Gulsun Karasu

The minimum required level of donor chimerism in hereditary hemophagocytic lymphohistiocytosis

Reduced-intensity conditioning has improved survival after hematopoietic stem cell transplantation (HSCT) for hemophagocytic lymphohistiocytosis (HLH) at the cost of more frequent mixed chimerism. The minimum level of donor chimerism (DC) required to prevent HLH reactivation in humans remains to be determined. In a multicenter retrospective study, 103 patients transplanted for hereditary HLH (2000-2013) and DC permanently or transiently <75% (overall, CD3(+), CD56(+)) were analyzed regarding DC, specific immunologic function, occurrence of systemic reactivations (≥5/8 HLH criteria), partial systemic flares (<5 criteria and HLH-directed treatment), isolated central nervous system reactivations, and management. Recurrence was reported in 18 patients (systemic reactivation n = 11, partial flare n = 3, isolated central nervous system reactivation n = 4). Ten events occurred during profound immune suppression before day 180 (median DC, 10%; range, 1-100%; CD3(+) if available, otherwise overall DC), which renders a differentiation between secondary post-HSCT HLH and HLH related to the genetic defect difficult. Eight events occurred between 0.5 and 6.7 years post-HSCT (median DC, 13%; range, 0-30%). In 5 patients, overall and lineage-specific DC were ≤10% for >6 months (median, 5.1; range, 1.1-10 years) without reactivation. A second HSCT was performed in 18 patients (median, DC 4%; range, 0-19%). Death from reactivation occurred in 4 patients (22% of recurrences). Six patients died of transplant complications following a second HSCT (33% of second HSCT). We conclude that a DC >20%-30% is protective against late reactivation. Lower levels do not, however, inescapably result in recurrences. The decision for or against second HSCT must be based on a thorough risk assessment.

Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders

Background: Rare DNA breakage repair disorders predispose to infection and lymphoreticular malignancies. Hematopoietic cell transplantation (HCT) is curative, but coadministered chemotherapy or radiotherapy is damaging because of systemic radiosensitivity. We collected HCT outcome data for Nijmegen breakage syndrome, DNA ligase IV deficiency, Cernunnos–XRCC4‐like factor (Cernunnos‐XLF) deficiency, and ataxia‐telangiectasia (AT). Methods: Data from 38 centers worldwide, including indication, donor, conditioning regimen, graft‐versus‐host disease, and outcome, were analyzed. Conditioning was classified as myeloablative conditioning (MAC) if it contained radiotherapy or alkylators and reduced‐intensity conditioning (RIC) if no alkylators and/or 150 mg/m2 fludarabine or less and 40 mg/kg cyclophosphamide or less were used. Results: Fifty‐five new, 14 updated, and 18 previously published patients were analyzed. Median age at HCT was 48 months (range, 1.5‐552 months). Twenty‐nine patients underwent transplantation for infection, 21 had malignancy, 13 had bone marrow failure, 13 received pre‐emptive transplantation, 5 had multiple indications, and 6 had no information. Twenty‐two received MAC, 59 received RIC, and 4 were infused; information was unavailable for 2 patients. Seventy‐three of 77 patients with DNA ligase IV deficiency, Cernunnos‐XLF deficiency, or Nijmegen breakage syndrome received conditioning. Survival was 53 (69%) of 77 and was worse for those receiving MAC than for those receiving RIC (P = .006). Most deaths occurred early after transplantation, suggesting poor tolerance of conditioning. Survival in patients with AT was 25%. Forty‐one (49%) of 83 patients experienced acute GvHD, which was less frequent in those receiving RIC compared with those receiving MAC (26/56 [46%] vs 12/21 [57%], P = .45). Median follow‐up was 35 months (range, 2‐168 months). No secondary malignancies were reported during 15 years of follow‐up. Growth and developmental delay remained after HCT; immune‐mediated complications resolved. Conclusion: RIC HCT resolves DNA repair disorder–associated immunodeficiency. Long‐term follow‐up is required for secondary malignancy surveillance. Routine HCT for AT is not recommended.

Idiopathic hyperammonemia after hematopoietic stem cell transplantation: A case report.

IHA is characterized by a sudden increase in plasma ammonia levels in the absence of any identifiable causes, which mostly results in intractable coma and high mortality. It has been reported in some patients after receiving intensive chemotherapy for hematological malignancy or HSCT. We describe a case of a patient with FA that developed acute idiopathic hyperammonemia after the preparative regimen for HSCT.

Haploidentical hematopoietic stem cell transplantation with post‐transplant high‐dose cyclophosphamide in high‐risk children: A single‐center study

Recently, haploidentical transplantations have been performed with unmanipulated BM or PBSC. This approach is becoming more widely adopted with the use of PTCY. However, there is limited evidence about this approach in children. We present 15 children who received 16 haploidentical HSCT with unmanipulated BM or PBSC using PTCY for GVHD prophylaxis. Post‐transplant CY(50 mg/kg IV) was given on the third and fifth day, and CsA or tacrolimus with MMF or MP was also used for GVHD prophylaxis. All patients engrafted at a median of 16 and 18 days for neutrophil and thrombocyte recovery, respectively. Grades II–III acute GVHD developed in seven patients, and mild chronic GVHD was found in two patients. Two patients died within the first 100 days due to sepsis (TRM 12.5%). Eleven patients are currently alive, with a median follow‐up of 12 months (range 6–22 months). The 12‐month OS and DFS were 75 ± 10.8% and 68.8 ± 11.6%, respectively. Our results with these high‐risk patients are encouraging for haploidentical HSCT in pediatric patients. Future studies should continue to assess haploidentical HSCT, including comparison of other modalities, in a primary pediatric population.

Outcome of autologous hematopoietic stem cell transplantation in children and adolescents with relapsed or refractory Hodgkin's lymphoma.

This study evaluates the outcome of 66 pediatric patients with rrHL who underwent autoHSCT. Twenty‐nine patients experienced early relapse, and 19 patients experienced late relapse. Of 18 newly diagnosed with HL, 13 were primary refractory disease and five had late responsive disease. At the time of transplantation, only 68% of the patients were chemosensitive. The majority of patients received BCNU + etoposide + ara‐C + melphalan for conditioning (45/66), and peripheral blood (56/66) was used as a source of stem cells. After a median follow‐up period of 39 months, 46 patients were alive. At five yr, the probabilities of OS, EFS, the relapse rate, and the non‐relapse mortality rate were 63.1%, 54.3%, 36.4%, and 9.1%, respectively. The probability of EFS in chemosensitive and chemoresistant patients at five yr was 72.3% and 19%, respectively (p < 0.001). Multivariate analysis showed that chemoresistant disease at the time of transplantation was the only factor predicting limited both OS (hazard ratio = 4.073) and EFS (hazard ratio = 4.599). AutoHSCT plays an important role for the treatment of rrHL in children and adolescents, and survival rates are better for patients with chemosensitive disease at the time of transplantation.

Risk factors predicting the survival of pediatric patients with relapsed/refractory non-Hodgkin lymphoma who underwent hematopoietic stem cell transplantation: a retrospective study from the Turkish pediatric bone marrow transplantation registry

Abstract We examined outcomes of 62 pediatric patients with relapsed or refractory non-Hodgkin lymphoma (rr-NHL) who underwent hematopoietic stem cell transplantation (HSCT). The overall survival (OS) and event-free survival (EFS) rates were 65% and 48%, respectively. Survival rates for patients with chemosensitive disease at the time of HSCT were significantly higher than those of patients with chemoresistant disease (69% vs. 37%, p = .019 for OS; 54% vs. 12%, p < .001 for EFS; respectively). A chemoresistant disease at transplantation was the only factor that predicted a limited OS (hazard ratio = 10.00) and EFS (hazard ratio = 16.39) rates. Intensive chemotherapy followed by HSCT could be an effective strategy for treating children with rr-NHL and may offer improved survival for a significant group of pediatric patients, particularly those with chemosensitive disease at transplantation.

Three relapses after a haploidentical transplantation in a pediatric patient: Cure with no further transplantation.

Isolated extramedullary relapse (EMR) after hematopoietic stem cell transplantation (HSCT) is a highly fatal condition that creates uncertainty regarding treatment options. Although certain approaches such as repeat HSCT and donor lymphocyte infusion are recommended, we report a patient with acute lymphoblastic leukemia who had three isolated EMRs after HSCT at different locations and at different times that were responsive to local and systemic therapies, without the need for a second transplantation.

Extracorporeal photopheresis did not prevent the development of an autoimmune disease: myasthenia gravis.

Myasthenia gravis (MG) is a neuromuscular disorder characterized by an autoimmune defect in the neuromuscular junction. In most patients, the autoimmune attack is mediated by antibodies against the acetylcholine receptor (AChR) on the postsynaptic membrane. Deficient immunoregulation, including regulatory T cells, is consistently observed. Extracorporeal photopheresis (ECP) leads to the induction of regulatory T cells that mediate immunologic tolerance in autoimmune diseases; however, the data regarding MG are very limited.

International study on outcomes of Haematopoietic Stem Cell transplant for DNA-DSB repair defects

Introduction: Initial trough Cyclosporine A (CsA) blood level can infl uence incidence of GVHD and relapse in patients with acute leukemia. We sought to evaluate the impact of initial CsA level (CSA-1) on the incidence of acute and chronic GVHD, relapse and survival and also explore factors that may aff ect CSA-1. Materials (or patients) and Methods: All patients who underwent allogeneic stem cell transplant (ASCT) for acute leukemia from January 2008 to March 2013 were included in this retrospective study. GVHD prophylaxis used was CsA (starting dose 1.5 mg/kg twice daily) from day -1 in combination with either methotrexate (MTX) or mycophenolate mofetil (MMF). CSA-1 was measured on day 4 or day 5 of starting CsA. Dose of CsA was modifi ed depending on CSA-1 to achieve therapeutic level of 150-200 ng/ml. For analysis, patients were divided into three groups based on modifi cation of CsA dose Group A (dose escalated), Group B (dose de-escalated) and Group C (dose unchanged). Comparisons were done between 3 groups for baseline characteristics, incidence of acute and chronic GVHD, incidence of relapse, transplant related mortality (TRM), relapse free survival (RFS) and overall survival (OS). Comparison between 3 groups was done by using chi-square test and survival outcomes by Kaplan Meier method. Multivariate analysis to determine factors predicting CsA dose escalation or de-escalation was done using logistic regression. Results: Seventy-four patients underwent 77 transplants; AML52, ALL-23, biphenotypic-2; 42 in CR1, 20 in CR2, 15 in relapsed/ refractory state; 65 from matched related, 10 from matched unrelated and 2 from haploidentical donors. Source of stem cells was peripheral blood in 70, bone marrow in 5 and cord blood in 2 transplants. The median age was 30 years (range 6-51). Conditioning regimen was full intensity (FI) i.e. TBI-Cy or Bu-Cy in 42 and reduced intensity (RI) i.e. fl udarabine based in 35 transplants. Total body irradiation (TBI) was used in 32 patients. GVHD prophylaxis was CsA+MTX in 53 and CsA+MMF in 24 patients. There were 27 patients in group A, 13 in group B and 37 in group C. On univariate analysis, use of FI regimen, cyclophosphamide and TBI; and Body Mass Index (BMI) <22 kg/m2 were associated with lower CSA-1 while use of fl udarabine, RI regimen and BMI>22 kg/m2 were associated with higher CSA-1. On multivariate analysis, fl udarabine use and BMI>22 kg/m2 predicted for higher CSA-1 requiring CsA dose de-escalation (P=0.038 and 0.034 respectively). Incidence of all grade and grade II-IV acute GVHD was 48% and 11% in group A, 38% and 31% in group B, and 43% and 19% in group C respectively (P= NS). Incidence of chronic GVHD was 52% in group A, 38% in group B and 57% in group C (P=NS). Incidence of relapse was 41% in group A, 23% in group B and 32% in group C (P= NS). TRM was 7% in group A, 38% in group B and 11% in group C (P= NS). OS and RFS at 4 years was 33% and 29% in group A, 43% and 46% in group B, and 53% and 45% in group C respectively (P=NS). Discussion: BMI <22 kg/m2 is associated with lower CSA-1 requiring CsA dose escalation. Use of fl udarabine based conditioning and BMI>22 kg/m2 is associated with higher CSA-1 requiring CsA dose de-escalation. Transplant outcomes including rates of acute and chronic GVHD, TRM, relapse incidence and overall survival are not signifi cantly aff ected by initial CsA level. Disclosure of Interest: None Declared.