Antibiotics and Imiquimod for Cutaneous T-Cell Lymphoma in Veterans: A Patient Population with Agent Orange Exposure

Lessons Learned

• Staphylococcus aureus infection in cutaneous T-cell lymphoma (CTCL) is thought to contribute to disease progression; thus, adjunctive treatment with antibiotics warrants further investigation.
• This trial of antibiotic therapy followed by imiquimod in early stage CTCL was not completed because of difficulties with patient accrual.

     

Melatonin and Metformin Failed to Modify the Effect of Dacarbazine in Melanoma

Lessons Learned

• Melatonin did not increase the efficacy of systemic chemotherapy in melanoma.
• Metformin did not increase the efficacy of systemic chemotherapy in melanoma.

     

Cabozantinib and Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer

Lessons Learned

• Antitumor activity was observed in the study population.
• Dose modifications of cabozantinib improve long-term tolerability.
• Biomarkers are needed to identify patient populations most likely to benefit.
• Further study of cabozantinib with or without panitumumab in patients with metastatic colorectal cancer is warranted.

     

Bevacizumab Combined with S-1 and Raltitrexed for Patients with Metastatic Colorectal Cancer Refractory to Standard Therapies: A Phase II Study

Lessons Learned

• Bevacizumab combined with S-1 and raltitrexed demonstrated positive antitumor efficacy and acceptable toxicity.
• This combination might represent a treatment option for refractory metastatic colorectal cancer.

     

Adoptive Transfer of Autologous Invariant Natural Killer T Cells as Immunotherapy for Advanced Hepatocellular Carcinoma: A Phase I Clinical Trial

Lessons Learned

• Administration of autologous invariant natural killer T (iNKT) cells was safe and well-tolerated in patients with hepatocellular carcinoma (Barcelona Clinic Liver Cancer stage B/C).
• Expanded iNKT cells produced T-helper 1–like responses with possible antitumor activity.
• No severe adverse events were observed in any of the enrolled patients, including one patient who received 10¹⁰ in vitro–expanded autologous iNKT cells as a single infusion.

     

Progress in Targeting the TGFβ Pathway

Signaling by the transforming growth factor-β (TGF-β) superfamily is important in the regulation of hematopoiesis and is dysregulated in myelodysplastic syndromes (MDS), contributing to ineffective hematopoiesis and clinical cytopenias. TGF-β, activins and growth differentiation factors exert inhibitory effects on red cell formation by activating canonical SMAD2/3 pathway signaling. SMAD2/3 overactivation is seen in numerous subtypes of MDS. Furthermore, reduced levels of inhibitory SMAD7 are

References

• 1.Valcarcel D, Verma A, Platzbecker U, et al. Phase 2 Study of Monotherapy Galunisertib (LY2157299 Monohydrate) in Very Low-, Low-, and Intermediate-Risk Patients with Myelodysplastic Syndromes. Blood. 2015;126:1669.
• 2.Suragani RN, Cawley SM, Li R, Wallner S, et al. Modified activin receptor IIB ligand trap mitigates ineffective erythropoiesis and disease complications in murine β-thalassemia. Blood. 2014 Jun 19;123(25):3864-72.
• 3.Dussiot M, Maciel TT, Fricot A, et al. Nat Med. 2014 Apr;20(4):398-407.
• 4.

     

Use of FLT3 Inhibitors in AML

Multiple FLT3 inhibitors that have been recently approved for use in FLT3 mutated acute myeloid leukemia (AML). These drug approvals represent a new standard of care for patients with FLT3 mutations, including the use of midostaurin in the frontline and gilteritinib in the salvage setting. The success of midostaurin used in combination with induction chemotherapy has prompted exploration of newer, more potent and targeted inhibitors in the upfront setting in combination with chemotherapy. At

FLT3 Inhibitors

Targeting of FLT3 signaling via small molecule inhibitors has been a heavily studied therapeutic strategy over the last decade and half. First generation, multi-targeted FLT3 tyrosine kinase inhibitors (TKIs) such as midostaurin, sorafenib and lestaurtinib were limited by poor drug selectivity, potency and unfavorable protein binding characteristics. Early monotherapy trials with these inhibitors showed little activity beyond transient decrease in circulating peripheral blasts, disappointing

Resistance to FLT3 Inhibitors

Despite observed clinical activity, resistance remains a ubiquitous clinical problem for all FLT3 inhibitors. On-target secondary KD mutations in FLT3 are the most common mechanism of acquired resistance in patients responding to type II inhibitors such as quizartinib and sorafenib, which bind only the inactive kinase conformation.^17-19 The most common resistance-causing mutations occur at the FLT3 gatekeeper F691 and activation loop D835 residues, but may also involve other residues in the

FLT3 Inhibitor Combinations and Maintenance Strategies

Based on the activity of first-generation, less targeted FLT3 inhibitors when used in combination with chemotherapy or with hypomethylating agent (HMA) treatment, current ongoing development efforts have focused on assessment of FLT3 TKI combination strategies.^8,9,24 Thus far, reported results of trials combining next-generation FLT3 TKIs with induction and consolidation chemotherapy in the first-line setting have been encouraging.^25-27 Based on these favorable early outcomes, multiple trials

References

• 1.Cancer Genome Atlas Research N, Ley TJ, Miller C, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059-2074.
• 2.Papaemmanuil E, Dohner H, Campbell PJ. Genomic Classification in Acute Myeloid Leukemia. N Engl J Med. 2016;375(9):900-901.
• 3.Bolouri H, Farrar JE, Triche T, Jr., et al. The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions. Nat Med.

     

A Phase I Open-Label Clinical Trial Evaluating the Therapeutic Vaccine hVEGF26–104/RFASE in Patients with Advanced Solid Malignancies

Lessons Learned

• The novel therapeutic vaccine hVEGF_26–104/RFASE was found to be safe and well tolerated in patients with cancer.
• hVEGF_26–104/RFASE failed to induce seroconversion against native hVEGF₁₆₅ and, accordingly, neither a decrease in circulating vascular endothelial growth factor (VEGF) levels nor clinical benefit was observed.
• Remarkably, hVEGF_26–104/RFASE induced VEGF₁₆₅-neutralizing antibodies in a nonhuman primate model. The absence of seroconversion in human calls for caution in the interpretation of efficacy of human vaccines in nonhuman primates.

     

IDH Inhibitors in AML

Acute myeloid leukemia (AML) is a clinically and biologically heterogeneous disease with variable response and survival outcomes to induction therapy. Over the last decade, better characterization and understanding of the molecular and epigenetic landscape of AML has led to significant progress in the prognostication and treatment of AML. As a disease of the elderly with a median age of 68 years at diagnosis, AML has been a challenging leukemia to treat.¹ Isocitrate dehydrogenase (IDH) 1 and 2

References

• 1.SEER Cancer Statistics Review, 1975–2014. Bethesda, MD: National Cancer Institute; 2017. April 25, 2018.
• 2.Medeiros BC, Fathi AT, DiNardo CD, Pollyea DA, Chan SM, Swords R. Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia. 2017;31(2):272-81.
• 3.DiNardo CD, Ravandi F, Agresta S, et al. Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML. Am J Hematol. 2015;90(8):732-6.
• 4.Wang F, Travins J, DeLaBarre B, et al. Targeted inhibition of mutant IDH2 in

     

Targeting Apoptosis Pathways in Acute Myeloid Leukemia

The anti-apoptotic protein BCL2 is overexpressed in hematological malignancies, including acute myeloid leukemia (AML), favoring tumor survival and chemoresistance. BCL2 inhibits BIM and BAX, effector proteins necessary for the formation of pores in the mitochondrial outer membrane, and its inhibition primes cells for the release of cytochrome c and subsequent apoptosis. Such priming can be facilitated by venetoclax, an oral BCL2 inhibitor, therefore representing an ideal strategy to induce

References

• 1.Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell. 2002;2(3):183-192.
• 2.Pan R, Hogdal LJ, Benito JM, et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov. 2014;4(3):362-375.
• 3.Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and Biological Correlates of Response in a Phase II Study of

     

Case Presentations: Allograft or Third-Line Therapy in Very Resistant CML

Tyrosine kinase inhibitors (TKIs) are a remarkable therapy for chronic phase CML and the vast majority of patients respond to initial therapy. However, resistance does occur, and resistance is associated with a higher risk of progression to advanced phase. What does one do after initial TKI therapy has failed the patient? Another TKI? Allogeneic transplant? In this case presentation, we will consider a case which has demonstrated resistance to two lines of TKI therapy and offer the pros and

The Case

JM is a 52 yo driftwood artist who is diagnosed with Sokal intermediate risk CML and started on imatinib 400 mg per day. His BCR-ABL level is 59% IS at diagnosis, 30% at 3 months, and 19% after 6 months of therapy. He claims adherence. Because of a suboptimal response, he is declared an imatinib failure. ABL tyrosine mutation studies show no mutation. Because of physician preference he switched to nilotinib.After 6 months of nilotinib (now 12 months from diagnosis) his BCR-ABL has fallen to 1%

Case Discussion

The options at this point are 1) try a third TKI, 2) opt for allogeneic transplant, 3) move to a clinical trial.In making this decision, there are several factors which enter the picture.

• 1.Age and comorbidities. While the upper age limit of allogeneic transplantation has increased with the age of transplanters, it and comorbidities still determine the allowable intensity of the preparative regimen. The decision-making equation weighs the amount of intensity needed for both engraftment and disease

References

• 1.Radich JP, Dai H, Mao M, et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci USA. 2006;103(8):2794-9.
• 2.Shah NP, Rousselot P, Schiffer CA, et al. Seven-Year (yr) Follow-up of Patients (pts) with Imatinib-Resistant or -Intolerant Chronic-Phase Chronic Myeloid Leukemia (CML-CP) Receiving Dasatinib in Study CA180-034, Final Study Results. Blood. 2014;124:520.
• 3.Cortes JE, Kantarjian HM, Brummendorf TH, et al. Safety and efficacy of

     

CML Case Studies: Impact of Comorbidities

Clinicians have the choice of five approved tyrosine kinase inhibitors (TKI) to select from for chronic phase CML patients. The best frontline drug for each patient and decisions about if and when to change to another TKI or to stop therapy need to be considered in the context of the comorbidities present. These issues are explored in three illustrative cases. The predominant toxicity issue for all of the TKIs except imatinib is vascular occlusive events, so a systematic approach to assessing

Discussion

The excellent long-term outcomes achieved in most CML patients has led to a revision of the goals of therapy.¹³ While preventing progression to blast crisis remains an important goal, avoiding organ toxicity may be equally important, since deaths from causes other than CML are much more common than CML-related deaths. Patients most at risk of organ toxicity are those patients with comorbidities, particularly those patients with comorbidities that increase their risk of vascular events.

References

• 1.Saußele S, Krauß MP, Hehlmann R, Lauseker M, Proetel U et al, Impact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized CML Study IV. Blood. 2015;126:42-49.
• 2.Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim D-W et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016; 30:1044–1054.
• 3.Castagnetti F, Gugliotta G, Breccia M,

     

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases: Where do we stand?

Plain Language Summary

• Patients with colorectal cancer that has spread to the lining of the abdomen (peritoneum) benefit from surgery to remove all the cancer.
• The addition of certain types of intra-abdominal chemotherapy during surgery improves survival for select patients.

     

Preventing Relapse After Allogeneic SCT

Myelodysplastic syndromes (MDS) mainly affect the elderly population which implicates that the majority of patients cannot tolerate intensive therapeutic approaches including allogeneic hematopoietic stem cell transplantation (allo-HSCT). The underlying impaired stem cell function leads peripheral cytopenia including a propensity to progress to acute myeloid leukemia (AML). Allo-HSCT is considered the only potentially curable therapy. On the one hand, reduced intensity conditioning (RIC)

Materials and Methods

This short overview is based on recent scientific evidence on the management of in patients with MDS after allo-HCT.

Results and Discussion

Considering the potential treatment-related complications associated with allo-HSCT in MDS patients, a serious selection process of patients is inevitable. Therefore, identification of patient and disease-related factors, predicting outcome after allo-HSCT, is mandatory. According to a decision model, patients with int-2 or high-risk MDS by IPSS criteria should be considered for allo-HSCT at the time of diagnosis. Further analyses in older patients receiving reduced-intensity conditioning could

Conclusions

In the absence of prospective trials, a careful individual selection should be done and MDS patients should be stratified according to comorbidities, performance status, and disease risk. Chronic GVHD and relapse are still the major challenges after SCT. Therefore, special attention should be paid to post-transplant care in term of MRD monitoring and prevention of relapse.

Acknowledgements

None.

References

• 1.Witte T De, Bowen D, Robin M, et al. Review Article Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel. Blood. 2017;129(13):1753–1763.
• 2.Platzbecker U, Mufti G. Allogeneic stem cell transplantation in MDS: How? When? Best Pract. Res Clin Haematol. 2013;26(4):421-429.
• 3.Cutler CS, Lee SJ, Greenberg P, et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: Delayed transplantation for

     

Targeted Therapy with Anlotinib for a Patient with an Oncogenic FGFR3-TACC3 Fusion and Recurrent Glioblastoma

We describe a case of recurrent glioblastoma treated with anlotinib in this report. The patient was administered anlotinib 12 mg p.o. once every day (days 1–14, with a 21-day cycle) (anlotinib clinical study NCT04004975) and oral temozolomide chemotherapy 100 mg/m² (days 1–7, days 15–21, 28-day cycle; 12 cycles). After 2 months of therapy, the patient achieved a partial response that has been maintained for >17 months of follow-up. Molecular characterization confirmed the presence of a TERT promoter mutation, wild-type IDH1/2, an FGFR3-TACC3 fusion, and FGFR3 amplification in the patient. Anlotinib is a multitarget tyrosine kinase inhibitor that was originally designed to inhibit VEGFR2/3, FGFR1–4, PDGFRα/β, and c-Kit. Patients with TERT promoter mutations and high-grade IDH-wild-type glioma have shorter overall survival than patients with IDH-wild-type glioma without TERT promoter mutations. However, this patient had a favorable clinic outcome, and FGFR3-TACC3 fusion may be a new marker for treatment of glioma with anlotinib.

Key Points

• This case study is believed to be the first report that FGFR3-TACC3 fusion could be a novel indication to treat recurrent glioblastoma with the drug anlotinib.
• This case exhibited an exceptional response (maintained partial response >17 months) after 2-month combined therapy of anlotinib and oral temozolomide chemotherapy.
• This case also underscores the importance of molecular diagnosis for clinically complex cases. Tumor tissue-based assessment of molecular biomarkers in brain tumors has been successfully translated into clinical application.

     

Iron Chelation Therapy in MDS – The Final Answer

The purpose of this paper is to report and discuss the available evidence supporting iron chelation therapy in iron overloaded patients with lower risk myelodysplasia.

Results

Several retrospective analyses, prospective registry studies and a meta-analyses have shown how iron chelation therapy can improve outcomes in lower-risk MDS patients.^5,6 Despite this evidence, considerable debate has remained on: 1) the clinical utility of ICT in this population particularly considering the above-mentioned methodological limitations; and, 2) the need for a randomized trial which has long been recognized.³Trying to provide the “final answer” to this debate, the TELESTO clinical

Discussion

Nowadays, the evidence supporting iron chelation therapy in lower risk MDS transfusion dependent patients is supported by several retrospective, prospective non-randomized, registry studies and finally by a randomized prospective placebo-controlled study.It should be clearly recognized that limitations are still present even in the TELESTO trial: EFS rather than overall survival as the primary endpoint; phase II rather than phase III trial; high dropout rate in the placebo arm; and,

Conclusion

Is TELESTO the final answer to the iron chelation debate? To date, this trial has the most stringent achievable evidence on the clinical benefit of iron chelation therapy in transfusion dependent patients. Because of the current therapy landscape and difficulties in enrolling and conducting the trial, it is unlikely that a similar, more highly powered trial will be performed in the near future. Considering current clinical evidence, preclinical studies and the above-mentioned limitations,

References

• 1.Angelucci E, Urru SAM, Pilo F, Piperno A. Myelodysplastic Syndromes and Iron Chelation Therapy. Mediterr J Hematol Infect Dis. 2017;9(1):e2017021.
• 2.Angelucci E, Barosi G, Camaschella C, Cappellini MD, Cazzola M, Galanello R, et al. Italian Society of Hematology practice guidelines for the management of iron overload in thalassemia major and related disorders. Haematologica. Haematologica; 2008 May;93(5):741–52.
• 3.Meerpohl JJ, Schell LK, Rücker G, Fleeman N, Motschall E, Niemeyer CM, et al.

     

How Have Prognostic Factors Changed with Novel Therapies?

Chronic lymphocytic leukemia (CLL) is characterized by a heterogeneous clinical course. A subset of patients never require treatment, while others progress from early stages to symptomatic disease requiring treatment within a few years. To estimate the likelihood of disease progression and survival much effort has been devoted to the identification of prognostic markers.¹ In addition to the clinical staging systems developed by Rai and Binet, molecular and genetic markers have provided

Disclosures

The authors is named as an inventor on a US patent held by NIH on the use of ZAP70 as a prognostic marker in CLL and has received royalty payments. The author has received research support from Pharmacyclics, an AbbVie company, Acerta, a member of the Astra-Zeneca group, and Merck.

References

• 1.Sun C, Wiestner A. Prognosis and therapy of chronic lymphocytic leukemia and small lymphocytic lymphoma. Cancer Treat Res. 2015;165:147-175.
• 2.Kipps TJ, Stevenson FK, Wu CJ, et al. Chronic lymphocytic leukaemia. Nat Rev Dis Primers. 2017;3:16096.
• 3.Hallek M, Cheson BD, Catovsky D, et al. Guidelines for diagnosis, indications for treatment, response assessment and supportive management of chronic lymphocytic leukemia. Blood. 2018;131(25):2745-2760.
• 4.Bulian P, Shanafelt TD, Fegan C, et al. CD49d is the

     

Novel Strategies in High-Risk AML

Both clinical and biological features are associated with adverse risk in patients with acute myeloid leukemia (AML) following cytotoxic chemotherapy. Several other biological and clinical factors also correlate with AML outcomes; these include clinical features such as age, performance status, and comorbidities, biological features such as mutation status, the persistence of measurable residual disease (MRD), and relapsed disease. In this article, we will review current features of high risk

Clinical Features Associated with High-Risk AML

Multiple clinical variables are associated with adverse risk in AML. Age is an important but problematically confounded variable. Older patients tend to present more often with poor performance, comorbidities, adverse mutations, and adverse karyotypes.^2,12 In large retrospective studies, age is one of the most significant univariate predictors of outcomes.¹ In multivariate analyses, both age and performance status appear to contribute independent prognostic information, with performance status

Clinical Strategies in High-Risk AML

Clinical success requires that patients tolerate the therapy and survive through infections and transfusions until the malignant clone is eliminated and normal hematopoiesis can recover. Therefore, well tolerated, rapidly acting therapy would be hoped-for in future approaches.Age and comorbidities can negatively impact survival regardless of therapy simply because these patients have greater vulnerability to the toxicities and end-organ damage experienced with treatment. Patients whose leukemia

Future Approaches for TP53 Mutated Patients

TP53 mutated AML represents one of the most difficult to treat subtypes. Several compounds have been developed to target mutant TP53 and are in various stages of clinical and pre-clinical characterization.The PRIMA-1 analogue APR-246 is currently in clinical trials (NCT03072043; NCT02098343; NCT02999893; NCT03391050). In vivo, this compound is converted to methylene quinuclidinone, a Michael acceptor that reacts with cystine and depletes glutathione. Specifically, it reacts with TP53 Cys 124

Conclusions

Both clinical and genomic variables are associated with high risk AML. Age, performance status, MRD positivity, secondary AML, monosomy karyotypes, and TP53 mutations have been robust clinical and genomic predictors of adverse outcomes. Delays in initial treatment, especially in patients with older age and leukopenia do not appear to adversely affect outcomes, and this provides sufficient time to complete molecular diagnostic work-ups before initiating therapy. Adverse risk karyotypes and TP53

Acknowledgments

JSW is supported by U01 SPORE 2P50CA17963, R01 CA235622, R01 HL128447, and by the Evans Foundation.

References

• 1.Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. N Engl J Med. 2016;374(23):2209-2221.
• 2.Buchner T, Berdel WE, Haferlach C, et al. Age-related risk profile and chemotherapy dose response in acute myeloid leukemia: a study by the German Acute Myeloid Leukemia Cooperative Group. J Clin Oncol. 2009;27(1):61-69.
• 3.Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood. 2006;107(9):3481-3485.
• 4.Walter RB, Othus, M.,

     

E-Cadherin in Colorectal Cancer: Relation to Chemosensitivity

Background

The conventional chemotherapy of colorectal cancer with irinotecan, 5-fluorouracil, and oxaliplatin remains one of the front-line treatments worldwide. However, its efficacy is quite low. Recently studies of the epithelial–mesenchymal transition (EMT) have become the focus of investigations into the cause of chemoresistance in several types of cancer, including colorectal cancer. The data about the role of EMT in chemosensitivity are controversial.

Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments

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