Desmoplastic small round cell tumor (DSRCT), a rare, aggressive neoplasm, has a poor prognosis. In this prospective study, we evaluated the role of myeloablative chemotherapy, followed by autologous ...stem cell transplant in improving survival in DSRCT. After high-dose induction chemotherapy and surgery, 19 patients with chemoresponsive DSRCT underwent autologous stem cell transplant. Myeloablative chemotherapy consisted of carboplatin (400–700 mg/m2/day for 3 days) + thiotepa (300 mg/m2/day for 3 days) ± topotecan (2 mg/m2/day for 5 days). All patients were engrafted and there was no treatment-related mortality. Seventeen patients received radiotherapy to sites of prior or residual disease at a median of 12 weeks after transplant. Five-year event-free and overall survival were 11 ± 7% and 16 ± 8%, respectively. Two patients survive disease-free 16 and 19 years after transplant (both in complete remission before transplant). 14 patients had progression and died of disease at a median of 18 months following autologous transplant. These data do not justify the use of myeloablative chemotherapy with carboplatin plus thiotepa in patients with DSRCT. Alternative therapies should be considered for this aggressive neoplasm.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Current European and US guidelines for recombinant hepatitis B vaccine (rHBV) after hematopoietic-cell transplantation (HCT) vary. The European Group for Blood and Marrow Transplantation (EBMT) ...recommends rHBV starting 6 to 12 months after HCT. Immunization is optional in the Centers for Disease Control and Prevention (CDC) guidelines. Nevertheless, rHBV is required for re-entry to school and certain workplaces. To determine the immunogenicity of rHBV following HCT, the prevaccine and postvaccine titers of 292 allogeneic transplant recipients who were immunized with rHBV were analyzed. Immunization was initiated in patients off immunosuppression who achieved specific minimal milestones of immune competence. Overall, 64% of patients seroconverted. In multivariate analyses, response was adversely affected by age older than 18 years (P < .01) and history of prior chronic graft-versus-host disease (GVHD; P < .001) but not by donor type or by use of T-cell depletion, adoptive immunotherapy, or rituximab. By comparison, 89% of rHBV nonresponders mounted a 3-fold or greater rise in polio titers following 3 doses of inactivated poliovirus. These data demonstrate that the rate of seroconversion following rHBV is lower in allogeneic HC transplant recipients compared with age-matched healthy controls. The data emphasize the need to document prevaccine and postvaccine titers to ensure response and suggest that immunization guidelines based on time interval from HCT, irrespective of immune competence, may not ensure adequate protection against certain vaccine-preventable diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Infusions of large numbers (>108/kg) of donor leukocytes can induce remissions in patients with chronic myeloid leukemia (CML) who relapse after marrow transplantation. We wanted to determine if ...substantially lower numbers of donor leukocytes could induce remissions and, if so, whether this would reduce the 90% incidence of graft-versus-host disease (GVHD) associated with this therapy. Twenty-two patients with relapsed CML were studied: 2 in molecular relapse, 6 in cytogenetic relapse, 10 in chronic phase, and 4 in accelerated phase. Each patient received escalating doses of donor leukocytes at 4- to 33-week intervals. Leukocyte doses were calculated as T cells per kilogram of recipient weight. There were 8 dose levels between 1 × 105 and 5 × 108. Lineage-specific chimerism and residual leukemia detection were assessed using sensitive polymerase chain reaction (PCR) methodologies. Nineteen of the 22 patients achieved remission. Remissions were achieved at the following T-cell doses: 1 × 107 (n = 8), 5 × 107 (n = 4), 1 × 108 (n = 3), and 5 × 108 (n = 4). To date, 15 of the 17 evaluable patients have become BCR-ABL negative by PCR. The incidence of GVHD was correlated with the dose of T cells administered. Only 1 of the 8 patients who achieved remission at a T-cell dose of 1 × 107/kg developed GVHD, whereas this complication developed in 8 of the 11 responders who received a T-cell dose of ≥5 × 107/kg. Three patients died in remission, 1 secondary to marrow aplasia, 1 of respiratory failure, and 1 of complications of chronic GVHD. Sixteen patients who were mixed T-cell chimeras before treatment became full donor T-cell chimeras at the time of remission. Donor leukocytes with a T-cell content as low as 1 × 107/ kg can result in complete donor chimerism together with a potent graft-versus-leukemia (GVL) effect. The dose of donor leukocytes or T cells used may be important in determining both the GVL response and the incidence of GVHD. In many patients, this potent GVL effect can occur in the absence of clinical GVHD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In marrow-transplant recipients, lymphoproliferative disorders associated with Epstein-Barr virus (EBV) usually present as malignant B-cell lymphomas of donor origin, which may be either polyclonal ...or monoclonal
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. Chemotherapy and radiation therapy have been ineffective. Although there are reports of successful treatment of polyclonal or oligoclonal proliferations with agents such as interferon alfa and intravenous gamma globulin, high-dose acyclovir, and anti-B-cell monoclonal antibodies, monoclonal disease has been refractory to treatment in marrow-transplant recipients
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We describe the successful eradication of EBV-associated lymphoproliferative disorders in five . . .
Objective: To examine the impact of bone marrow transplantation (BMT), using high-dose chemotherapy and hyperfractionated total body irradiation, on gonadal function in survivors of acute leukemia ...treated during childhood.
Study design: We conducted a retrospective study of 33 subjects (17 boys) who underwent a BMT for acute leukemia (acute lymphoblastic leukemia, n = 20; acute myelogenous leukemia, n = 13) at a single institution. All patients were prepubertal at the time of BMT (median age, 7.1 years 3.7 to 11.6 years); at the time of their last examination the boys were a median of 14 years (10.4 to 17.1 years) of age and the girls were a median of 16.9 years (9.5 to 21.9 years) of age.
Results: Of 17 boys, 14 (82%) entered puberty spontaneously and 13 demonstrated age-appropriate plasma concentrations of testosterone. Two boys (aged 10.5 and 11 years) remain clinically and hormonally prepubertal, and one boy has overt Leydig cell failure requiring androgen replacement therapy. Thirty-six percent of pubertal boys have elevated plasma concentrations of luteinizing hormone and 64% have raised levels of follicle-stimulating hormone. Boys with increased levels of luteinizing hormone were significantly younger at BMT (5.4 ± 0.8 vs 7.8 ± 0.8 years;
p = 0.024). Of 16 girls, 9 (56%) had spontaneous puberty with onset of menarche at a median age of 13 years (9.5 to 15.8 years). Though six (67%) of these nine girls have had increased plasma concentrations of luteinizing and follicle-stimulating hormones, normalization has occurred in two during a period of 4 to 7 years. The remaining seven subjects required hormone replacement because of clinical and biochemical evidence of ovarian failure. One of these subjects has recovered ovarian function after 5
½ years. Female patients with ovarian failure were significantly older at BMT compared with female patients with spontaneous puberty/menarche (8.6 ± 23 years vs 6.1 ± 1.8;
p = 0.03).
Conclusion: Our results indicate that most prepubertal boys undergoing BMT with chemotherapy and hyperfractionated total body irradiation can expect to enter and progress normally through puberty. For prepubertal girls treated with these regimens, at least 50% retain adequate ovarian function to enter puberty and menstruate regularly. (J Pediatr 1997;130:210-6)
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IJS, IMTLJ, KILJ, KISLJ, NUK, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Chimeric antigen receptor (CAR) T cells have demonstrated clinical benefit in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We undertook a multicenter clinical ...trial to determine toxicity, feasibility, and response for this therapy. A total of 25 pediatric/young adult patients (age, 1-22.5 years) with R/R B-ALL were treated with 19-28z CAR T cells. Conditioning chemotherapy included high-dose (3 g/m2) cyclophosphamide (HD-Cy) for 17 patients and low-dose (≤1.5 g/m2) cyclophosphamide (LD-Cy) for 8 patients. Fifteen patients had pretreatment minimal residual disease (MRD; <5% blasts in bone marrow), and 10 patients had pretreatment morphologic evidence of disease (≥5% blasts in bone marrow). All toxicities were reversible, including severe cytokine release syndrome in 16% (4 of 25) and severe neurotoxicity in 28% (7 of 25) of patients. Treated patients were assessed for response, and, among the evaluable patients (n = 24), response and peak CAR T-cell expansion were superior in the HD-Cy/MRD cohorts, as compared with the LD-Cy/morphologic cohorts without an increase in toxicity. Our data support the safety of CD19-specific CAR T-cell therapy for R/R B-ALL. Our data also suggest that dose intensity of conditioning chemotherapy and minimal pretreatment disease burden have a positive impact on response without a negative effect on toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01860937.
•We present results of a clinical trial that show the safety of CD19-specific CAR T-cell therapy for R/R B-ALL.•Conditioning chemotherapy dose intensity and minimal pretreatment disease burden positively impact response without increase in toxicity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
BACKGROUNDAdoptive transfer of donor-derived EBV-specific cytotoxic T-lymphocytes (EBV-CTLs) can eradicate EBV-associated lymphomas (EBV-PTLD) after transplantation of hematopoietic cell (HCT) or ...solid organ (SOT) but is unavailable for most patients.METHODSWe developed a third-party, allogeneic, off-the-shelf bank of 330 GMP-grade EBV-CTL lines from specifically consented healthy HCT donors. We treated 46 recipients of HCT (n = 33) or SOT (n = 13) with established EBV-PTLD, who had failed rituximab therapy, with third-party EBV-CTLs. Treatment cycles consisted of 3 weekly infusions of EBV-CTLs and 3 weeks of observation.RESULTSEBV-CTLs did not induce significant toxicities. One patient developed grade I skin graft-versus-host disease. Complete remission (CR) or sustained partial remission (PR) was achieved in 68% of HCT recipients and 54% of SOT recipients. For patients who achieved CR/PR or stable disease after cycle 1, one year overall survival was 88.9% and 81.8%, respectively. In addition, 3 of 5 recipients with POD after a first cycle who received EBV-CTLs from a different donor achieved CR or durable PR (60%) and survived longer than 1 year. Maximal responses were achieved after a median of 2 cycles.CONCLUSIONThird-party EBV-CTLs of defined HLA restriction provide safe, immediately accessible treatment for EBV-PTLD. Secondary treatment with EBV-CTLs restricted by a different HLA allele (switch therapy) can also induce remissions if initial EBV-CTLs are ineffective. These results suggest a promising potential therapy for patients with rituximab-refractory EBV-associated lymphoma after transplantation.TRIAL REGISTRATIONPhase II protocols (NCT01498484 and NCT00002663) were approved by the Institutional Review Board at Memorial Sloan Kettering Cancer Center, the FDA, and the National Marrow Donor Program.FUNDINGThis work was supported by NIH grants CA23766 and R21CA162002, the Aubrey Fund, the Claire Tow Foundation, the Major Family Foundation, the Max Cure Foundation, the Richard "Rick" J. Eisemann Pediatric Research Fund, the Banbury Foundation, the Edith Robertson Foundation, and the Larry Smead Foundation. Atara Biotherapeutics licensed the bank of third-party EBV-CTLs from Memorial Sloan Kettering Cancer Center in June 2015.
Background
Pneumatosis intestinalis (PI) is characterized by the presence of intramural gas in the gastrointestinal (GI) tract. The overall aim of this study was to review risk factors and outcome of ...pediatric oncology patients at our institution who developed PI.
Procedure
Patients diagnosed with PI between 2007 and 2018 were identified from ICD‐10 coding of radiology reports at Memorial Sloan Kettering Kids, a tertiary pediatric oncology center. Outcomes of interest were (a) resolution and time to resolution of PI, (b) surgical intervention within 2 weeks of diagnosis of PI, or (c) death secondary to PI. To capture the resolution of PI, we defined the “time to recovery (TTR)” as the time elapsed between date of PI diagnosis and the date of recovery.
Results
Forty‐two patients were identified. Within 30 days of diagnosis of PI, three patients had surgical intervention for PI (7%) and two patients died (5%) due to non‐PI causes. Median TTR of PI was 4.5 days (95% CI: 3–7 days). In univariable and multivariable analyses, only steroid use in the prior 30 days was significantly associated with a faster TTR of PI (HR = 2.27 95% CI: 1.17–4.41, p = .02).
Conclusions
This is the largest case series of patients with PI in the pediatric oncology population, which reveals significantly lower surgical and mortality rates than other published PI series. For the majority of patients, conservative medical management is indicated. A prospective study is warranted to define diagnosis and management guidelines for PI in the pediatric oncology population in a cooperative group setting.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Passive transfer of broadly neutralizing HIV antibodies can prevent infection, which suggests that vaccines that elicit such antibodies would be protective. Thus far, however, few broadly ...neutralizing HIV antibodies that occur naturally have been characterized. To determine whether these antibodies are part of a larger group of related molecules, we cloned 576 new HIV antibodies from four unrelated individuals. All four individuals produced expanded clones of potent broadly neutralizing CD4-binding-site antibodies that mimic binding to CD4. Despite extensive hypermutation, the new antibodies shared a consensus sequence of 68 immunoglobulin H (IgH) chain amino acids and arise independently from two related IgH genes. Comparison of the crystal structure of one of the antibodies to the broadly neutralizing antibody VRC01 revealed conservation of the contacts to the HIV spike.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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