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Acute Lymphoblastic Leukemia
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Wednesday, September 21, 2016 4:00 PM|Suzuki, Okuno, Kawashima, Muramatsu, Okuno, Wang, Kataoka, Sekiya, Hamada, Murakami, Kojima, Narita, Narita, Sakaguchi, Sakaguchi, Yoshida, Nishio, Hama, Takahashi, Kudo, Kato, Kojima|Journal of Clinical Oncology Current Issue|Labels: ALL
Purpose

Acute lymphoblastic leukemia (ALL) makes up a significant proportion of all pediatric cancers, and relapsed ALL is a leading cause of cancer-associated deaths in children. Identification of risk factors and druggable molecular targets in ALL can lead to a better stratification of treatments and subsequent improvement in prognosis.

Patients and Methods

We enrolled 59 children with relapsed or primary refractory ALL who were treated in our institutions. We primarily performed RNA sequencing (RNA-seq) using patients’ leukemic cells to comprehensively detect gene fusions and analyze gene expression profiles. On the basis of results obtained by RNA-seq, we performed genetic validation, functional analysis, and in vitro drug sensitivity testing using patients’ samples and an exogenous expression model.

Results

We identified a total of 26 gene fusions in 22 patients by RNA-seq. Among these, 19 were nonrandom gene fusions already described in ALL, and four of the remaining seven involved identical combination of MEF2D and BCL9. All MEF2D-BCL9–positive patients had B-cell precursor immunophenotype and were characterized as being older in age, being resistant to chemotherapy, having very early relapse, and having leukemic blasts that mimic morphologically mature B-cell leukemia with markedly high expression of HDAC9. Exogenous expression of MEF2D-BCL9 in a B-cell precursor ALL cell line promoted cell growth, increased HDAC9 expression, and induced resistance to dexamethasone. Using a primary culture of leukemic blasts from a patient, we identified several molecular targeted drugs that conferred inhibitory effects in vitro.

Conclusion

A novel MEF2D-BCL9 fusion we identified characterizes a novel subset of pediatric ALL, predicts poor prognosis, and may be a candidate for novel molecular targeting.

Wednesday, September 21, 2016 12:52 PM|Oshima, K., Khiabanian, H., da Silva-Almeida, A. C., Tzoneva, G., Abate, F., Ambesi-Impiombato, A., Sanchez-Martin, M., Carpenter, Z., Penson, A., Perez-Garcia, A., Eckert, C., Nicolas, C., Balbin, M., Sulis, M. L., Kato, M., Koh, K., Paganin, M., Basso, G., Gastier-Foster, J. M., Devidas, M., Loh, M. L., Kirschner-Schwabe, R., Palomero, T., Rabadan, R., Ferrando, A. A.|PNAS - RSS feed of Early Edition articles|Labels: RAS, ALL
Although multiagent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die because of chemorefractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape at relapse in pediatric ALL cases. These analyses identified numerous...
Monday, September 19, 2016 8:20 AM|Onclive Articles|Labels: ALL
Chimeric antigen receptor T-cell therapy targeting CD19 demonstrated a nearly 80% complete remission rate across relapsed/refractory B-cell acute lymphoblastic leukemia patients with multiple levels of disease burden.
Friday, September 16, 2016 7:08 AM|Müller, F., Cunningham, T., Liu, X. F., Wayne, A. S., Pastan, I.|Clinical Cancer Research Online First Articles|Labels: ALL

Purpose: Recombinant immunotoxins (rITs) targeting CD22 are highly active in hairy cell leukemia, but less so in acute lymphoblastic leukemia (ALL). This study aims to understand the variable activity of an rIT against ALL toward improving responses in clinical application.

Experimental Design: We determined in vitro activity of rITs by WST-8 assays and the time needed to kill ALL cell lines and patient-derived ALL blasts by flow cytometry. The findings were translated into two systemic ALL xenograft models. Differences in time needed to kill KOPN-8 cells for distinct rITs were addressed biochemically.

Results: In vitro activity (IC50) of anti-CD22 rIT varied 210-fold from 0.02 to 4.6 ng/mL. Activity also varied greatly depending on the time ALL cells were exposed to immunotoxin from < 30 minutes to > 4 days. For KOPN-8, the difference in exposure time was related to intracellular rIT processing. We showed in newly developed ALL xenograft models, where immunotoxins have a short half-life, that the needed exposure time in vitro predicted the responses in vivo. By replacing bolus dose with small doses at frequent intervals or with continuous infusion, responses were substantially improved. We confirmed exposure time variability on patient-derived ALL samples and showed a correlation between exposure time needed to reach maximal cytotoxicity in vitro and their clinical response.

Conclusions: The exposure time needed for rITs targeting CD22 to kill ALL cells varies widely. Our results suggest that ALL patients would have a better response rate to anti-CD22 immunotoxins if treated by continuous infusion rather than by bolus injections. Clin Cancer Res; 22(19); 1–10. ©2016 AACR.

Friday, September 16, 2016 7:00 AM|Anonymous|American Pharmacists Association - Improving medication use. Advancing patient care.|Comments|Labels: ALL

Rituximab, which targets the CD20 antigen, has been an effective treatment for non-Hodgkin lymphoma. That same antigen may also be present in patients with B-lineage acute lymphoma leukemia (ALL), giving researchers hope that the drug may improve outcomes in these patients as well. In a randomized trial, 209 CD-positive ALL patients were assigned to undergo chemotherapy with or without rituximab. After followup of about 2.5 years, event-free survival proved to be greater for the rituximab group.

Thursday, September 15, 2016 1:00 AM|RxList - News and Features|Labels: ALL
Although the past 10 years has seen major improvements in outcomes for adults with acute lymphoblastic leukemia (ALL), targeted therapy holds the promise of even greater survival gains in certain disease subtypes.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: mTOR, ALL
Laboratory and other studies suggest that, the study drug, Everolimus (RAD001), may prevent tumor cell growth and also may increase the efficacy of other chemotherapy drugs. Everolimus is approved for use in the United States for certain types of cancer, such as kidney cancer. It has been extensively studied in people with various types of cancer as a single agent (a drug that is used alone to treat the cancer) or in combination with a number of other drugs. Studies in adults with cancer have also evaluated Everolimus in combination with other anti-tumor drugs. Information from lab studies and some other clinical trials suggests that Everolimus may kill leukemia cells on its own, and also make it more likely that steroids (such as prednisone) are able to kill leukemia cells. In this research study, we are looking to learn more about how Everolimus works in combination with other drugs which are commonly used to treat relapsed acute lymphoblastic leukemia (prednisone, vincristine, PEG-asparaginase, and doxorubicin). The main goal of the study is to evaluate the side effects of this treatment combination in order to determine a safe dose of Everolimus which can be given with these other 4 drugs.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: ALL, CLL, clinical trial, NHL
This phase I/II trial studies the side effects and best dose of laboratory treated T cells to see how well they work in treating patients with chronic lymphocytic leukemia, non-Hodgkin lymphoma, or acute lymphoblastic leukemia that have come back or have not responded to treatment. T cells that are treated in the laboratory before being given back to the patient may make the body build an immune response to kill cancer cells.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: ALL, clinical trial
This partially randomized phase III clinical trial is studying different combinations of risk-adapted chemotherapy regimens and their side effects and comparing how well they work in treating younger patients with newly diagnosed standard-risk acute lymphoblastic leukemia. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy), giving the drugs in different doses, and giving the drugs in different combinations may kill more cancer cells.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: ALL, clinical trial
This randomized phase III trial is studying how well combination chemotherapy works in treating young patients with newly diagnosed high-risk acute lymphoblastic leukemia. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) and giving the drugs in different doses and in different combinations may kill more cancer cells.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: ALL, clinical trial
This randomized phase III trial compares how well combination chemotherapy works when given with or without bortezomib in treating patients with newly diagnosed T-cell acute lymphoblastic leukemia or stage II-IV T-cell lymphoblastic lymphoma. Bortezomib may help reduce the number of leukemia or lymphoma cells by blocking some of the enzymes needed for cell growth. It may also help chemotherapy work better by making cancer cells more sensitive to the drugs. It is not yet known if giving standard chemotherapy with or without bortezomib is more effective in treating T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: ALL, clinical trial
This randomized phase III trial studies how well blinatumomab works compared with standard combination chemotherapy in treating patients with B-cell acute lymphoblastic leukemia that has returned after a period of improvement (relapsed). Monoclonal antibodies, such as blinatumomab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether standard combination chemotherapy is more effective than blinatumomab in treating relapsed B-cell acute lymphoblastic leukemia.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: ALL, clinical trial
This randomized phase III trial studies compliance to a mercaptopurine treatment intervention compared to standard of care in younger patients with acute lymphoblastic leukemia in remission. Assessing ways to help patients who have acute lymphoblastic leukemia to take their medications as prescribed may help them in taking their medications more consistently and may improve treatment outcomes.
This study evaluates ADCT-301 in patients with Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL). Patients will participate in a dose-escalation phase (Part 1) and receive ADCT-301 every 3 weeks. In Part 2 of the study, patients will receive a recommended dose of ADCT-301 every 3 weeks.
Tuesday, September 13, 2016 8:19 PM|Na Xu, Yu-ling Li, Xuan Zhou, Rui Cao, Huan Li, Qi-si Lu, Lin Li, Zi-yuan Lu, Ji-xian Huang, Jing Sun, Qi-fa Liu, Qing-feng Du, Xiao-li Liu|Journal of Cancer (RSS 2.0)|Labels: Bcr-Abl, CDK, ALL

Deletion of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) is well known in many hematologic malignancies, but only few reports have investigated this deletion effect on clinical prognosis. This study performed analysis of the CDKN2 deletion in 215 adult B- lineage acute lymphoblastic leukemia (B-ALL) patients, and related cytogenetic prognostic factors (BCR/ABL; E2A/PBXl; TEL/AML1; Mixed Lineage Leukemia (MLL) rearrangement; MYC, Immunoglobulin heavy locus (IGH) translocation). The prevalence of CDKN2 deletions in all study populations was 28.4%. There is no difference between patients with CDKN2 deletion and wild-type patients in sex, age, white blood cells (WBC) count, BM blast percentage, extra infiltration and induction complete remission (CR) rate. Analysis in relapse patients revealed that the distribution of CDKN2 deletion is higher in relapse patients (44.6%) than all patients (28.4%, P=0.006). Deletion of CDKN2 was significantly associated with poor outcomes including decreased overall survival (OS) (P<0.001), lower disease free-survival (DFS) (P<0.001), and increased cumulative incidence of relapse (P=0.002); Also, CDKN2 deletion was strongly associated with IGH translocation (P=0.021); and had an adverse effect on patients with BCR-ABL fusion gene or with MLL rearrangement. Patients with CDKN2 gene deletion benefited from allogenic hematopoietic stem cell transplantation (Allo-HSCT). Deletion of CDKN2 gene was commonly observed through leukemia progression and was poor prognostic marker in long-term outcomes.

Tuesday, September 13, 2016 3:29 PM|Open Journal of Hematology, ISSN: 2075-907X|Labels: Bcr-Abl, ALL, AML

Molecular genetics and Cytogenetics data of 317 patients with de novo acute leukemia
Open Journal of Hematology, 2015, 6-3 [Research Article]
Catharina Brant Campos, Carolina Pereira de Souza Melo, Siliana Maria Duarte, Joaquim Caetano Aguirre Neto, Álvaro Pimenta Dutra, Ângelo Atalla, Mara Albonei Dudeque Pianovski, Edna Kakitani Carbone, Luciana Barros Quintão Lares, Hélio Moraes-Souza, Shirlei Octacílio-Silva, Alessandro Clayton de Souza Ferreira, Juliana Godoy Assumpção

Abstract:

Background/Aims: Cytogenetic and molecular genetics play a pivotal role in treatment of acute leukemias. We prospectively evaluated genetic alterations in Brazilian patients with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) and their association with clinical and laboratorial data.

Methods: Flow cytometry, conventional cytogenetics (CC), FISH, PCR, RT-PCR and sequencing were performed on samples from 161 de novo ALL and 155 AML.

Results: Main CC findings in AML were t(15;17) (19.4%), +8 (17.4%), complex karyotype (14.6%), t(8;21) (7.6%); in ALL main CC findings were high hyperdiploidy (18.7%), low hyperdiploidy (9.7%), t(1;19) (9.7%), t(9;22) (8.2%). Frequencies of gene fusions and mutations in AML were PML-RARa 21.9%, RUNX1-RUNX1T1 7.1%, CBFB-MYH11 and MLL-AF9 2.6%, FLT3-ITD 14.2%, NPM1mut 13.6%. In ALL, ETV6-RUNX1 and BCR-ABL were present in 11.5% of the cases, TCF3-PBX1 in 10.8% and MLL-AF1 in 1.5%. Results were discordant between CC and RT-PCR in 3.6% of the cases. PML-RARa was associated with younger age, lower WBC and platelet; FLT3-ITD with higher hemoglobin and WBC; NPM1mut with higher platelet and WBC, older age and normal karyotype. BCR-ABL was associated with higher age; MLL-AF1 with higher WBC and EGIL BI-subtype.

Conclusions: The incidence of some aberrations in AML differed from international literature. Discrepancies found between methodologies reinforce the importance of both CC and PCR in the diagnosis of leukemias.
Tuesday, September 13, 2016 3:29 PM|Open Journal of Hematology, ISSN: 2075-907X|Labels: ALL

B Cell Acute Lymphoblastic Leukemia Associated with t(8;22)(p11.2q11.2): Role of Additional Cytogenetic Anomalies
Open Journal of Hematology, 2013, 4-2 [Case Report]
Kate M. Serdy, Shireen R. Khoury, Louis DePalma

Abstract:

B lymphoblastic leukemia (B-ALL) may be associated with recurrent cytogenetic and molecular abnormalities. We describe the fourth-known case of B-ALL associated with the t(8;22)(p11.2q11.2) – a translocation seen more frequently in T lymphoblastic leukemia and acute myelogenous leukemia. This patient’s leukemia involves a combination of additional cytogenetic anomalies not yet described in the literature, including del(11)(q13q23), add(9)(p22), and monosomy 7. Given the role in B cell differentiation of genes in the affected regions, including MEN1 (11q13), ATM (11q22), ETS1(11q23), MLL (11q23), AF9 (9p22), and IKZ-F1 (7p12), this case may provide further insight into B cell leukemogenesis associated with the t(8;22). Deletion or mutation of these genes may be critical in targeting the B cell population, and this cytogenetic profile of a B-ALL suggests additional gene targets for diagnostic and therapeutic consideration.
Thursday, September 8, 2016 10:00 AM|R. B.|JournalTOCs API - Blood (22 articles)|Labels: Bcl-2, ALL

Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia
Khaw, S. L Suryani, S, Evans, K, Richmond, J, Robbins, A, Kurmasheva, R. T, Billups, C. A, Erickson, S. W, Guo, Y, Houghton, P. J, Smith, M. A, Carol, H, Roberts, A. W, Huang, D. C. S, Lock, R. B.
Blood, Vol. 128, No. 10 (2016) pp. 1382 - 1395
The clinical success of the BCL-2-selective BH3-mimetic venetoclax in patients with poor prognosis chronic lymphocytic leukemia (CLL) highlights the potential of targeting the BCL-2-regulated apoptotic pathway in previously untreatable lymphoid malignancies. By selectively inhibiting BCL-2, venetoclax circumvents the dose-limiting, BCL-XL-mediated thrombocytopenia of its less selective predecessor navitoclax, while enhancing efficacy in CLL. We have previously reported the potent sensitivity of many high-risk childhood acute lymphoblastic leukemia (ALL) xenografts to navitoclax. Given the superior tolerability of venetoclax, here we have investigated its efficacy in childhood ALL. We demonstrate that in contrast to the clear dependence of CLL on BCL-2 alone, effective antileukemic activity in the majority of ALL xenografts requires concurrent inhibition of both BCL-2 and BCL-XL. We identify BCL-XL expression as a key predictor of poor response to venetoclax and demonstrate that concurrent inhibition of both BCL-2 and BCL-XL results in synergistic killing in the majority of ALL xenografts. A notable exception is mixed lineage leukemia&ndash;rearranged infant ALL, where venetoclax largely recapitulates the activity of navitoclax, identifying this subgroup of patients as potential candidates for clinical trials of venetoclax in childhood ALL. Conversely, our findings provide a clear basis for progressing navitoclax into trials ahead of venetoclax in other subgroups.

CONCLUSIONSPatients with relapsed/refractory ALL who achieve MRD negativity in S1 can have long‐term survival. Patients in S2 generally have poor outcomes, regardless of their MRD status. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Friday, September 2, 2016 3:47 AM|PBR - Regulatory Affairs News|Labels: ALL, regulatory
The US Food and Drug Administration (FDA) has approved Amgen's supplemental Biologics License Application (sBLA) for BLINCYTO (blinatumomab) to include new data supporting the treatment of pediatric patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
Wednesday, August 31, 2016 10:05 PM|Trinquand, A., dos Santos, N. R., Tran Quang, C., Rocchetti, F., Zaniboni, B., Belhocine, M., Da Costa de Jesus, C., Lhermitte, L., Tesio, M., Dussiot, M., Cosset, F.-L., Verhoeyen, E., Pflumio, F., Ifrah, N., Dombret, H., Spicuglia, S., Chatenoud, L., Gross, D.-A., Hermine, O., Macintyre, E., Ghysdael, J., Asnafi, V.|Cancer Discovery current issue|Labels: ALL

Cancer onset and progression involves the accumulation of multiple oncogenic hits, which are thought to dominate or bypass the physiologic regulatory mechanisms in tissue development and homeostasis. We demonstrate in T-cell acute lymphoblastic leukemia (T-ALL) that, irrespective of the complex oncogenic abnormalities underlying tumor progression, experimentally induced, persistent T-cell receptor (TCR) signaling has antileukemic properties and enforces a molecular program resembling thymic negative selection, a major developmental event in normal T-cell development. Using mouse models of T-ALL, we show that induction of TCR signaling by high-affinity self-peptide/MHC or treatment with monoclonal antibodies to the CD3 chain (anti-CD3) causes massive leukemic cell death. Importantly, anti-CD3 treatment hampered leukemogenesis in mice transplanted with either mouse- or patient-derived T-ALLs. These data provide a strong rationale for targeted therapy based on anti-CD3 treatment of patients with TCR-expressing T-ALL and demonstrate that endogenous developmental checkpoint pathways are amenable to therapeutic intervention in cancer cells.

Significance: T-ALLs are aggressive malignant lymphoid proliferations of T-cell precursors characterized by high relapse rates and poor prognosis, calling for the search for novel therapeutic options. Here, we report that the lineage-specific TCR/CD3 developmental checkpoint controlling cell death in normal T-cell progenitors remains switchable to induce massive tumor cell apoptosis in T-ALL and is amenable to preclinical therapeutic intervention. Cancer Discov; 6(9); 972–85. ©2016 AACR.

See related commentary by Lemonnier and Mak, p. 946.

This article is highlighted in the In This Issue feature, p. 932

Wednesday, August 31, 2016 10:05 PM|Lemonnier, F., Mak, T. W.|Cancer Discovery recent issues|Labels: ALL

Summary: Thymic negative selection is a process that aims to eliminate autoreactive T cells by inducing the apoptosis of thymocytes expressing a T-cell receptor (TCR) with high affinity for self-MHC. In this issue, Trinquand and colleagues demonstrate that TCR engagement or anti-CD3 stimulation of TCR-expressing T acute lymphoblastic leukemia cells results in their apoptosis. This cell death is reminiscent of thymic negative selection and has the potential for therapeutic exploitation. Cancer Discov; 6(9); 946–8. ©2016 AACR.

See related article by Trinquand et al., p. 972.

Thursday, August 18, 2016 10:00 AM|Irving, J. A. E., Enshaei, A., Parker, C. A., Sutton, R., Kuiper, R. P., Erhorn, A., Minto, L., Venn, N. C., Law, T., Yu, J., Schwab, C., Davies, R., Matheson, E., Davies, A., Sonneveld, E., den Boer, M. L., Love, S. B., Harrison, C. J., Hoogerbrugge, P. M., Revesz, T., Saha, V., Moorman, A. V.|Blood CLINICAL TRIALS AND OBSERVATIONS|Labels: ALL

Somatic genetic abnormalities are initiators and drivers of disease and have proven clinical utility at initial diagnosis. However, the genetic landscape and its clinical utility at relapse are less well understood and have not been studied comprehensively. We analyzed cytogenetic data from 427 children with relapsed B-cell precursor ALL treated on the international trial, ALLR3. Also we screened 238 patients with a marrow relapse for selected copy number alterations (CNAs) and mutations. Cytogenetic risk groups were predictive of outcome postrelapse and survival rates at 5 years for patients with good, intermediate-, and high-risk cytogenetics were 68%, 47%, and 26%, respectively (P < .001). TP53 alterations and NR3C1/BTG1 deletions were associated with a higher risk of progression: hazard ratio 2.36 (95% confidence interval, 1.51-3.70, P < .001) and 2.15 (1.32-3.48, P = .002). NRAS mutations were associated with an increased risk of progression among standard-risk patients with high hyperdiploidy: 3.17 (1.15-8.71, P = .026). Patients classified clinically as standard and high risk had distinct genetic profiles. The outcome of clinical standard-risk patients with high-risk cytogenetics was equivalent to clinical high-risk patients. Screening patients at relapse for key genetic abnormalities will enable the integration of genetic and clinical risk factors to improve patient stratification and outcome. This study is registered at www.clinicaltrials.org as #ISCRTN45724312.

CONCLUSIONSAn assessment of residual D14 BM blasts in patients with ALL is highly predictive of the achievement of CR with induction chemotherapy and of EFS and OS. However, the impact on long‐term outcomes is less prognostic when an MRD assessment is also available. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Sunday, July 31, 2016 10:05 PM|Richmond, J., Robbins, A., Evans, K., Beck, D., Kurmasheva, R. T., Billups, C. A., Carol, H., Heatley, S., Sutton, R., Marshall, G. M., White, D., Pimanda, J., Houghton, P. J., Smith, M. A., Lock, R. B.|Cancer Research recent issues|Labels: SMAC, TNF, ALL
Ph-like acute lymphoblastic leukemia (ALL) is a genetically defined high-risk ALL subtype with a generally poor prognosis. In this study, we evaluated the efficacy of birinapant, a small-molecule mimetic of the apoptotic regulator SMAC, against a diverse set of ALL subtypes. Birinapant exhibited potent and selective cytotoxicity against B-cell precursor ALL (BCP-ALL) cells that were cultured ex vivo or in vivo as patient-derived tumor xenografts (PDX). Cytotoxicity was consistently most acute in Ph-like BCP-ALL. Unbiased gene expression analysis of BCP-ALL PDX specimens identified a 68-gene signature associated with birinapant sensitivity, including an enrichment for genes involved in inflammatory response, hematopoiesis, and cell death pathways. All Ph-like PDXs analyzed clustered within this 68-gene classifier. Mechanistically, birinapant sensitivity was associated with expression of TNF receptor TNFR1 and was abrogated by interfering with the TNFα/TNFR1 interaction. In combination therapy, birinapant enhanced the in vivo efficacy of an induction-type regimen of vincristine, dexamethasone, and L-asparaginase against Ph-like ALL xenografts, offering a preclinical rationale to further evaluate this SMAC mimetic for BCP-ALL treatment. Cancer Res; 76(15); 4579–91. ©2016 AACR.
CONCLUSIONSThe clinical outcome of patients treated with HCVAD plus ponatinib appears to be superior to that of patients treated with HCVAD plus dasatinib among individuals with Ph+ ALL. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Thursday, July 28, 2016 1:56 PM|Leukemia News -- ScienceDaily|Labels: ALL
Researchers have developed a hybrid treatment that harnesses a monoclonal antibody to deliver antisense DNA to acute lymphoblastic leukemia (ALL) cells and that may lead to less toxic treatments for the disease.
Thursday, July 14, 2016 10:05 PM|Wang, Y., Liu, Q.-F., Xu, L.-P., Liu, K.-Y., Zhang, X.-H., Ma, X., Wu, M.-Q., Wu, D.-P., Huang, X.-J.|Clinical Cancer Research recent issues|Labels: ALL, clinical trial

Purpose: Although matched-sibling donor (MSD) hematopoietic stem-cell transplantation (HSCT) has an established role in the management of adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR1), the effect of haploidentical donor (HID) HSCT as post-remission treatment for this portion of patients is not defined.

Experimental Design: Transplantation outcomes from HIDs or MSDs were compared in a disease-specific, biologically phase III randomized, multicenter study. Between July 2010 and December 2013, 210 patients with Philadelphia-negative high-risk ALL in CR1 were assigned to undergo unmanipulated HIDs (121 patients) or MSDs HSCT (89 patients) according to donor availability on an intent-to-treat (ITT) basis.

Results: Overall, 24 of the 210 patients had lost transplant eligibility. Therefore, 186 of 210 (88%) patients were finally transplanted from MSD (n = 83) or HID (n = 103). Based on the ITT principle, the 3-year disease-free survival (DFS) did not differ between HID and MSD groups [61%, 95% confidence interval (CI), 52%–70%; vs. 60%, CI, 49%–71%; P = 0.91] from CR, neither did DFS differ between the two groups (68%, CI, 58%–78%; vs. 64%, CI, 52%–76%; P = 0.56) from time of the graft, with cumulative incidence of nonrelapse mortality of 13% (CI, 7%–19%) and 11% (CI, 4%–18%; P = 0.84) and relapse rates of 18% (CI, 10%–26%) and 24% (CI, 14%–34%; P = 0.30), respectively.

Conclusions: Haploidentical HSCT achieves outcomes similar to those of MSD-HSCT for Philadelphia-negative high-risk ALL patients in CR1. Such transplantation could be a valid alternative as post-remission treatment for high-risk ALL patients in CR1 lacking an identical donor. Clin Cancer Res; 22(14); 3467–76. ©2016 AACR.

Wednesday, June 29, 2016 10:30 AM|Dave Levitan|Chronic Myeloid Leukemia on Cancer Network|Labels: ALL, CML
Maintenance therapy with TKIs following allogeneic HSCT is feasible and may improve outcomes in patients with high-risk Philadelphia chromosome–positive leukemia.
Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a standard of care for patients with Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL). The introduction of tyrosine kinase inhibitors (TKIs) to first‐line therapy has improved overall outcomes; however, a significant proportion of patients still relapse after alloHSCT. Posttransplant TKI maintenance was demonstrated to reduce the risk of relapse in a large retrospective study and, therefore, should be considered a valuable option. This consensus paper, written on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, presents an overview of clinical studies on the use of TKIs after alloHSCT and proposes practical recommendations regarding the choice...
Sunday, June 12, 2016 8:58 AM|Leukemia News -- ScienceDaily|Labels: ALL, clinical trial
In a randomized Phase III study of the drug inotuzumab ozogamicin, a statistically significant percentage of patients with acute lymphoblastic leukemia (ALL) whose disease had relapsed following standard therapies, qualified for stem cell transplants.
CONCLUSIONSAlthough survival for children and AYAs with ALL, AML, and HL has improved over the past 4 decades, differences persist between black, white, and Hispanic children and AYAs; survival disparities between black and white children with ALL have been nearly eliminated. Strategies aimed at identifying causality and reducing disparities are warranted. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Thursday, June 2, 2016 10:05 PM|Teachey, D. T., Lacey, S. F., Shaw, P. A., Melenhorst, J. J., Maude, S. L., Frey, N., Pequignot, E., Gonzalez, V. E., Chen, F., Finklestein, J., Barrett, D. M., Weiss, S. L., Fitzgerald, J. C., Berg, R. A., Aplenc, R., Callahan, C., Rheingold, S. R., Zheng, Z., Rose-John, S., White, J. C., Nazimuddin, F., Wertheim, G., Levine, B. L., June, C. H., Porter, D. L., Grupp, S. A.|Cancer Discovery recent issues|Labels: ALL, biomarker diagnostic

Chimeric antigen receptor (CAR)–modified T cells with anti-CD19 specificity are a highly effective novel immune therapy for relapsed/refractory acute lymphoblastic leukemia. Cytokine release syndrome (CRS) is the most significant and life-threatening toxicity. To improve understanding of CRS, we measured cytokines and clinical biomarkers in 51 CTL019-treated patients. Peak levels of 24 cytokines, including IFN, IL6, sgp130, and sIL6R, in the first month after infusion were highly associated with severe CRS. Using regression modeling, we could accurately predict which patients would develop severe CRS with a signature composed of three cytokines. Results were validated in an independent cohort. Changes in serum biochemical markers, including C-reactive protein and ferritin, were associated with CRS but failed to predict development of severe CRS. These comprehensive profiling data provide novel insights into CRS biology and, importantly, represent the first data that can accurately predict which patients have a high probability of becoming critically ill.

Significance: CRS is the most common severe toxicity seen after CAR T-cell treatment. We developed models that can accurately predict which patients are likely to develop severe CRS before they become critically ill, which improves understanding of CRS biology and may guide future cytokine-directed therapy. Cancer Discov; 6(6); 664–79. ©2016 AACR.

See related commentary by Rouce and Heslop, p. 579.

This article is highlighted in the In This Issue feature, p. 561

CONCLUSIONSIntensified chemotherapy can result in improved outcomes in comparison with historical data. Additional studies of similarly intensive regimens are warranted in this population. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
CONCLUSIONSOlder adults with r/r ALL who were treated with single‐agent blinatumomab were found to have similar hematologic response rates and incidence of grade ≥3 AEs compared with younger adults but had more neurologic events, which were reversible and primarily resolved with treatment interruption. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Wednesday, February 24, 2016 4:17 AM|Francis, O. L., Milford, T.-A. M., Beldiman, C., Payne, K. J.|Journal of Investigative Medicine recent issues|Labels: ALL

Many leukemias are characterized by well-known mutations that drive oncogenesis. Mice engineered with these mutations provide a foundation for understanding leukemogenesis and identifying therapies. However, data from whole genome studies provide evidence that malignancies are characterized by multiple genetic alterations that vary between patients, as well as inherited genetic variation that can also contribute to oncogenesis. Improved outcomes will require precision medicine approaches–targeted therapies tailored to malignancies in each patient. Preclinical models that reflect the range of mutations and the genetic background present in patient populations are required to develop and test the combinations of therapies that will be used to provide precision medicine therapeutic strategies. Patient-derived xenografts (PDX) produced by transplanting leukemia cells from patients into immune deficient mice provide preclinical models where disease mechanisms and therapeutic efficacy can be studied in vivo in context of the genetic variability present in patient tumors. PDX models are possible because many elements in the bone marrow microenvironment show cross-species activity between mice and humans. However, several cytokines likely to impact leukemia cells are species-specific with limited activity on transplanted human leukemia cells. In this review we discuss the importance of PDX models for developing precision medicine approaches to leukemia treatment. We illustrate how PDX models can be optimized to overcome a lack of cross-species cytokine activity by reviewing a recent strategy developed for use with a high-risk form of B-cell acute lymphoblastic leukemia (B-ALL) that is characterized by overexpression of CRLF2, a receptor component for the cytokine, TSLP.

Wednesday, February 24, 2016 4:17 AM|Gowda, C. S., Song, C., Ding, Y., Kapadia, M., Dovat, S.|Journal of Investigative Medicine recent issues|Labels: ALL

Protein signaling and regulation of gene expression are the two major mechanisms that regulate cellular proliferation in leukemia. Discerning the function of these processes is essential for understanding the pathogenesis of leukemia and for developing the targeted therapies. Here, we provide an overview of one of the mechanisms that regulates gene transcription in leukemia. This mechanism involves the direct interaction between Casein Kinase II (CK2) and the Ikaros transcription factor. Ikaros (IKZF1) functions as a master regulator of hematopoiesis and a tumor suppressor in acute lymphoblastic leukemia (ALL). Impaired Ikaros function results in the development of high-risk leukemia. Ikaros binds to the upstream regulatory elements of its target genes and regulates their transcription via chromatin remodeling. In vivo, Ikaros is a target for CK2, a pro-oncogenic kinase. CK2 directly phosphorylates Ikaros at multiple amino acids. Functional experiments showed that CK2-mediated phosphorylation of Ikaros, regulates Ikaros’ DNA binding affinity, subcellular localization and protein stability. Recent studies revealed that phosphorylation of Ikaros by CK2 regulates Ikaros binding and repression of the terminal deoxytransferase (TdT) gene in normal thymocytes and in T-cell ALL. Available data suggest that the oncogenic activity of CK2 in leukemia involves functional inactivation of Ikaros and provide a rationale for CK2 inhibitors as a potential treatment for ALL.

Wednesday, January 13, 2016 4:00 PM|Cancer Research|MedWorm: Cancer Therapy|Comments|Labels: Bcl-2, ALL
Conclusions: Here, we show that BET-bromodomain inhibition can sensitize BCL2-positive human T-ALL to ABT-199 treatment by interfering with the balance of pro- and anti-apoptotic BCL2 family members.Citation Format: Sofie Peirs, Filip Matthijssens, Tim Pieters, Niels Vandamme, Geert Berx, Bruce Poppe, Pieter Van Vlierberghe. BRD4 inhibition improves the efficacy of ABT-199 in T-cell acute lymphoblastic leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B39. (Source: Cancer Research)