Tisagenlecleucel therapy has shown promising efficacy for relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, relapses occur in 30-50% of patients. ...Determinants for CD19
versus CD19
relapses are poorly characterized. We report on 51 patients with R/R BCP-ALL (median age 17 years) infused with tisagenlecleucel after lymphodepletion. Complete remission rate at D28 was 96%. Prior blinatumomab increased the risk of early failure at D28. The 18-month cumulative incidence of relapse (CIR), event-free survival (EFS), and overall survival (OS) were 51%, 44%, and 74%, respectively, at a median follow-up of 15.5 months. Factors associated with a high tumor burden (occurrence of cytokine release syndrome) and prior blinatumomab were associated with an increased CIR, and a shorter EFS and OS. Pre-lymphodepletion high disease burden (MRD ≥ 10
, SHR 10.4, p = 0.03) and detectable MRD at D28 (SHR 7.2, p = 0.006) correlated with an increased risk of CD19
relapse. Low disease burden (SHR 5.3, p = 0.03) and loss of B-cell aplasia (BCA) (SHR 21.7, p = 0.004) predicted an increased risk of CD19
relapses. These data highlight the impact of prior therapy on patient outcome. Finally, detectable MRD at D28 and loss of BCA both define patients at high risk of relapse for whom additional interventions are needed.
Allogeneic stem cell transplantation remains the only curative treatment for sickle cell anemia (SCA), but the place of myeloablative conditioning in the procedure remains to be defined. The aim of ...the present study was to analyze long-term outcomes, including chimerism, SCA-related events and biological data (hemoglobin, reticulocytes, HbS%), and fertility in a French series of 234 SCA patients under 30 years of age who, from 1988 to 2012, received a matched-sibling-donor stem cell transplantation following standardized myeloablative conditioning busulfan, cyclophosphamide and rabbit antithymocyte globulin (ATG). Since the first report of the series (1988-2004), 151 new consecutive patients with SCA have been similarly transplanted. Considering death, non-engraftment or rejection (donor cells <5%) as events, the 5-year event-free survival was 97.9% (95% confidence interval: 95.5-100%), confirming, since the year 2000, an at least 95% chance of cure. In the overall cohort (n=234, median follow up 7.9 years), event-free survival was not associated with age, but chronic-graft-
-host disease (cGvHD) was independently associated with recipient's age >15 years (hazard ratio=4.37;
=0.002) and lower (5-15
20 mg/kg) ATG dose (hazard ratio=4.55;
=0.001). At one year, 44% of patients had mixed chimerism (5-95% donor cells), but those prepared with ATG had no graft rejection. No events related to SCA occurred in patients with mixed chimerism, even those with 15-20% donor cells, but hemolytic anemia stigmata were observed with donor cells <50%. Myeloablative transplantation with matched-sibling donor currently has a higher event-free survival (98%) in patients under 30 years of age than that reported for non-myeloablative conditioning (88%). Nevertheless, the risk of cGvHD in older patients and the need to preserve fertility might be indications for a non-myeloablative conditioning.
Introduction
The preservation of fertility is an integral part of care of children requiring gonadotoxic treatments for cancer or non‐malignant diseases. In France, the cryopreservation of ovarian ...tissue has been considered and has been offered as a clinical treatment since its inception. The aim of this study is to review 20 years of activity in fertility preservation by ovarian tissue cryopreservation (OTC) for children and the feasibility of oocyte isolation and cryopreservation from the ovarian tissue at a single center.
Material and methods
Retrospective study including patients aged 15 years or younger who underwent OTC, combined for some with oocyte cryopreservation of isolated oocytes, before a highly gonadotoxic treatment for malignant or non‐malignant disease was initiated. We describe the evolution of activities in our program for fertility preservation and patient characteristics at the time of OTC and follow up.
Results
From April 1998 to December 2018, 418 girls and adolescents younger than 15 years of age underwent OTC, representing 40.5% of all females who have had ovarian tissue cryopreserved at our center. In all, 313 patients had malignant diseases and 105 had benign conditions. Between November 2009 and July 2013, oocytes were isolated and also cryopreserved in 50 cases. The mean age of patients was 6.9 years (range 0.3‐15). The most frequent diagnoses in this cohort included neuroblastoma, acute leukemia and hemoglobinopathies; neuroblastoma being the most common diagnosis in very young patients. During follow up, three patients requested the use of their cryopreserved ovarian tissue. All had undergone ovarian tissue transplantation, one for puberty induction and the two others for restoring fertility. So far, no pregnancies have been achieved. Eighty‐four patients who had OTC died.
Conclusions
Ovarian tissue cryopreservation is the only available technique for preserving fertility of girls. To our knowledge this is the largest series of girls and adolescents younger than 15 years so far reported on procedures of OTC before highly gonadotoxic treatment in a single center.
There is little data on the long-term respiratory development of children after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We describe the respiratory assessment 10 years after ...allo-HSCT of 35 children transplanted between 2000 and 2004. During this period, 90 children were transplanted at our center. Twenty-five children died, thirty were lost to follow-up, and thirty-five came to have a pulmonary investigation. The thirty-five participants answered a questionnaire asking if they had pulmonary symptoms, and pulmonary function tests (PFTs) were performed. The median age of these children 10 years after the transplant was 16 years old. Just over a third of them had pulmonary symptoms. Among them, 5/13 (38%) had bronchiolitis obliterans syndrome (BOS). The majority of children (62.8%) did not have respiratory symptoms. PFTs were abnormal in one-third of asymptomatic children, revealing restrictive lung disease that was always mild to moderate (
p
= 0.02).
Conclusion
: In the long term, research at the time of the medical examination for the presence of chronic cough, shortness of breath on exertion, or wheezing helps to guide the clinician as to the need for further lung exploration. Similarly, informing patients and their families about these symptoms, which can be underestimated, should allow for more specific management.
What is Known:
• Pulmonary complications are a major cause of hematopoietic stem cell transplantation (HSCT) morbidity and mortality.
• A long time after allogeneic HSCT, pulmonary function tests abnormalities may occur in children, but it is not always related to symptoms.
What is New:
• The occurrence of respiratory symptoms: cough, dyspnea on exertion, chronic bronchitis, and wheezing should be systematically investigated in the follow-up of allografted patients, even at a distance.
• The presence of respiratory symptoms should lead to a respiratory functional investigation to detect the presence of an obstructive syndrome.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the ...lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Digestive graft-versus-host disease (GVHD) is a frequent complication after bone marrow transplantation, but small bowel obstruction is an extremely rare event. We present herein the first pediatric ...series of 4 cases of small bowel obstruction after bone marrow transplantation with detailed gross, histological data and their genetic status of the NOD2 gene. All patients had a history of severe acute GVHD treated by immunosuppressive agents and/or infliximab (in 3 cases). Acute or progressively worsening abdominal pain accompanied by small bowel occlusion occurred 5-16 months after graft, and computed tomographic scan revealed multiple small intestinal stenoses. Failure of intensive medical treatment led to surgical resection of affected loops. Stigmata of acute (apoptosis of crypts and satellitosis) and chronic GVHD features (submucosal fibrosis and serosae sclerolipomatosis), as well as extensive ulcerations, were observed in all ileal specimens. NOD2 mutation was found in only 1 patient. The follow-up showed successful outcome after surgery.
•This is the first pediatric series of 4 cases of small bowel obstruction after BMT.•Small bowel stenosis should be considered as a manifestation of intestinal chronic GVHD.•Pediatric patients may also benefit from surgical treatment of refractory intestinal stenosis.
Asparaginase is an essential component of combination chemotherapy for childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma. The value of asparaginase was further addressed in a group of ...non-very high-risk patients by comparing prolonged (long-asparaginase)
standard (short-asparaginase) native
asparaginase treatment in a randomized part of the phase III 58951 trial of the European Organization for Research and Treatment of Cancer Children's Leukemia Group. The main endpoint was disease-free survival. Overall, 1,552 patients were randomly assigned to long-asparaginase (775 patients) or short-asparaginase (777 patients). Patients with grade ≥2 allergy to native
asparaginase were switched to equivalent doses of
or pegylated
asparaginase. The 8-year disease-free survival rate (±standard error) was 87.0±1.3% in the long-asparaginase group and 84.4±1.4% in the short-asparaginase group (hazard ratio: 0.87;
=0.33) and the 8-year overall survival rate was 92.6±1.0% and 91.3±1.2% respectively (hazard ratio: 0.89;
=0.53). An exploratory analysis suggested that the impact of long-asparaginase was beneficial in the National Cancer Institute standard-risk group with regards to disease-free survival (hazard ratio: 0.70;
=0.057), but far less so with regards to overall survival (hazard ratio: 0.89). The incidences of grade 3-4 infection during consolidation (25.2%
14.4%) and late intensification (22.6%
15.9%) and the incidence of grade 2-4 allergy were higher in the long-asparaginase arm (30%
21%). Prolonged native
asparaginase therapy in consolidation and late intensification for our non-very high-risk patients did not improve overall outcome but led to an increase in infections and allergy.
Background
Hyperammonemic encephalopathy caused by
Ureaplasma
spp. and
Mycoplasma hominis
infection has been reported in immunocompromised patients undergoing lung transplant, but data are scarce in ...patients with hematological malignancies.
Case Presentation
We describe the cases of 3 female patients aged 11–16 years old, developing initially mild neurologic symptoms, rapidly evolving to coma and associated with very high ammonia levels, while undergoing intensive treatment for acute leukemia (chemotherapy: 2 and hematopoietic stem cell transplant: 1). Brain imaging displayed cerebral edema and/or microbleeding. Electroencephalograms showed diffuse slowing patterns. One patient had moderate renal failure. Extensive liver and metabolic functions were all normal.
Ureaplasma
spp. and
M. hominis
were detected by PCR and specific culture in two patients, resulting in prompt initiation of combined antibiotics therapy by fluoroquinolones and macrolides. For these 2 patients, the improvement of the neurological status and ammonia levels were observed within 96 h, without any long-term sequelae.
M. hominis
was detected post-mortem in vagina, using 16S rRNA PCR for the third patient who died of cerebral edema.
Conclusion
Hyperammonemic encephalopathy linked to
Ureaplasma
spp. and
M. hominis
is a rare complication encountered in immunocompromised patients treated for acute leukemia, which can lead to death if unrecognized. Combining our experience with the few published cases (n=4), we observed a strong trend among female patients and very high levels of ammonia, consistently uncontrolled by classical measures (ammonia-scavenging agents and/or continuous kidney replacement therapy). The reversibility of the encephalopathy without sequelae is possible with prompt diagnosis and adequate combined specific antibiotherapy. Any neurological symptoms in an immunocompromised host should lead to the measurement of ammonia levels. If increased, and in the absence of an obvious cause, it should prompt to perform a search for
Ureaplasma
spp. and
M. hominis
by PCR as well as an immediate empirical initiation of combined specific antibiotherapy.
From the Hôpital Henri Mondor, Créteil (SM); France Greffe de Moelle (FGM), Saint Denis (M-LB-A); Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC), Saint Denis (ZC); Hôpital ...Haut Lévêque, Pessac (J-MB); Hôpital Debrousse, Lyon (CG); Hôpital Robert Debré, Paris (KY); Hôpital de Brabois, Nancy (PB); Hôpital Charles Nicolle, Rouen (AM-C); Hôpital Hotel Dieu, Nantes (NM); Hôpital Hôtel Dieu, Clermont Ferrand (JK); Hôpital Necker Adultes, Paris (NM); Hôpital Saint-Louis, Paris, France (GS)
Correspondence: Sébastien Maury, M.D., Ph.D., Service dHématologie, Hôpital Henri, Mondor, 51, Avenue du Mal de Lattre, de Tassigny, 94010 Créteil, France. E-mail: sebastien.maury{at}hmn.aphp.fr
Background and Objectives: Severe acquired aplastic anemia (SAA) is a potentially fatal bone marrow failure syndrome occurring mainly in children and young adults. Immunosuppressive regimens and hematopoietic stem cell transplantation (HSCT) are the only two available curative treatments. Patients who lack an HLA-identical sibling donor may receive HSCT from an unrelated donor, a strategy historically associated with high mortality rates. Thus, for patients refractory to immunosuppressive regimens, the decision to transplant stem cells from unrelated donors is weighed against supportive care and often represents a dilemma for physicians. We aimed to determine whether outcome after unrelated HSCT has improved in recent years and, if so, to determine the factors responsible for the improvement.
Design and Methods: We analyzed the outcome of 89 patients (median age 17 years, range 0–52) with acquired SAA undergoing HSCT from an unrelated donor between 1989 and 2004. Cases were consecutively reported to the French Registry (SFGM-TC) by 25 centers.
Results: Patients transplanted during two successive time-periods (1989–1998 and 1999–2004) had different 5-year survival probabilities (±95% confidence interval): 29±7% and 50±7%, respectively ( p <0.01). The main difference between the two cohorts concerned HLA matching between donors and recipients at the allelic level for the ten HLA-A, -B, -C, -DRB1 and -DQB1 antigens, which was more frequent in 1999–2004 than in the former period ( p =0.0004). In multivariate analysis, the only two factors affecting survival were HLA allelic matching ( p <0.01) and younger age of recipient ( 17 years, p <0.0001). Survival reached 78±11% at 5 years for the younger, fully HLA-matched patients.
Interpretation and Conclusions: Survival after unrelated HSCT for SAA has improved significantly over the past 15 years, mainly due to better HLA matching. Results for young patients who are fully HLA-matched at the allelic level with their donor are comparable to those observed after HSCT from a related donor.
Key words: aplastic anemia, volunteer donors, HLA matching, prognostic factors.
BackgroundThe risk of radiation-induced benign and malignant thyroid nodules is well known.ObjectiveThe aim of this study was to determine the occurrence of thyroid nodules and carcinomas after ...fractionated total body irradiation (TBI) preceding hematopoietic stem cell transplantation (HSCT) for malignant hematological disease during childhood.MethodsWe conducted a retrospective university hospital-based observational study. The participants were 76 patients receiving fractionated TBI between 1989 and 2009 as part of the conditioning regimen for HSCT to treat malignant hematological disease, with a median age of 8.2 (5.7–11.4) years, for whom the last ultrasound examination was performed at a median age of 14.2 (11.2–17) years. The main outcome measure was cumulative incidence of thyroid nodules detected by ultrasound scans followed by biopsy if necessary.ResultsThyroid nodules were examined in 21 (28%) patients, six (29%) of whom were diagnosed with thyroid carcinoma at the age of 2.2–18.6 years after TBI. The cumulative incidence of nodule occurrence increased with increasing time from diagnosis. The 10-year cumulative incidence of benign and malignant thyroid nodules was 16% (95% confidence interval (CI) 4–27%) and 8% (95% CI 0–16%) respectively. Seventeen (22%) patients had hypothyroidism (compensated n=12, in five patients it was transient). No significant independent risk factors were identified in the multivariable competing risk model as a function of nodule occurrence.ConclusionShort-term and life-long monitoring, with screening for nodules of the thyroid gland using ultrasound scans, is recommended for survivors subjected to TBI for HSCT during childhood.