed Ikaros function on cell cycle regulation in various in vitro and in vivo assays (the latter on mouse xenograft models) and showed that decreased Ikaros activity due to the deletion or inactivating mutation of a single IKZF1 allele results in repression of genes regulation cell cycle promotion. Ikaros function was impaired by the pro-oncogenic casein kinase II (CK2), and CK2 is overexpressed in leukemia. CK2 inhibition restored Ikaros function as transcriptional repressor of cell cycle, resulting in an antileukemia effect. CK2 inhibition on mouse xenografts led to decrease in leukemic burden

* Restoration of Ikaros tumor suppressor activity via inhibition of CK2 might be a new target in high-risk leukemia with deletion of one IKZF1 allele.

The genomic landscape of juvenile myelomonocytic leukemia

Stieglitz, E, 2015, Nature Genetics  (Link to abstract)                                                            

Previous studies have characterized JMML as “Rasopathy”, mostly driven by activation of the Ras-MAPK pathway through mutations in NF1, NRAS, KRAS, PTPN11 or CBL. Seeking to understand the mutational landscape of JMML and identify additional pathways involved in disease initiation and progression, the authors performed whole-exome sequencing in serial samples from patients at diagnosis, relapse and transformation to AML.

In addition to known genetic hits, the group identified 2 new mutations in the Ras-MAPK pathway (SH2B3 and RRAS2), as well as activation of JAK-STAT signaling and epigenetic modification through the PRC2 and spliceosome complexes as important in leukemogenesis in JMML. In 16/22 patients that were analyzed over time, the mutations identified at diagnosis were invariably maintained at relapse. Several mutated genes, previously unknown to be implicated in JMML, were identified at relapse (JAK3 and RUNX1).

Contrary to previous reports, they found no difference in outcome between patients harboring different somatic mutations; when corrected for other variables, the number - rather than the type - of mutations at diagnosis was the main determinant of outcome.

* JMML is more than a Rasopathy and the discovery of additional molecular alterations provides rationale for new therapeutic approaches (such as demethylating agents[NW2] ) and better patient stratification.

Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia

Karol SE (2015) Blood (Link to abstract)

The authors performed a genome-wide association study of single nucleotide polymorphisms (SNPs) in a discovery cohort with 2285 children with ALL, treated on the Children’s Oncology Group AALL0232 protocol. They found a SNP near the glutamate receptor GRIN3A locus (9q31.1) associated with higher risk of corticosteroid-induced osteonecrosis (hazard ratio = 2.03). In 2 different other cohorts this association was confirmed. The control cohorts included 361 children with ALL on St. Jude’s Total XV protocol and 309 non-ALL patients from Vanderbilt University’s BioVU repository treated with glucocorticoids. Multivariate analysis revealed age >10 y, and female gender to be associated with higher risk of osteonecrosisIn a meta-analysis osteonecrosis-associated glutamate receptor variants were also associated with other vascular phenotypes including cerebral ischemia and arterial embolism and thrombosis.

* This article provides insight into genetic predisposition in glucocorticoid-associated osteonecrosis.

Affinity-Tuned ErbB2 or EGFR Chimeric Antigen Receptor T Cells Exhibit an Increased Therapeutic Index against Tumors in Mice

Liu et al (2015) Cancer Research

Link to abstract:

Both of these groups published similar results in the same issue. One of the problems with CAR-T cells is that they can be engineered to detect a variety of tumor-related antigens but many of these, such as EGFR, are also present on normal tissues and this leads to toxicity. Both groups tested antigen receptors with high affinity for EGFR against those with moderate affinity.

*Those with high affinity targeted tumor and normal tissue but the moderate affinity ones targeted mostly only tumor tissue and left normal tissue alone.

Tuning Sensitivity of CAR to EGFR Density Limits Recognition of Normal Tissue While Maintaining Potent Antitumor Activity

Caruso et al (2015) Cancer Research

Link to abstract:

The potential of clofarabine in MLL -rearranged infant acute lymphoblastic leukaemia

Stumpel et al (2015) European Journal of Cancer                                             

Link to abstract:

MLL-rearranged acute lymphoblastic leukaemia (ALL) in infants is the most difficult-to-treat type of childhood ALL, displaying a chemotherapy-resistant phenotype, and unique histone modifications, gene expression signatures and DNA methylation patterns. Clofarabine effectively targeted primary MLL-rearranged infant ALL cells in vitro at the lowest concentrations, Interestingly, clofarabine displayed synergistic cytotoxic effects in combination with cytarabine. Higher concentration of clofarabine induced demethylation of the promoter region of the tumour suppressor gene FHIT (Fragile Histidine Triad), a gene typically hypermethylated in MLL-rearranged ALL.

Clofarabine might be a good candidate in combination with standard chemotherapy treated high-risk infant leukemia as cytotoxic and epigenomic modifier.

Risk factors and timing of relapse after allogeneic transplantation in pediatric ALL: for whom and when should interventions be tested?

Pulsipher et al (2015) Bone Marrow Transplantation                                      

Link to abstract:

The study looked at the effect of established leukemia disease risk-classification groups, pre- and post-HCT MRD detection, and the occurrence of GvHD on relapse and survival reviewing COG protocol ASCT0431 from 2007 to 2011 including 105 patients. Pre-HCT MRD <0.1% and aGvHD by day +55 were associated with decreased relapse and improved event-free survival (EFS). Patients with pre-HCT MRD <0.1% who did not experience aGvHD had higher rates of relapse than those who did develop aGvHD (40% vs 13%; P = 0.008).

The population at highest risk of poor outcome was HR CR1/CR2 patients who were MRD+ pre-HCT who then did not experience grade I–III aGvHD (EFS 12%). 59% of all relapses occurred between days +100 and +400 in patients without aGvHD.

*This analysis clarifies that both pre-HCT and post-HCT factors (disease risk, pre- and post-HCT MRD and aGvHD) can be used to define populations with poor outcome. An optimal window to initiate intervention to prevent relapse occurs between day +55 and +200 after HCT. Study of interventions with maintenance courses of immunotoxins or weaning immune suppression followed by agents designed to enhance anti-tumor effect may prevent relapse in appropriately defined high-risk populations.

Childhood and Adolescent nodular lymphocyte predominant Hodgkin lymphoma – A review of clinical outcome based on the histological variants

Shankar et al (2015) British Journal of Haematology

Link to abstract:

Retrospective data collection, with pathological review of 60 biopsies (CCLG, Euronet PHL-LP1, OK Children’s Cancer Study Group HD3) between 2001 and 2014.  Aim to evaluate treatment outcome in patients with histopathological variants of nodular lymphocyte predominant HL (nLPHL) after de-escalation of therapy.  Patients: 5-16 years (med: 14y.o.); 47 with typical (nLPHL), 13 with variant nLPHL. 14 were treated with excision alone; 46 treated with chemo (40 CVP, 16 other regimens). 

*Compared to nLPHL, variant nLPHL is associated with lower complete response rates (CCR: 46% vs 81%) p = 0.029.  There were trends seen which were not significant: Higher stage at diagnosis (stage III: 23% vs 6%) and increased risk of relapse (15% vs 4%).

Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia

Churchman et al (2015) Cancer Cell                                        

Link to abstract:

Multiple methods were used in mouse models and human-derived cell cultures to reach the following findings:

  • IKZF1 and Arf mutations confer lymphoid stem cell lineage in Ph+ cells. Ph+ cells in the absence of IKZF1 mutations are much more likely to develop into a myeloid phenotype.
  • IKZF1 mutations increase the adhesiveness of leukemia cells and this increases their ability to adhere to the bone marrow niche.
  • Mice with Ph+/IKZF1+/- or combined with other Ikaros-related downstream mutations had a poorer survival with dasatinib therapy than Ph+ with wild type IKZF1
  • Retinoids improved the response to dasatinib in in vitro assays as well as in the mouse model and was better than a combination of dasatinib with conventional chemotherapy (in mice with Ph+ and an Ikaros mutation).

Recommendations on hematopoietic stem cell transplantation for inherited bone marrow failure syndromes

R Peffault de Latour (2015) Bone Marrow Transplantation                                          

Link to abstract:

This report summarizes the recommendations for transplanting children with IBMF including indications for HSCT, timing, stem cell source and conditioning regimen for inherited bone marrow failure syndromes. HSCT remains the only curative treatment option for disturbances of hematopoiesis in IBMFS. Prospective international clinical trials are urgently required in order to enhance the management of these rare disorders, and in time, lead to improved outcomes.

CD200/BTLA deletions in pediatric precursor B-cell acute lymphoblastic leukemia treated according to the EORTC-CLG 58951 protocol

Ghazavi, F (2015) Haematologica                                            

Link to abstract:

CD200 and BTLA recurrent deletions (on 3q13.2) were screened for in 1154 patients (<18 years old) with high-risk precursor B-ALL treated with the EORTC-CLG 58951 protocol and identified in 4.8%. They are strongly associated with ETV6-RUNX1 translocations. CD200/BTLA deletion was associated with higher proportion of positive MRD at end of induction and inferior event free survival (70.2% vs 83.5%) and poorer disease free survival (72.8% vs 84.4%), but not overall survival  (91% vs 87%) at 8 years compared to those without deletion. The highest number of patients with this mutation, were in the poor prognosis group (as per EORTC-CLG classification).  

*Multivariate analysis indicates the deletion of CD200/BTLA as an independent prognostic factor on EFS. This has an implication for disease stratification and therapeutic planning – contextualizes relapsed disease though no prospective testing of intensified therapy.

Prognostic Significance of Diffuse Large B-Cell Lymphoma Cell of Origin Determined by Digital Gene Expression in Formalin-Fixed Paraffin-Embedded Tissue Biopsies

Scott D et al, 2015 Journal of Clinical Oncology                                 

Link to abstract:

Diffuse Large B-Cell Lymphoma (DLBCL) can be classified into 2 distinct subtypes depending on the stage of development of B-cells using gene expression analysis: germinal center B-cell–like (GCB) and activated B-cell–like (ABC) subtypes.  These groups have distinct biology and treatment outcome.   In adult oncology most clinicians still use International Prognostic Index (IPI) score and MYC/BCL2 co-expression status in routine practice to prognosticate, as the requirement for fresh frozen biopsies and microarray technology to determine sub-group seemed insurmountable.

In this paper the authors compared these “old-fashioned” markers to a recently described gene expression-based assay, the Lymph2Cx assay.  The Lymph2Cx assay can be applied to formalin fixed tissue and has been shown to be highly accurate and concordant in sub-group assignment between laboratories.  The authors applied the assay to pretreatment FFPE biopsies from 344 patients (>16 years) with de novo diffuse large B-cell lymphoma (DLBCL) uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the British Columbia Cancer Agency. 

*They found that patients with activated B-cell–like DLBCL had significantly inferior outcomes compared with patients with germinal center B-cell–like DLBCL and that this was independent of IPI score and MYC/BCL2 immunohistochemistry.  Could similar technology be used in children with DLBCL to prognosticate (in particular in the AYA population) and to drive trial questions?

Disease evolution and outcomes in familial AML with germline CEBPA mutations

Tawana K et al, 2015 Blood                                                       

Link to abstract:

24 individuals from 10 families with CEBPA germline mutations and AML had whole-exome (WES) and deep sequencing on leukemic cells. The results showed that germline CEBPA mutations clustered within the N-terminal and were highly penetrant, with AML presenting at a median age of 24.5 years (range, 1.75-46 years). In all diagnostic tumors tested (n = 18), a second CEBPA mutation was detected, with the acquired (somatic) mutations preferentially targeting the C-terminal. Deep sequencing of diagnostic and relapse paired samples suggested that recurrence was triggered by novel, independent clones with different CEBPA mutations than at presentation. The cumulative incidence of relapse in patients with this syndrome was 56% at 10 years (n = 11), and 3 patients experienced ≥3 disease episodes over a period of 17 to 20 years; still, long-term overall survival was favorable (10-year overall survival, 67%).

*In conclusion, this article states that relapse in patients with germline CEBPA mutatuion is due to additional novel mutations and not recurrence of the initially seen one and that treatment for relapse might therefore be more successful than in other types of leukemia as shown by the relatively good survival rate.

Transmembrane TNF-α preferentially expressed by leukemia stem cells and blasts is a potent target for antibody therapy

Zhou X et al, 2015 Blood                                                             

Link to abstract:

Transmembrane tumor necrosis factor-a (tmTNF-a) in leukemia is preferentially expressed in leukemia cells of human bone marrow samples with AML (n = 69), B- or T-ALL (n = 30) compared to non-malignant anemia (n = 30). TmTNF-a+ expression seemed to correlate with poor prognosis. Knockdown of tmTNF-a+ expression rendered leukemia cells more sensitive to chemotherapy in vitro and delayed regeneration of leukemia in a mouse model. These mice transplanted with leukemia cell lines were treated with a monoclonal antibody targeting tmTNF-a. This resulted in leukemia cell killing via antibody-dependent cell-mediated and complement-dependent cytotoxicity in vitro and inhibited leukemia cell growth in vivo while simultaneously sparing normal hematopoietic cells.

*TmTNF-a represents a novel target antigen in acute leukemia.

A phase 1 dosing study of ruxolitinib in children with relapsed or refractory solid tumors, leukemias, or myeloproliferative neoplasms: A COG phase 1 consortium study (ADVL1011)

Loh ML et al, 2015 Pediatric blood and cancer                                                    

Link to abstract:

Phase 1 study including >12 m/o to <22 y/o with recurrent/refractory solid tumors (including lymphoma), or relapsed/recurrent ALL, AML or MPN.  Ruxolitinib (JAK1/2 inhibitor) given BID x 28 days/cycle. 

Forty-nine patients enrolled, 28 ST in dose escalation component (27 evaluated), 17 leukemia pts, 4 with MPN (10/21 evaluated). Median of 1 cycle given.  5 patients had dose limiting toxicity (nausea/vomiting, neutropenia, elevated CK, elevated Cr with AKI).  In ST pts, 4/27 pts had grade 4 hematologic toxicity on cycle 1 (lymphopenia, neutropenia), 2/36 cycles with grade 4 hematologic toxicity on subsequent cycles (lymphopenia, thrombocytopenia).  In all pts, 1/37 with grade 4 non-hematologic toxicity in cycle 1 (elevated ALT), 1/36 pts on subsequent cycles with grade 4 non-hematologic toxicity (elevated AST).

No objective response in ST pts.  12/37 pts with stable disease after cycle 1 (8 ST pts, 4 hematologic malignancy pts).  1 pt with polycythemia vera had PR and got 18 cycles.

PK data – peak plasma concentration achieved 1 hour after first oral dose (range 1-4 hours), half-life 2.3±0.9 hours. Pharmacodynamics showed inhibition in vitro of JAK/STAT pathway.  In vivo inhibition seen in 3 pre-B ALL patients, but not complete inhibition with dose studied. In pts with leukemia, none had JAK1/2 point mutation. 

*Bottom line – Ruxolitinib was well tolerated at all dose levels tested.  No response seen, however only 1 patient enrolled in this trial (pt with PV) had a JAK mutation.  May have more effect in pts with JAK mutations.  Should be tested with chemotherapy in pts with JAK mutation.

Ceritinib in patients with advanced anaplastic lymphoma kinase–rearranged anaplastic large-cell lymphoma

Richly et al, 2015 Blood                                                                

Link to abstract:

Ceritinib is a novel, selective ALK inhibitor, which has been shown to induce complete tumor regression of crizotinib-resistant xenograft models of ALK+ ALCL. This study reported on 3 patients with ALK+ ALCL relapse who received Ceritinib on a phase I dose escalation trial as part of an expansion cohort of 304 patients with ALK+ve tumors (ASCEND-1 trial). Two patients achieved a complete response (CR) and 1 had a partial response (PR, 94.8% tumor reduction). Response was seen for at least 20 months in all treated patients. 

*This outlines Ceritinib as a potential agent in ALK+ ALCL.

Biomarkers for Diagnosis and Prognosis of Sinusoidal Obstruction Syndrome after Hematopoietic Cell Transplantation

Akil A et al (2015) Biology of Blood and Marrow Transplantation                                                              

Link to abstract:

In this study, candidate protein biomarkers of SOS (VOD) were identified using a quantitative mass spectrometry–based proteomics approach by comparing plasma pooled from 20 patients with and 20 patients without SOS. Six proteins were selected and then evaluated for diagnostic potential on samples from 80 patients with five more proteins, which were selected from the literature.

*The results identified a suggestive biomarker panel for diagnosis of SOS measured as early as on the day of transplant showing >80% correct prediction of SOS onset.

Unrelated cord blood transplantation for childhood acute myelogenous leukemia: the influence of cytogenetic risk group stratification

Michel et al (2015) Leukemia                                                     

Link to abstract:

The authors aim to look at results of UCBT in childhood AML according to cytogenetic risk group stratification and disease status at time of transplant. The study included 293 patients with AML, who received single unit UCBT. For time of transplant, 114 in CR1, 133 in CR2, 46 had more advanced phase of disease. Median follow up 49 months.  According to karyotype, patients classified into favorable, intermediate and unfavorable groups.

*They concluded that the best results were achieved for patients with unfavorable karyotype in CR1 (DFS 73%) and favorable karyotype in CR2 (DFS

Outcome of relapsed infant acute lymphoblastic leukemia treated on the interfant-99 protocol

Driessen et al (2015) Leukemia                                                 

Link to abstract:

Infant ALL is known to have high relapse rate, but published data on the outcome of relapsed infant ALL is limited. This paper report on clinical outcome of infant ALL patients who relapsed in the Interfant-99 study (202 out of 478 patients). Median follow up 5.2 years (1 month – 10 years).

159 patients (78.7%) received relapsed treatment with curative intent, 87 underwent HSCT. The 3-year OS was 24.9%. For prognostic factors, young age, high WBC count at initial diagnosis, early relapse (within 2 years from initial diagnosis), and BM involvement were associated with inferior outcome. Comparison on treatment by chemotherapy alone vs HSCT showed advantage of HSCT for patients who had early relapse, but no advantage for patients who relapsed later.

*Authors concluded that relapsed infant ALL was not invariably lethal, treatment with curative intents and new therapeutic strategies may be beneficial.

Heterogeneous cytogenetic subgroups and outcomes in childhood acute megakaryoblastic leukemia: a retrospective international study

Inaba et al (2015) Blood                                                               

Link to abstract:

This international retrospective study (including COG, St Jude’s, and BFM data) included 490 patients (age ≤18 years) with non–Down syndrome AMKL diagnosed from 1989 to 2009. This AML subtype occurred in 7.8% of pediatric AML. Five-year event-free (EFS) and overall survival (OS) were 49.0% ± 2.7% in the cohort from 2000 to 2009 - significantly lower than for other AML subtypes. It was noted that patients treated in 2000 to 2009 received higher cytarabine doses and had better EFS and OS than those diagnosed in 1989 to 1999. The authors classified AMKL into 3 risk groups based on cytogenetics:

  • Good risk—7p abnormalities (5 year EFS 74%, 5 year OS 77%)
  • Intermediate risk—others including t(1;22)(p13;q13)/OTT-MAL (RBM15-MKL1) and 11q23/MLL except t(9;11). (5 year EFS 50%, 5 year OS 56%)
  • Poor risk—normal karyotypes, –7, 9p abnormalities including t(9;11)(p22;q23)/MLL-MLLT3, –13/13q-, and –15 (5 year EFS 22%, 5 year OS 24%)

*This risk stratification might help tailor treatments to each subgroup better.