Limited clinical benefit for surveillance PET-CT scanning in patients with histologically transformed lymphoma in complete metabolic remission following primary therapy.

The optimum follow-up of patients with transformed indolent lymphoma (TrIL) is not well defined. We sought to determine the utility of surveillance positron emission tomography-computed tomography (PET-CT) in patients with TrIL achieving complete metabolic remission (CMR) after primary therapy. We performed a retrospective analysis of patients with TrIL treated at Peter MacCallum Cancer Centre between 2002 and 2012 who achieved CMR after primary therapy who had ≥1 subsequent surveillance PET-CT. Of 55 patients with TrIL, 37 (67 %) received autologous stem cell transplantation as consolidation following chemoimmunotherapy. After a median follow-up of 34 (range 3-101) months, the actuarial 3-year progression-free (PFS) and overall survival (OS) were 77 % (95 %CI 62-86 %) and 88 % (75-94 %), respectively. Of 180 surveillance PET-CT scans, there were 153 true negatives, 4 false positives, 1 false negative, 7 indeterminate and 15 true positives. Considering indeterminate scans as false positives, the specificity of PET-CT for detecting relapse was 94 %, sensitivity was 83 %, positive predictive value was 63 % and negative predictive value was 98 %. All seven subclinical (PET detected) relapses were of low-grade histology; in contrast, all nine relapses with diffuse large B cell lymphoma (DLBCL) were symptomatic. In our cohort of patients with TrIL achieving CMR, PET-CT detected subclinical low-grade relapses but all DLBCL relapses were accompanied by clinical symptoms. Thus, surveillance imaging of patients with TrIL achieving CMR is of limited clinical benefit. PET-CT should be reserved for evaluation of clinically suspected relapse.

How I treat patients who mobilize hematopoietic stem cells poorly.

Transplantation with 2-5 × 10(6) mobilized CD34(+)cells/kg body weight lowers transplantation costs and mortality. Mobilization is most commonly performed with recombinant human G-CSF with or without chemotherapy, but a proportion of patients/donors fail to mobilize sufficient cells. BM disease, prior treatment, and age are factors influencing mobilization, but genetics also contributes. Mobilization may fail because of the changes affecting the HSC/progenitor cell/BM niche integrity and chemotaxis. Poor mobilization affects patient outcome and increases resource use. Until recently increasing G-CSF dose and adding SCF have been used in poor mobilizers with limited success. However, plerixafor through its rapid direct blockage of the CXCR4/CXCL12 chemotaxis pathway and synergy with G-CSF and chemotherapy has become a new and important agent for mobilization. Its efficacy in upfront and failed mobilizers is well established. To maximize HSC harvest in poor mobilizers the clinician needs to optimize current mobilization protocols and to integrate novel agents such as plerixafor. These include when to mobilize in relation to chemotherapy, how to schedule and perform apheresis, how to identify poor mobilizers, and what are the criteria for preemptive and immediate salvage use of plerixafor.

Mantle cell lymphoma with central nervous system involvement: frequency and clinical features.

Reported rates of central nervous system (CNS) involvement in mantle cell lymphoma (MCL) are highly variable but substantial (4-26%). Data is lacking regarding risk factors for CNS relapse, and for those patients in whom CNS prophylaxis could be beneficial. We present single institution retrospective analysis of data of baseline features, clinical course, rate of CNS disease and putative risk factors in 62 patients with MCL (18 female, 44 male). CNS disease (all cases were symptomatic) occurred in four patients at a median of 12 months (range 1-58) from diagnosis, with a crude incidence of 6.5% and 5-year actuarial incidence of 5 +/- 3%. Two cases had blastic MCL at diagnosis. Survival after CNS relapse ranged from 2-9 months. Patients who developed CNS disease had a significantly shorter survival from diagnosis than those who did not (P = 0.0024). Symptomatic CNS disease in patients with MCL either at presentation or relapse is an uncommon but devastating complication. In younger patients, more aggressive immuno-chemotherapy regimens containing CNS-penetrating agents may reduce the incidence of CNS disease. While not routinely justified for all patients, CNS prophylaxis may particularly benefit patients with blastic histology at diagnosis, or those with systemic relapse after first-line treatment.

The use of experimental murine models to assess novel agents of hematopoietic stem and progenitor cell mobilization.

The recent explosion in the understanding of the cellular and molecular mechanisms underlying hematopoietic stem and progenitor cell (HSPC) mobilization has facilitated development of novel therapeutic agents, targeted at improving mobilization kinetics as well as HSPC yield. With the development of new agents comes the challenge of choosing efficient and relevant preclinical studies for the testing of the HSPC mobilization efficacy of these agents. This article reviews the use of the mouse as a convenient small animal model of HSPC mobilization and transplantation, and outlines the range of murine assays that can be applied to assess novel HSPC mobilizing agents. Techniques to demonstrate murine HSPC mobilization are discussed, as well as the role of murine assays to confirm human HSPC mobilization, and techniques to investigate the biologic phenotype of HSPC mobilized by these novel agents. Technical aspects regarding mobilization regimens and control arms, and choice of experimental animals are also discussed.

Granulocyte colony-stimulating factor and an RARalpha specific agonist, VTP195183, synergize to enhance the mobilization of hematopoietic progenitor cells.

BACKGROUND: Failure to mobilize adequate numbers of hematopoietic stem and progenitor cells (HSPC) is an important clinical problem. Since bone marrow (BM) neutrophils play a central role in HSPC mobilization, we hypothesized that granulocyte colony-stimulating factor (G-CSF)-mediated mobilization would be enhanced by further expanding the size of the BM granulocyte pool. METHODS: We tested the potential of the retinoic acid receptor alpha (RARalpha) specific agonist VTP195183, and the pan-RAR agonist all-trans retinoic acid (ATRA), to enhance G-CSF-mediated mobilization of HSPC, in two mouse strains. RESULTS: Pretreatment of mice with VTP195183 significantly increased the number of leukocytes, colony-forming cells, and early engrafting hematopoietic stem cells (HSC) mobilized in the blood in response to G-CSF. In contrast, ATRA had only a marginal effect on G-CSF-induced mobilization. HSPC mobilization synergy between VTP195183 and G-CSF occurred only when mice were preconditioned with VTP195183 prior to G-CSF. This preconditioning was shown to increase the numbers of granulocyte/macrophage progenitors in the BM. Treatment with VTP195183 and G-CSF was accompanied by enhanced levels of active neutrophil proteases in the BM extracellular fluid compared to G-CSF treatment alone. CONCLUSIONS: VTP195183 treatment increases the numbers of immature granulocyte progenitors in BM and subsequently synergizes to enhance G-CSF-mediated mobilization of HSPC. These data demonstrate a novel approach to improve G-CSF-induced mobilization by accelerating granulocyte maturation in the BM. These findings are currently being tested in a clinical trial of VTP195183 plus G-CSF for mobilization of HSPC in human patients.

Ante-mortem diagnosis of localized invasive esophageal aspergillosis in a patient with acute myeloid leukemia.

Opportunistic infection with invasive aspergillosis (IA) is increasingly frequent in immunocompromised patients, particularly in those with hematological malignancies. In this setting, IA typically involves the lung, with extra-pulmonary involvement usually occurring in the setting of disseminated infection. We report a case of localized gastrointestinal IA complicating induction chemotherapy for acute myeloid leukemia (AML). Oral voriconazole was successful as primary treatment, with no evidence of progressive infection despite further myelosuppressive chemotherapy. A review of the literature suggests that although localized gastrointestinal IA is rare, involvement of the gastrointestinal tract is not uncommon in disseminated infection. Thus, in patients with hematological malignancies who develop significant gastrointestinal symptoms, we recommend that endoscopic investigations and biopsies are performed to exclude IA as a potential cause.

The utility and limitations of (18)F-fluorodeoxyglucose positron emission tomography with computed tomography in patients with primary mediastinal B-cell lymphoma: single institution experience and literature review.

There are limited data regarding the role of (18)F-fluorodeoxyglucose positron emission tomography with computed tomography (FDG PET-CT) scanning in primary mediastinal B-cell lymphoma (PMBL). We analyzed 28 patients with PMBL treated with chemotherapy, of whom 25 (89%) also received rituximab and 17 (61%) radiotherapy. PET-CT scans were interpreted using visual analysis and a 5-point scale. After a median follow-up of 2.6 years, four patients relapsed and two died. The 2-year progression-free survival and overall survival were 86% and 94%. PET-CT has excellent negative predictive value (interim, 86-87%; end of treatment, 95%) but limited positive predictive value due to the high frequency of positive scans. Several patients with persistent metabolically active masses underwent biopsies, which showed necrosis but no lymphoma. Thus a negative PET-CT is an excellent predictor of subsequent outcome. However, residual metabolically active masses after treatment should be biopsied to confirm viable lymphoma prior to salvage therapy.

Mobilisation strategies for normal and malignant cells.

This review evaluates the latest information on the mobilisation of haemopoietic stem cells for transplantation, with the focus on what is the current best practice and how new understanding of the bone marrow stem cell niche provides new insights into optimising mobilisation regimens. The review then looks at the mobilisation of mesenchymal stromal cells, immune cells as well as malignant cells and what clinical implications there are.

The role of ancestim (recombinant human stem-cell factor, rhSCF) in hematopoietic stem cell mobilization and hematopoietic reconstitution.

The mobilization and collection of hematopoietic stem and progenitor cells (HSPC) is central to many potentially curative treatments for cancer and some non-malignant conditions. Recombinant human cytokines have been the mainstay of therapeutic HSPC mobilization, particularly G-CSF. Even with currently used mobilization regimens using G-CSF with or without chemotherapy, up to 60% of patients can fail to mobilize enough HSPC for a transplant procedure. Recombinant human stem cell factor (ancestim, rhSCF, Stemgen) is another such cytokine, which has shown promising synergy when used in combination with G-CSF for HSPC mobilization. It provides a useful second-line option for prior failed-mobilizer patients and those who are anticipated to mobilize poorly due to recognised risk factors. It may also have utility in promoting bone marrow recovery in cases of refractory bone marrow failure such as aplastic anaemia and prolonged non-engraftment after allogeneic HSPC transplantation. We review the literature supporting the use of rhSCF in the context of HSPC mobilization and bone marrow failure. The emergence of other novel agents for HSPC mobilization such as plerixafor (AMD3100, Mozobil) will further demarcate the role of Ancestim as a second- or third-line mobilization agent for the mobilization-refractory patient.

Alemtuzumab: effective monotherapy for simultaneous B-cell chronic lymphocytic leukaemia and Sézary syndrome.

The simultaneous presentation of chronic lymphocytic leukaemia (CLL) and cutaneous T-cell lymphoma (CTCL) is a very rare occurrence where optimal treatment is unknown. We present the case of a 65-yr-old man who was successfully treated with alemtuzumab monotherapy for both disorders, but at a cost of severe infectious morbidity and prolonged pancytopenia.