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Answer questions and earn CME/CNEOral complications resulting from cancer and cancer therapies cause acute and late toxicities that may be underreported, underrecognized, and undertreated. Recent advances in cancer treatment have led to changes in the incidence, nature, and severity of oral complications. As the number of survivors increases, it is becoming increasingly recognized that the aggressive management of oral toxicities is needed to ensure optimal long‐term oral health and general well‐being. Advances in care have had an impact on previously recognized oral complications and are leading to newly recognized adverse effects. Here, the authors briefly review advances in cancer therapy, including recent advances in surgery, oral care, radiation therapy, hematopoietic cell transplantation, and medical oncology; describe how these advances affect oral health; and discuss the frequent and/or severe oral health complications associated with cancer and cancer treatment and their effect upon long‐term health. Although some of the acute oral toxicities of cancer therapies may be reduced, they remain essentially unavoidable. The significant impact of long‐term complications requires increased awareness and recognition to promote prevention and appropriate intervention. It is therefore important for the primary oncologist to be aware of these complications so that appropriate measures can be implemented in a timely manner. Prevention and management is best provided via multidisciplinary health care teams, which must be integrated and communicate effectively in order to provide the best patient care in a coordinated manner at the appropriate time. CA Cancer J Clin 2012. © 2012 American Cancer Society.

Immunotherapeutic ablation of lymphoma is a conceptually attractive treatment strategy that is the subject of intense translational research. Cytotoxic T lymphocytes (CTL) that are genetically modified to express CD19- or CD20-specific, single-chain-antibody-derived chimeric antigen receptors (CARs) display HLA-independent antigen-specific recognition/killing of lymphoma targets. Here, we describe our initial experience in applying CAR-redirected autologous CTL adoptive therapy to patients with recurrent lymphoma. Using plasmid vector electrotransfer/drug selection systems, cloned and polyclonal CAR+ CTL were generated from autologous peripheral blood mononuclear cells and expanded in vitro to cell numbers sufficient for clinical use. In two FDA-authorized trials, patients with recurrent diffuse large cell lymphoma (DLCL) were treated with cloned CD8+ CTL expressing a CD20-specific CAR (along with NeoR) following autologous HSCT, while patients with refractory follicular lymphoma (FL) were treated with polyclonal T cell preparations expressing a CD19-specific CAR (along with HyTK, a fusion of hygromycin resistance and HSV-1 thymidine kinase suicide genes) and low-dose s.c. rhuIL-2. A total of fifteen infusions were administered (five at 108cells/m2, seven at 109cells/m2, three at 2×109cells/m2) to four patients. Overt toxicities attributable to CTL administration were not observed. However, detection of transferred CTL in the circulation, measured by Q-PCR, was short (24hrs-7d), and cellular anti-transgene immune rejection responses were detected in two patients. These studies reveal the primary barrier to therapeutic efficacy is limited persistence and provide the rationale to prospectively define T cell populations intrinsically programmed for survival following adoptive transfer and to modulate the immune status of recipients to prevent/delay anti-transgene rejection responses.

To our knowledge, PROPEL (Pralatrexate in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma) is the largest prospective study conducted in patients with relapsed or refractory PTCL. Pralatrexate induced durable responses in relapsed or refractory PTCL irrespective of age, histologic subtypes, amount of prior therapy, prior methotrexate, and prior autologous stem-cell transplant. These data formed the basis for the US Food and Drug Administration approval of pralatrexate, the first drug approved for this disease.

Purpose RG7112 is a small-molecule MDM2 antagonist. MDM2 is a negative regulator of the tumor suppressor p53 and frequently overexpressed in leukemias. Thus, a Phase I study of RG7112 in patients with hematologic malignancies was conducted. Experimental Design Primary study objectives included determination of the dose and safety profile of RG7112. Secondary objectives included evaluation of pharmacokinetics, pharmacodynamics, such as TP53-mutation status and MDM2 expression, and preliminary clinical activity. Patients were divided into 2 cohorts: Stratum A (relapsed/refractory AML (except APL), ALL, and CML) and Stratum B (relapsed/refractory CLL/sCLL). Some Stratum A patients were treated at the MTD to assess clinical activity. Results RG7112 was administered to 116 patients (96 patients in Stratum A and 20 patients in Stratum B). All patients experienced at least 1 adverse event, and 3 DLTs were reported. PK analysis indicated that twice-daily dosing enhanced daily exposure. Anti-leukemia activity was observed in the 30 patients with AML assessed at the MTD included 5 patients who met IWG criteria for response. Exploratory analysis revealed TP53 mutations in 14% of Stratum A patients and in 40% of Stratum B patients. Two patients with TP53 mutations exhibited clinical activity. p53 target genes were induced only in TP53 wild-type leukemic cells. Baseline expression levels of MDM2 correlated positively with clinical response. Conclusions RG7112 demonstrated clinical activity against relapsed/refractory AML and CLL/sCLL. MDM2 inhibition resulted in p53 stabilization and transcriptional activation of p53-target genes. We provide proof-of-concept that MDM2 inhibition restores p53 function and generates clinical responses in hematologic malignancies.

Key Points TCM-derived CD19 CAR T–cell therapy is safe for treatment of poor-risk NHL patients undergoing autologous HSCT. Addition of a CD28 costimulatory domain to the CAR, plus changes to T-cell product manufacturing, resulted in improved T-cell expansion.

Relapse of B-lineage acute lymphoblastic leukemia (B-ALL) after allogeneic hematopoietic stem cell transplantation (HSCT) commonly results from the failure of a graft-versus-leukemia (GVL) effect to eradicate minimal residual disease. Augmenting the GVL effect by the adoptive transfer of donor-derived B-ALL-specific T-cell clones is a conceptually attractive strategy to decrease relapse rates without exacerbating graft-versus-host disease (GVHD). Toward this end, we investigated whether a genetic engineering approach could render CD8 ؉ cytotoxic T lymphocytes ( 1 (LFA-1), and LFA-3. We observed that recognition of B-lineage tumor lines by CD19-specific CTLs was not impaired by low levels of ICAM-1, LFA-1, and LFA-3 cell surface expression, a functional attribute that is likely a consequence of our high-affinity CD19-specific chimeric immunoreceptor. Furthermore, the CD19-specific CTLs could lyse primary B-ALL blasts. These preclinical observations form the basis for implementing clinical trials using donor-derived CD19-specific T-cell clones to treat or prevent relapse of B-ALL after alloge-

Total body irradiation (TBI) is an important part of bone marrow transplantation conditioning regimens. In TBI, dose escalation is difficult, because of associated normal organ toxicities. A method to deliver a more targeted dose of TBI preferentially to sites of greatest tumor burden is needed to reduce the dose to normal organs, reduce toxicities, and permit dose escalation. The purpose of this study was to evaluate, through a dosimetric analysis, the potential advantages and feasibility of selectively delivering targeted myeloablative doses of radiation to bone and marrow using a recently developed image-guided tomographic intensity-modulated radiation therapy delivery system (helical tomotherapy). Whole-body computed tomography datasets from 3 patients, age 5, 20, and 53 years, were used for treatment planning studies to evaluate 2 targeted TBI strategies: total marrow irradiation (TMI), in which the target region was defined as the skeletal bone, and total marrow and lymphoid irradiation (TMLI), in which the target regions were defined as bone, major lymph node chains, liver, spleen, and sanctuary sites, such as brain. Organ doses and dose distributions were compared with those in conventional TBI. A 1.7- to 7.5-fold reduction in median organ doses was observed with TMI and TMLI compared with conventional TBI. With this more targeted approach, a dose-volume histogram analysis predicted the potential to escalate the dose to bone (and containing marrow) up to 20 Gy, while maintaining doses to normal organs at lower levels than in conventional TBI to 12 Gy. Results were similar for the adult and pediatric patients, indicating that this form of targeted TBI will be applicable to most patients regardless of frame size. TMI to 10 Gy was delivered as part of a tandem transplant regimen to the 53-year-old patient with multiple myeloma. Clinical results confirmed the treatment planning predictions. After TMI, the patient experienced the expected blood count nadir, followed by successful engraftment. Grade 2 nausea and grade 1 emesis occurred only briefly on day 2 of TMI. Skin erythema, oral mucositis, esophagitis, and enteritis were not observed. This report demonstrates the feasibility and potential dosimetric advantages of selectively delivering myeloablative doses of radiation to bone and marrow using an image-guided tomographic intensity-modulated radiation therapy delivery system. Organ doses are substantially lower than those associated with standard TBI and predict the potential to significantly reduce associated toxicities and allow for dose escalation. The results also suggest that this form of targeted TBI may have potential advantages over other forms of targeted TBI, such as radioimmunotherapy or bone-seeking radionuclide therapy. Ongoing clinical trials will define the maximum TMI and TMLI doses achievable and define the potential advantages and limitations of this new approach for patients undergoing hematopoietic stem cell transplantation.