ABSTRACT
Histiocytic neoplasms are rare hematologic disorders accounting for less than 1% of cancers of the soft tissue and lymph nodes. Clinical presentation and prognosis of these disorders can be highly variable, leading to challenges for diagnosis and optimal management of these patients. Treatment often consists of systemic therapy, and recent studies support use of targeted therapies for patients with these disorders. Observation ("watch and wait") may be sufficient for select patients with mild disease. These NCCN Guidelines for Histiocytic Neoplasms include recommendations for diagnosis and treatment of adults with the most common histiocytic disorders: Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease.
Subject(s)
Erdheim-Chester Disease , Hematologic Neoplasms , Histiocytosis, Langerhans-Cell , Histiocytosis, Sinus , Adult , Erdheim-Chester Disease/drug therapy , Histiocytosis, Langerhans-Cell/diagnosis , Histiocytosis, Langerhans-Cell/drug therapy , Histiocytosis, Langerhans-Cell/pathology , Histiocytosis, Sinus/diagnosis , Histiocytosis, Sinus/drug therapy , Histiocytosis, Sinus/pathology , Humans , PrognosisABSTRACT
To define the tolerability and outcome of allogeneic hematopoietic stem cell transplant (allo-HSCT) following CAR T-cell therapy, we retrospectively reviewed pediatric/young adult patients with relapsed/refractory B-ALL who underwent this treatment. Fifteen patients (median age 13 years; range 1-20 years) with a median potential follow-up of 39 months demonstrated 24-month cumulative incidence of relapse, cumulative incidence of TRM, and OS of 16% (95% CI: 0-37%), 20% (95% CI: 0-40%), and 80% (95% CI: 60-100%), respectively. Severe toxicity following CAR T cells did not impact OS (p = 0.27), while greater time from CAR T cells to allo-HSCT (>80 days) was associated with a decrease in OS. In comparing CD34-selected T-cell depleted (TCD; n = 9) vs unmodified (n = 6) allo-HSCT, the cumulative incidence of relapse, TRM, and OS at 24 months was 22% (95% CI: 0-49%) vs 0% (p = 0.14), 0% vs 50% [95% CI: 10-90%] (p = 0.02) and 100% vs 50% [95% CI: 10-90%] (p = 0.02). In this small cohort of patients, CAR T cells followed by a CD34-selected TCD allo-HSCT appears to result in less TRM and favorable OS when compared with unmodified allo-HSCT. There was no evidence that disease control was impacted by the type of consolidative allo-HSCT, which demonstrates the feasibility of this approach.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Child , Humans , Immunotherapy, Adoptive , Infant , Neoplasm Recurrence, Local , Retrospective Studies , T-Lymphocytes , Young AdultABSTRACT
Disease relapse and toxicity are the shortcomings of reduced-intensity conditioning (RIC) for allogeneic hematopoietic cell transplantation (alloHCT). We hypothesized that adding total body irradiation (TBI) to and decreasing melphalan (Mel) from a base RIC regimen of fludarabine (Flu) and Mel would increase cytoreduction and improve disease control while decreasing toxicity. We performed a phase II trial of Flu 160 mg/m2, Mel 50 mg/m2, and TBI 400 cGy (FluMelTBI-50, nâ¯=â¯61), followed by a second phase II trial of Flu 160 mg/m2, Mel 75 mg/m2, and TBI 400cGy (FluMelTBI-75, nâ¯=â¯94) as RIC for alloHCT. Outcomes were compared with a contemporaneous cohort of 162 patients who received Flu 125 mg/m2 and Mel 140 mg/m2. Eligibility criteria were equivalent for all 3 regimens. All patients were ineligible for myeloablative/intensive conditioning. The median (range) follow-up for all patients was 51 (15 to 103) months. Day 100 donor lymphoid chimerism and transplant-related mortality, neutrophil and platelet engraftment, acute and chronic graft versus host disease incidence, overall survival (OS), and progression-free survival (PFS) were equivalent between FluMel, FluMelTBI-50, and FluMelTBI-75. Stomatitis wasdecreased for FluMelTBI versus FluMel (P < .01). PFS for patients not in complete remission on alloHCT was improved for FluMelTBI-75 versus FluMel (Pâ¯=â¯.03). On multivariate analysis, OS (Pâ¯=â¯.05) and PFS (Pâ¯=â¯.05) were significantly improved for FluMelTBI-75 versus FluMel. FluMelTBI-75 is better tolerated than FluMel, with improved survival and disease control.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Melphalan/therapeutic use , Transplantation Conditioning/methods , Transplantation, Homologous/methods , Vidarabine/analogs & derivatives , Whole-Body Irradiation/methods , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Child , Female , Humans , Male , Melphalan/pharmacology , Middle Aged , Vidarabine/pharmacology , Vidarabine/therapeutic use , Young AdultABSTRACT
Assay of cell-free DNA in blood offers an approach to assessment of tumor DNA. We sought to determine whether Epstein-Barr virus (EBV) DNA in cell-free blood is also a good surrogate for the presence of tumor DNA in children with Hodgkin lymphoma, as it is in adults, and whether it correlates with pediatric outcomes. Pediatric patients enrolled in a Children's Oncology Group trial (AHOD0031) were studied at baseline and at 8 days after the initiation of treatment. At baseline, EBV DNA in cell-free blood correlated with the presence of EBV in tumor, and EBV DNA 8 days after the initiation of therapy predicted inferior event-free survival. EBV DNA in cell-free blood warrants further investigation as a marker of inadequate tumor response in Hodgkin lymphoma. This trial was registered at www.clinicaltrials.gov as #NCT00025259.
ABSTRACT
Pearson marrow pancreas syndrome (PS) is a multisystem disorder caused by mitochondrial DNA (mtDNA) deletions. Diamond-Blackfan anemia (DBA) is a congenital hypoproliferative anemia in which mutations in ribosomal protein genes and GATA1 have been implicated. Both syndromes share several features including early onset of severe anemia, variable nonhematologic manifestations, sporadic genetic occurrence, and occasional spontaneous hematologic improvement. Because of the overlapping features and relative rarity of PS, we hypothesized that some patients in whom the leading clinical diagnosis is DBA actually have PS. Here, we evaluated patient DNA samples submitted for DBA genetic studies and found that 8 (4.6%) of 173 genetically uncharacterized patients contained large mtDNA deletions. Only 2 (25%) of the patients had been diagnosed with PS on clinical grounds subsequent to sample submission. We conclude that PS can be overlooked, and that mtDNA deletion testing should be performed in the diagnostic evaluation of patients with congenital anemia.
Subject(s)
Acyl-CoA Dehydrogenase, Long-Chain/deficiency , Anemia, Diamond-Blackfan/diagnosis , Anemia, Diamond-Blackfan/genetics , DNA, Mitochondrial/genetics , Lipid Metabolism, Inborn Errors/diagnosis , Lipid Metabolism, Inborn Errors/genetics , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/genetics , Muscular Diseases/diagnosis , Muscular Diseases/genetics , Acyl-CoA Dehydrogenase, Long-Chain/genetics , Child , Child, Preschool , Congenital Bone Marrow Failure Syndromes , DNA Mutational Analysis , Diagnosis, Differential , Humans , Infant , Mutation , Sequence DeletionABSTRACT
BACKGROUND: Adenoviral infections cause morbidity and mortality in blood and marrow transplantation and pediatric oncology patients. Cidofovir is active against adenovirus, but must be used judiciously because of its nephrotoxicity and unclear indications. Therefore, before introducing cidofovir use during an adenoviral outbreak, we developed a clinical algorithm to distinguish low risk patients from those who merited cidofovir therapy because of significant adenoviral disease and high risk for death. OBJECTIVE: This study was conducted to determine whether the algorithm accurately predicted severe adenovirus disease and whether selective cidofovir treatment was beneficial. STUDY DESIGN: A retrospective analysis of a pediatric oncology/blood and marrow transplantation cohort prealgorithm and postalgorithm implementation was performed. RESULTS: Twenty patients with adenovirus infection were identified (14 high risk and 6 low risk). All low-risk patients cleared their infections without treatment. Before algorithm implementation, all untreated high-risk patients died, 4 out of 5 (80%), from adenoviral infection. In contrast, cidofovir reduced adenovirus-related mortality in the high-risk group postalgorithm implementation (9 patients treated, 1 patient died; RR 0.14, P<0.05) and all treated high-risk patients cleared their virus. CONCLUSIONS: The clinical algorithm accurately identified patients at high risk for severe fatal adenoviral disease who would benefit from selective use of cidofovir.
Subject(s)
Adenoviridae Infections/diagnosis , Adenoviridae Infections/drug therapy , Algorithms , Antiviral Agents/administration & dosage , Bone Marrow Transplantation , Cytosine/analogs & derivatives , Organophosphonates/administration & dosage , Adenoviridae Infections/mortality , Child , Child, Preschool , Cidofovir , Cohort Studies , Cytosine/administration & dosage , Female , Humans , Male , Retrospective Studies , Risk Factors , Transplantation, Autologous , Transplantation, HomologousABSTRACT
We report a novel regimen for refractory post-transplant T-cell lymphoma (PTL). Our patient presented with non-Epstein-Barr virus (EBV) related, T-cell post-transplant lymphoproliferative disease (PTLD) 3.5 years after liver transplantation. Initially diagnosed as polyclonal PTLD, the disease progressed to a monoclonal, T-cell PTL that was refractory to several chemotherapy regimens but responded to a regimen consisting of fludarabine, cyclophosphamide, cytarabine, and alemtuzumab. Consolidation therapy included high-dose chemotherapy, autologous hematopoietic stem cell rescue, and radiation therapy. She remains in remission 2.5 years later. T-cell PTL is a rare disease with a poor prognosis; this regimen provides a novel, potentially curative approach for its treatment.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Liver Transplantation , Lymphoma, T-Cell, Peripheral/therapy , Lymphoproliferative Disorders/therapy , Postoperative Complications/therapy , Alemtuzumab , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized , Antibodies, Neoplasm/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Biliary Atresia/surgery , Carboplatin/administration & dosage , Carmustine/administration & dosage , Cyclophosphamide/administration & dosage , Cytarabine/administration & dosage , Disease Progression , Doxorubicin/administration & dosage , Etoposide/administration & dosage , Female , Granulocyte Colony-Stimulating Factor/administration & dosage , Hematopoietic Stem Cell Transplantation , Humans , Ifosfamide/administration & dosage , Immunocompromised Host , Immunosuppressive Agents/adverse effects , Lymphoma, T-Cell, Peripheral/drug therapy , Lymphoma, T-Cell, Peripheral/etiology , Lymphoma, T-Cell, Peripheral/radiotherapy , Lymphoma, T-Cell, Peripheral/surgery , Lymphoproliferative Disorders/etiology , Melphalan/administration & dosage , Mesna/administration & dosage , Postoperative Complications/drug therapy , Postoperative Complications/etiology , Postoperative Complications/radiotherapy , Postoperative Complications/surgery , Prednisone/administration & dosage , Radiotherapy, Adjuvant , Transplantation, Autologous , Vidarabine/administration & dosage , Vidarabine/analogs & derivatives , Vincristine/administration & dosageABSTRACT
PURPOSE: Therapy for patients with chronic graft-versus-host disease (cGVHD) is based on prolonged immunosuppression with corticosteroids. There is no standard therapy for patients whose cGVHD does not resolve with corticosteroid treatment. Pentostatin, a potent inhibitor of adenosine deaminase, has activity in acute GVHD. We examined the toxicity and efficacy of pentostatin in a prospective phase II trial in corticosteroid-refractory cGVHD. PATIENTS AND METHODS: Patients of any age were eligible. Patients received pentostatin 4 mg/m2 intravenously every 2 weeks for 12 doses, and continued therapy as long as benefit was documented. Corticosteroid taper was begun after three doses of pentostatin. Responses were graded in real time in the skin, mouth, and liver using objective response criteria. RESULTS: Fifty-eight heavily pretreated (median, four prior regimens) patients (median age, 33 years) were enrolled. Results are shown as an intent-to-treat analysis. Of the 58 patients, a total of 32 (55%; 95% CI, 42% to 68%) had an objective response, as evaluated by use of a new grading scale. Infection was the most significant toxicity, with 11 grade 3 to 4 infectious events. The survival at 1 and 2 years was 78% (95% CI, 64% to 86%) and 70% (95% CI, 57% to 80%), with cGVHD with/without infection accounting for the majority of deaths. CONCLUSION: Pentostatin has immunosuppressive effects that are currently being explored further for treatment of cGVHD.
Subject(s)
Adrenal Cortex Hormones/pharmacology , Graft vs Host Disease/drug therapy , Immunosuppressive Agents/therapeutic use , Leukemia/complications , Pentostatin/therapeutic use , Adolescent , Adult , Child , Child, Preschool , Drug Resistance , HLA Antigens/metabolism , Humans , Leukemia/therapy , Middle Aged , Treatment OutcomeABSTRACT
OBJECTIVE: Demonstrate that high-dose cyclophosphamide (CY) is effective therapy for hepatitis-associated aplastic anemia (HAA). BACKGROUND: HAA is a sequence of seronegative hepatitis followed by aplastic anemia. Optimal treatment is matched-sibling allogeneic bone marrow transplantation (BMT). The combination of antithymocyte globulin (ATG) and cyclosporine (CSA) has also been studied, but there are scarce data regarding treatment of HAA. PROCEDURE: Five patients (median age 14 years; range 6-17 years) with HAA and without an HLA-matched sibling were treated with high-dose CY (50 mg/kg/day IV x 4 days) followed by granulocyte-colony stimulation factor (G-CSF). RESULTS: After at least 1 year of follow-up, four of five patients are in remission without further immune suppression beyond high-dose CY. Of the 4 responders, median time to absolute neutrophil count (ANC) >500 microl(-1) was 51 days (range 44-369). Median time to transfusion independence for erythrocytes and platelets was 109 (range 57-679) and 160 (range 48-679) days, respectively. The fifth patient did not respond and proceeded to an unrelated donor transplant. One patient met criteria for autoimmune hepatitis (AIH) in addition to HAA. In this case, high-dose CY successfully induced remission of both diseases. CONCLUSIONS: High-dose CY induces durable remissions in HAA and may be an effective treatment for AIH.
Subject(s)
Anemia, Aplastic/drug therapy , Cyclophosphamide/administration & dosage , Hepatitis, Viral, Human/drug therapy , Adolescent , Anemia, Aplastic/etiology , Anemia, Aplastic/pathology , Child , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Follow-Up Studies , Granulocyte Colony-Stimulating Factor/administration & dosage , Hepatitis, Viral, Human/complications , Hepatitis, Viral, Human/pathology , Humans , Infusions, Intravenous , Male , Prospective Studies , Remission Induction , Treatment OutcomeABSTRACT
We present the case of a 6-year-old male who received an allogeneic bone marrow transplant as part of treatment for acute lymphoblastic leukemia. The patient relapsed 5 months after transplantation and received additional chemotherapy. He acquired an angioinvasive fungal infection that required transfusion of granulocytes. Approximately 5 weeks after relapsing (181 days after transplant), a bone marrow specimen was taken for molecular engraftment analysis and flow cytometry to assess graft loss as well as residual disease. The engraftment results generated by the multiple short tandem repeat loci tested were inconsistent, and alleles were present at several loci that were of neither patient nor donor origin. An error in specimen identification was initially considered. Further investigation into the circumstances surrounding procurement of the patient's bone marrow aspirate revealed that the patient had received a granulocyte transfusion approximately 10 hours before the bone marrow specimen was taken. In addition, morphological and flow cytometric analyses of the same bone marrow aspirate demonstrated a significant degree of peripheral blood contamination. We determined that the unknown alleles in the bone marrow engraftment specimen were derived from the donor of the transfused granulocytes. This case illustrates that white cell transfusion can lead to erroneous bone marrow engraftment results, particularly if only one microsatellite locus is used to monitor engraftment.
Subject(s)
Bone Marrow Transplantation , DNA/analysis , Graft Survival/genetics , Leukocyte Transfusion , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Child , DNA/genetics , Flow Cytometry , Granulocytes/transplantation , Humans , Male , Microsatellite Repeats , Precursor Cell Lymphoblastic Leukemia-Lymphoma/surgery , Transplantation, HomologousABSTRACT
Pentostatin (deoxycoformycin), is one of a number of purine analogues. The drug was originally designed to mimic a form of severe combined immune deficiency, characterised by marked T lymphopenia but variable B cell function. Clinically, the drug has been used primarily to treat a rare type of leukaemia - hairy cell leukaemia. Recently, the drug has seen increasing attention as an immunosuppressant. This review will cover the basic pharmacology and immunological effects of pentostatin. The clinical use of this agent in prevention and treatment of graft-versus-host disease will be examined. Although many of these studies are ongoing, this agent has promise as a novel immunosuppressive agent with a new mechanism of action.
Subject(s)
Immunosuppressive Agents/therapeutic use , Pentostatin/therapeutic use , Bone Marrow Transplantation , Clinical Trials as Topic , Graft vs Host Disease/drug therapy , Graft vs Host Disease/immunology , Graft vs Host Disease/prevention & control , Humans , Immunologic Tests , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/pharmacokinetics , Pentostatin/chemistry , Pentostatin/pharmacokineticsABSTRACT
The ability to cure increasing numbers of individuals for malignant and non-malignant diseases with the use of stem cell transplantation has resulted in a growing number of long-term survivors with unique medical issues. Chronic graft versus host disease (GvHD) continues to be a significant problem in the allogeneic stem cell transplant setting and, as we continue to use alternative stem cell sources and attempt to modulate the immune system to increase an anti-tumour effect, we will probably see rising numbers of patients with this complication. The capacity to treat this problem and improve both the immediate quality of life as well as long-term effects is imperative and requires the ability of haematologists/oncologists to identify chronic GvHD and its multi-organ system presentations. We describe the risk factors for developing chronic GvHD, its presentation and the current treatment options for both initial therapy and secondary treatment.
Subject(s)
Graft vs Host Disease/immunology , Stem Cell Transplantation/adverse effects , Adult , Child , Child, Preschool , Chronic Disease , Glucocorticoids/therapeutic use , Graft vs Host Disease/diagnosis , Graft vs Host Disease/therapy , Graft vs Tumor Effect , Humans , Immunosuppressive Agents/therapeutic use , Risk Factors , Transplantation Immunology , Transplantation, HomologousABSTRACT
Carboplatin is currently recommended to be dosed according to renal function. In adults, dosing by the Calvert formula is based on evidence that carboplatin clearance closely parallels glomerular filtration rate. Several studies have attempted to validate the Calvert formula and its derivations in pediatrics, but no final consensus has been achieved. As a result, different versions of the original formula exist in the pediatric literature. Other factors may also contribute to confusion when applying the formula to young patients, including the manner in which renal function is measured and reported. We describe how misinterpretation of the Calvert formula resulted in carboplatin overdosing in 2 pediatric patients with high-risk neuroblastoma undergoing peripheral blood stem cell transplantation. Measures to avoid such errors have been instituted.