Krishna V. Komanduri

Maintenance Therapy With Low-Dose Azacitidine After Allogeneic Hematopoietic Stem Cell Transplantation for Recurrent Acute Myelogenous Leukemia or Myelodysplastic Syndrome: A Dose and Schedule Finding Study

Recurrence is a major cause of treatment failure after allogeneic transplantation for acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), and treatment options are very limited. Azacitidine is a DNA methyltransferase inhibitor with activity in myeloid disease. The authors hypothesized that low‐dose azacitidine administered after transplant would reduce recurrence rates, and conducted a study to determine a safe dose/schedule combination.

Transplantation of ex vivo expanded cord blood cells using the copper chelator tetraethylenepentamine: a phase I/II clinical trial.

The copper chelator tetraethylenepentamine (TEPA; StemEx) was shown to attenuate the differentiation of ex vivo cultured hematopoietic cells resulting in preferential expansion of early progenitors. A phase I/II trial was performed to test the feasibility and safety of transplantation of CD133+ cord blood (CB) hematopoietic progenitors cultured in media containing stem cell factor, FLT-3 ligand, interleukin-6, thrombopoietin and TEPA. Ten patients with advanced hematological malignancies were transplanted with a CB unit originally frozen in two fractions. The smaller fraction was cultured ex vivo for 21 days and transplanted 24 h after infusion of the larger unmanipulated fraction. All but two units contained <2 × 107 total nucleated cells (TNCs) per kilogram pre-expansion. All donor–recipient pairs were mismatched for one or two HLA loci. Nine patients were beyond first remission; median age and weight were 21 years and 68.5 kg. The average TNCs fold expansion was 219 (range, 2–620). Mean increase of CD34+ cell count was 6 (over the CD34+ cell content in the entire unit). Despite the low TNCs per kilogram infused (median=1.8 × 107/kg), nine patients engrafted. Median time to neutrophil and platelet engraftment was 30 (range, 16–46) and 48 (range, 35–105) days. There were no cases of grades 3–4 acute graft-versus-host disease (GVHD) and 100-day survival was 90%. This strategy is feasible.

Detection of Gliotoxin in Experimental and Human Aspergillosis

ABSTRACT Gliotoxin was measured in the lungs (mean, 3,976 ± 1,662 ng/g of tissue) and sera (mean, 36.5 ± 30.28 ng/ml) of mice with experimentally induced invasive aspergillosis (IA), and levels decreased with antifungal therapy. Gliotoxin could also be detected in the sera of cancer patients with documented (proven or probable) IA.

Loss of Cytomegalovirus-Specific CD4+ T Cell Responses in Human Immunodeficiency Virus Type 1–Infected Patients with High CD4+ T Cell Counts and Recurrent Retinitis

Clinical histories are reported for 2 patients treated with highly active antiretroviral therapy (HAART) who experienced multiple relapses of cytomegalovirus (CMV) retinitis, despite suppression of human immunodeficiency virus type 1 (HIV-1) viremia and improvement in CD4+ T cell counts (to >400 cells/microL). CMV-specific CD4+ T cell immune reconstitution was measured directly, using cytokine flow cytometry, which revealed persistent deficits in CMV-specific CD4+ T cell responses in both patients. CMV-specific T cells constituted 0.14% and 0.05% of the total CD4+ T cell count in these patients, which is significantly lower than the percentages for 34 control subjects (0.6%-46%; CD4+ T cell count range, 7-1039 cells/microL; P=.019). Deficits in pathogen-specific immune responses may persist in some individuals, despite suppression of HIV-1 replication and substantial increases in circulating CD4+ T cells after HAART, and such deficits may be associated with significant morbidity from opportunistic infections.

Chimeric antigen receptor T-cell therapy — assessment and management of toxicities

Immunotherapy using T cells genetically engineered to express a chimeric antigen receptor (CAR) is rapidly emerging as a promising new treatment for haematological and non-haematological malignancies. CAR-T-cell therapy can induce rapid and durable clinical responses, but is associated with unique acute toxicities, which can be severe or even fatal. Cytokine-release syndrome (CRS), the most commonly observed toxicity, can range in severity from low-grade constitutional symptoms to a high-grade syndrome associated with life-threatening multiorgan dysfunction; rarely, severe CRS can evolve into fulminant haemophagocytic lymphohistiocytosis (HLH). Neurotoxicity, termed CAR-T-cell-related encephalopathy syndrome (CRES), is the second most-common adverse event, and can occur concurrently with or after CRS. Intensive monitoring and prompt management of toxicities is essential to minimize the morbidity and mortality associated with this potentially curative therapeutic approach; however, algorithms for accurate and consistent grading and management of the toxicities are lacking. To address this unmet need, we formed a CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group, comprising investigators from multiple institutions and medical disciplines who have experience in treating patients with various CAR-T-cell therapy products. Herein, we describe the multidisciplinary approach adopted at our institutions, and provide recommendations for monitoring, grading, and managing the acute toxicities that can occur in patients treated with CAR-T-cell therapy.

Risk factors associated with late cytomegalovirus reactivation after allogeneic stem cell transplantation for hematological malignancies.

We analyzed the clinical factors associated with late cytomegalovirus (CMV) reactivation in a group of 269 consecutive recipients of allogeneic stem cell transplant (SCT) for hematological malignancies. Eighty-four subjects (31%) experienced late CMV reactivation, including 64 with prior early reactivation and 20 with isolated late reactivation. Multivariate analyses were conducted in patients with early CMV reactivation to identify factors associated with late recurrence. Important risk factors included lymphoid diagnosis, occurrence of graft-versus-host disease (GVHD), greater number of episodes of early reactivation, persistent day 100 lymphopenia and the use of a CMV-seronegative donor graft. We combined these risk factors in a predictive model to identify those at relatively low, intermediate and high risk. The low-risk group (15% cumulative incidence, CI) encompassed patients without early CMV reactivation, and subjects transplanted for a myeloid malignancy from a matched-related (MR) donor without subsequent acute GVHD. The high-risk patients (73% CI) met all of the following criteria: (1) received an MR graft but developed GVHD, or received a non-MR graft irrespective of GVHD; (2) had more than two episodes of early reactivation; and (3) received a CMV-seronegative graft and/or remained persistently lymphopenic at day 100 after SCT. The remaining patients had an intermediate incidence of 32%.

Double-chimaerism after transplantation of two human leucocyte antigen mismatched, unrelated cord blood units

Summary. The small number of progenitor cells is the major limitation to the use of umbilical cord blood (UCB) for the transplantation of adults. We tested the hypothesis that two units transplanted simultaneously could each contribute to haematopoietic reconstitution. A patient with advanced acute lymphocytic leukaemia received a mismatched, unrelated UCB transplant using units from two donors after conditioning. The recipient achieved a complete remission without graft‐versus‐host disease. Double chimaerism was documented in several leucocyte subpopulations; both units contributed to haematopoiesis until relapse. Triple chimaerism was present from relapse until death due to leukaemia. This approach may potentially improve UCB transplantation outcome for adults lacking a histocompatible donor.

Inhaled corticosteroids stabilize constrictive bronchiolitis after hematopoietic stem cell transplantation

Post transplantation constrictive bronchiolitis (PTCB) is the most common pulmonary complication among long-term survivors of allogeneic hematopoietic stem cell transplantation (HSCT). It is a late manifestation of GVHD. Its treatment with high-dose systemic corticosteroids and other immunosuppressive regimens is associated with multiple side effects. Topical corticosteroids are used for the treatment of other manifestations of GVHD to minimize these side effects. We conducted a retrospective analysis of a series of adult patients to evaluate the efficacy of high-dose inhaled corticosteroids in the treatment of PTCB. Seventeen patients with new-onset airflow obstruction were diagnosed with PTCB. Their forced expiratory volume in 1 s (FEV1) declined from a median of 84% (range, 56–119) before HSCT to 53% (26–82) after HSCT. All patients received inhaled fluticasone propionate 500–940 μg two times daily. Symptoms of airway obstruction improved and FEV1 stabilized 3–6 months after treatment. We conclude that high-dose inhaled corticosteroids may be effective in the treatment of PTCB and propose a plausible mechanism of its action. A prospective evaluation of its efficacy is warranted.

Overexpressed differentiation antigens as targets of graft-versus-leukemia reactions

The graft-versus-leukemia (GVL) effect associated with allogeneic blood and marrow transplantation has largely been a clinically described phenomenon until recently. We are beginning to understand the cellular and molecular nature of GVL, and in this review the authors highlight the potential for self-antigen–specific T lymphocytes to contribute to GVL. The authors focus on myeloid tissue–restricted proteins as GVL target antigens in CML and AML, and in particular on proteinase 3 and other azurophil granule proteins as targets for both autologous and allogeneic T-cell responses. Finally, the authors discuss myeloid self-antigen–directed alloreactivity in the context of our evolving understanding of the critical molecular determinants of allogeneic T-cell recognition. By altering T-cell receptor affinity, peptide specificity can be maintained and the potency of immunity can be enhanced in the MHC-mismatched setting.

Ex vivo expanded umbilical cord blood T cells maintain naive phenotype and TCR diversity

BACKGROUND Umbilical cord blood (CB) is a promising source of hematopoietic stem cells for allogeneic transplantation. However, delayed engraftment and impaired immune reconstitution remain major limitations. Enrichment of donor grafts with CB T cells expanded ex vivo might facilitate improved T-cell immune reconstitution post-transplant. We hypothesized that CB T cells could be expanded using paramagnetic microbeads covalently linked to anti-CD3 and anti-CD28 Ab. METHODS CB units were divided into three fractions: (1) cells cultured without beads, (2) cells cultured with beads and (3) cells cultured with beads following CD3+ magnetic enrichment. All fractions were cultured for 14 days in the presence of IL-2 (200 IU/mL). RESULTS A mean 100-fold expansion (range 49-154) of total nucleated cells was observed in the CD3+ magnetically enriched fraction. Following expansion, CB T cells retained a naive and/or central memory phenotype and contained a polyclonal TCR diversity demonstrated by spectratyping. DISCUSSION Our data provide evidence that naive and diverse CB T cells may be expanded ex vivo and warrant additional studies in the setting of human CB transplantation.