To the Editor: Glanzmann thrombasthenia (GT) is characterized by the lack of platelet aggregation due to a defect in platelet membrane glycoprotein (GP) IIb/IIIa receptor [1]. Patients with GT are at risk of alloimmunization and development of anti-platelet alloantibodies including anti–human leukocyte antigen (HLA) and/or anti–GPIIb/IIIa antibodies [2-5]. Alloimmunized patients can become refractory to platelet transfusions, making bleeding management difficult [3]. Hematopoietic stem cell transplant (HSCT) is a curative option in alloimmunized patients and those with severe bleeding [6-10]. There is no standardized management strategy for severe bleeding in alloimmunized patients with GT. Management typically focuses on immunosuppressive or immunomodulatory approaches [7, 11]. Imlifidase is a novel protease enzyme that cleaves IgG molecules, leading to a rapid decline in circulating IgG-antibody titers [12-16]. The medication demonstrated efficacy in managing sensitized kidney transplant recipients with anti-HLA antibodies [12-16]. Here, we present a child with GT and anti-GPIIb/IIIa and anti-HLA alloimmunization and severe platelet refractoriness following HSCT. Our patient was diagnosed with GT at 4 months of age after platelet GP expression testing confirmed the absence of platelet GPIIb/IIIa expression. Genetic testing revealed that the patient is homozygous in the ITGB3 gene for a variant designated c. 1788del, which results in a frameshift and premature protein termination. This mutation has not been previously described in the literature. She was referred for HSCT at 4 years of age due to increased frequency of her bleeding and the severity of her bruising. Pretransplant evaluation revealed normal platelet count. No screening for anti-GPIIb/IIIa antibodies was done pre-HSCT as the patient had no prior history of platelet transfusions. The patient received umbilical cord stem cell transplant, and 4 days later developed Escherichia coli bacteremia, and required to have her first platelet transfusion (Figure 1). By Day +9, the patient had undetectable platelet count and was refractory to transfusions. Qualitative testing on Day +12 confirmed the presence of anti-GPIIb/IIIa antibodies among others. By Day +28, patient was in primary graft failure with high-titer anti-HLA-A2 antibodies. By the second week post transplant, patient developed severe bleeding requiring transfusion support [17]. Bleeding-control strategies included the use of thrombopoietin receptor agonist, romiplostim, and low-rate continuous platelet transfusion. More intensive management strategies during active bleeding included faster rate platelet transfusion (10 mL/kg over 1 hour) and the use of recombinant activated factor VII concentrate (rFVIIa). Systemic tranexamic acid infusion was used as an adjunct in the absence of contraindications. Octreotide infusion was used to manage gastrointestinal (GI) bleeding. As part of our antibody-management strategy, the patient first received two courses of high-dose intravenous immunoglobulin (IVIG). Due to the lack of platelet response, therapeutic plasma exchange (TPE) was administered for a total of seven sessions concurrently with high-dose corticosteroids. Thereafter, targeted immunotherapies with daratumumab, bortezomib, and rituximab were used, but no platelet response was attained. Given the urgency to control life-threatening bleeds, we considered the use of imlifidase [18]. After regulatory approvals, compassionate doses of the drug were provided by the manufacturer. The patient received two doses of imlifidase on Days +82 and +84 from first HSCT, which corresponded to Days −1 and +1 of the second HSCT. Imlifidase was well tolerated with no side effects. Platelet refractoriness resolved immediately, and the continuous platelet drip was discontinued (Figure 1). Testing at 4 hours and 30 days from the last dose of imlifidase confirmed the absence of anti-platelet antibodies. The patient later developed several transplant-related complications, including transplant-associated thrombotic microangiopathy (TA-TMA), graft-versus-host disease, and various infections, all of which contributed to subsequent non-antibody-mediated platelet consumption and thrombocytopenia. In addition to receiving antibody-directed therapies for management of her refractory thrombocytopenia earlier on, the patient required additional immunosuppression for management of her transplant-related complications. She unfortunately later succumbed, and passed away 220 days following her first transplant. Developing anti-platelet antibodies and severe refractoriness immediately following HSCT was unique about our case. Certain homozygous mutations in GT correlate with higher risk of antibody formation [19]. While the specific deletion variant identified in our patient was not previously reported in the literature, it is possible the identified mutation variant correlated with the severity of platelet refractoriness. Correlating molecular variants with phenotype is difficult in rare disorders such as GT. Developing both anti-HLA-A2 and anti-GPIIb/IIIa antibodies not only explained platelet refractoriness but also why our patient had primary graft failure [20, 21]. Evidence suggests that even human hematopoietic stem cells can express GPIIb/IIIa antigen [22]. The persistence of severe platelet refractoriness despite using IVIG, corticosteroids, and TPE highlighted the severity of the alloimmunization. The successful off-label use of daratumumab and bortezomib in immune thrombocytopenia (ITP) has been previously reported [23, 24]. However, patients in these reports required several prolonged courses of therapy before showing any response [23-27]. Our patient had critical bleeding justifying our search for an alternative treatment option that could offer more rapid response. The FDA granted imlifidase orphan drug designation for management of several antibody-mediated disorders, including antibody-mediated kidney transplant rejections [13-15]. Its efficacy stems primarily from its ability to rapidly degrade both plasma and extravascular pools of IgG [12-16]. The ultimate goal behind using imlifidase in our patient was to provide hemostasis and to create a time window that would permit a successful second HSCT, which was ultimately achieved. In conclusion, we report the novel and effective use of imlifidase in (a) pediatric case, (b) patient with anti-GPIIb/IIIa antibodies in GT with severe platelet refractoriness, and (c) anti-HLA antibodies pre-HSCT. The platelet refractoriness observed in our case was so severe that one has to wonder if it relates to the newly identified mutation in the patient. We acknowledge that our patient received several antibody-directed therapies prior to imlifidase including a second myeloablative conditioning regimen. However, the dramatic increase in platelet count following imlifidase administration after lack of platelet response to all other therapies proves its efficacy in IgG neutralization. The antibody therapies used prior to infusing imlifidase must have played a role in having sustained rise in platelet count in spite of the patient developing transplant-related complications known to increase platelet consumption. This report supports the need for additional research into expanding the use of imlifidase to refractory ITP, HSCT, and pediatric population. The authors of this manuscript have no conflicts of interest to declare. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
Despite significant improvement in outcomes for patients with pediatric non-Hodgkin lymphomas (NHL), relapsed disease is associated with poor long-term survival. Hematopoietic stem cell transplant (HSCT) is used to improve outcome in this setting but there are limited data in pediatric patients with NHL. We now report on 29 pediatric patients who underwent allogeneic HSCT at our institute between 1999-2013. There were 16 male and 13 female patients and the median age was 14 years (range 5-23 years). Histological categories were anaplastic large cell lymphoma (ALCL) (n=9), lymphoblastic lymphoma (LL) (n=8), diffuse large B cell lymphoma (DLBCL) (n=7), other B cell lymphomas (Burkitt's lymphoma=1, Small cell, non-Burkitt's high grade lymphoma=1, and T-cell rich, B-cell lymphoma=1), and other T-cell lymphoma (Stem cell myeloproliferative/T-cell lymphoma=1, and hepatosplenic T-cell lymphoma=1). 9 patients received grafts from matched-related donors, 8 from matched-unrelated donors, 8 from mismatched-unrelated donors and 4 from haploidentical donors. 21/29 received a myeloablative conditioning regimen (MAC) while 8/29 patients received a reduced intensity conditioning regimen (RIC). At the time of transplant, 23/28 patients were in complete remission (CR=10) or partial remission (PR=13), while 5/28 patients had persistent or progressive disease based on standard established criteria. The 3–year relapse free survival (RFS) was 59% (95%CI: 37%-75%). The overall outcomes varied based on the subtype of lymphoma: patients with ALCL had the best outcomes (9/9 patients are alive and disease free) while those with LL had the worst (1 /8 patients is alive and disease free). Relapsed/progressive disease was the cause of death for all 7 of the LL patients who died. Patients with other B-cell and T-cell lymphomas also fared well (4/7 with DLBCL and 2/3 other B-cell lymphomas and 2/2 other T-cell lymphomas are alive and disease free). Patients in CR or PR had a better OS (18/23) compared with those patients with persistent or progressive disease at time of transplant (0/5). 11/29 patients died (9 from relapse and 2 from treatment related mortality). HSCT offers the possibility of cure for patients with NHL, especially for patients with ALCL and for those patients that have a good response to re-induction therapy prior to transplant. Relapsed disease post-transplant remains a major challenge for patients with LL and for patients transplanted with non-responsive disease. Post transplant therapies to target residual disease should be evaluated in these patients.
Hematopoietic stem cell transplantation (HSCT) is the only curative option for a subset of patients with high-risk or relapsed acute lymphoblastic leukemia (ALL). Given evolving practices, it is important to continually evaluate outcomes for pediatric ALL following HSCT. Outcomes after HSCT are influenced by the type of donor used as this determines the degree and method of T cell depletion used and, consequently, specific transplant-related morbidities. We retrospectively analyzed HSCT data from our center for transplants performed between January 2008 and May 2016, comparing outcomes among different donor types. One hundred and twenty-four pediatric patients underwent HSCT from a matched sibling donor (MSD; n = 48), an unrelated matched donor (UMD; n = 56), or a haploidentical donor (n = 20). We observed a similar 3-year event-free survival (EFS) for MSD recipients (of .64) and for UMD recipients (.62), but a significantly lower EFS for recipients of haploidentical transplants (.35; P = .01). Relapse was the main cause of HSCT failure and was significantly higher in the haploidentical donor group (.47 versus .19 for MSD and .24 for UMD; P = .02). Treatment-related mortality was evenly distributed among the donor groups (.17, .16, and .15 for the MSD, UMD, and haploidentical groups, respectively). Rates of infection-related mortality were lower than previously reported. Relapse is the main obstacle for successful HSCT in the contemporary era, and this effect is most evident in recipients of haploidentical donor grafts. Newer methods to improve graft-versus-leukemia effect are being evaluated and will need to be incorporated into the management of high-risk patients.
specificdata supports this theory. Our study revealed a lower incidence of HPV disease than in other cohorts, likely related to the lowermeanageofourHPV-negativecohortandexcellentengraftment of T, B, and NK cells in our entire cohort. We propose that poor NK cell engraftment and function represents a more likely contributor to the development of severe HPV disease in our 4 patients. It is possible that pre-HSCT myeloablation improved NK cell engraftment and function, allowing for improved response to HPVexposure in later life and thus disease limitation. With improvementsinearlydiagnosisandcurativetreatmentinSCID,itis imperative to review and determine the etiology of long-term adverse events like severe HPV disease following transplant.
Abstract Relapsed ALK ‐positive ALCL often is responsive to CRZ monotherapy. The subsequent role of allogeneic HCT after achieving second remission is poorly understood. We report 6 children who underwent allogeneic HCT for relapsed ALCL after CRZ . Age at transplant ranged from 10.7 to 22.6 years. Follow‐up ranged from 0.9 to 4.5 years. All patients engrafted. Three of 4 patients that received a reduced‐toxicity conditioning regimen containing fludarabine, alemtuzumab, and low‐dose irradiation showed progressive mixed chimerism. Five patients remain in remission. One patient developed isolated CNS relapse 3.6 years after HCT despite a lack of previous CNS involvement. No acute transplant‐related complications were experienced. One patient developed chronic renal disease secondary to transplant‐associated microangiopathy and one patient chronic GVHD secondary to DLI . Ultimately, allogeneic HCT appears safe and potentially curative after remission induction with CRZ . The role of conditioning therapy, ablative or reduced intensity, remains uncertain for patients’ post‐ CRZ monotherapy, and further studies may be warranted.
We describe here a case of Purtscher-like retinopathy (PLR) linked with Hematopoietic Stem Cell Transplant (HSCT) associated thrombotic microangiopathy (TA-TMA). TA-TMA causes endothelial damage and results in micro-thrombi in capillaries and arterioles. PLR is associated with micro-thrombi that occlude the retinal arteries and cause retinal injury. This report describes the clinical course for PLR which has similar features to and can mimic hypertensive retinopathy.
Recurrence of hematological malignancies is one of the most common indications for a second hemotopoeitic stem cell transplant (HSCT). However there are limited outcomes data after second HSCT in pediatric patients. We report the results of second HSCT in 42 patients with relapsed lymphoid (n-12) or myeloid (n-30) malignancies after first HSCT performed at our institution between 2000-2012. The median age at the time of the second transplant was 7 years (range: 2-19 years). 20/42 patients had active disease at the time of second transplant. The median time to relapse after a first transplant was 242 days (range: 138d-731d) for lymphoid malignancies and 202.5days (range: 50d-1687d) for myeloid malignancies. 20/42 received a haplo-identical donor (haplo), 19/42 received a matched or mismatched unrelated donor (MUD/MMUD) and 3/42 received a matched or mismatched related donor (MRD/MMRD). 16 patients had myeloablative conditioning and 26 reduced intensity conditioning. Overall survival and disease free survival (DFS) were 30% (13/42) and 26% (11/42), respectively with a median follow up of 1496 days (range: 37d-3434d). 5/16 of these survivors had received myeloablative conditioning versus 6/26 who received reduced intensity conditioning. The DFS by disease type was 16% (2/12) for lymphoid and 30% (9/30) for myeloid malignancies (MDS/AML, n=6/10; AML, n=2/17; biphenotypic, n=1/1), respectively. Patients with MDS/AML had better outcome than patients with AML alone. Survival also varied according to donor type (7/20 haplo, 4/19 MUD/MMUD, and 0/3 MRD/MMRD). Of the 11 disease free survivors, 8 were in remission at the time of the second transplant and 9 had relapsed >240 days post transplant. Overall median survival was 4.6 years (range: 0.2-9.7 years). The primary cause of death was relapse/persistent disease in 24/42 or infection/ GVHD in 7/42. Additionally, 7 of these patients underwent a third HSCT for relapsed disease after second HSCT and all 7 had active disease at time of third transplant. No patients survived after a third transplant. Hence 26% of relapsed patients may be long term disease free survivors after a second HSCT from a haploidentical or unrelated donor. Patients transplanted in full remission with relapse >240 days after first HSCT and a diagnosis of MDS/AML are likely to be favorable prognostic factors.
We have previously shown that small numbers of ex vivo-expanded trivirus-specific T-cells (tVSTs) targeting EBV, CMV, and Adv are safe, effective and protective in vivo. However, broader implementation is limited by a manufacturing process that is prolonged (8-12wks), complex and requires infectious virus (EBV) and vector (Adv). Moreover, antigenic competition limits extension to additional viruses. We have now made T-cell lines with activity against 5 common post-transplant viruses (EBV, CMV, Adv, BK, HHV6), using a simplified 10-day procedure that excludes viral components, and show that a single line can be clinically effective against multiple viruses. With NHLBI-PACT support 45 clinical-grade pentavalent (p)VSTs have been generated. By exposing 30x106 PBMCs to overlapping peptide libraries spanning Adv (Hexon, Penton), CMV (pp65, IE1), EBV (LMP2, EBNA1, BZLF1), BK (Large T, VP1) and HHV6 (U11, U14, U90) antigens we expanded a median of 345x106 cells (range 99-825x106) over 9-11 days. The lines were polyclonal, comprising both CD4+ (58±5%) and CD8+ (34±5%) cells, that expressed activation and memory markers. pVST specificity was dependent on the donor's prior viral exposure; 42/45 lines had Adv activity (Hexon: 453±159; Penton: 367±199 SFC/2x105), 24/45 against CMV (IE1: 315±135; pp65: 969±442), 34/45 against EBV (LMP2: 145±78; EBNA1: 115±46; BZLF1: 106±78), 24/45 against BK (Large T: 139±65; VP1: 223±93) and 26/45 against HHV6 (U90: 114±82; U11: 38±17; U14: 90±27). None of the lines reacted against recipient cells. To date 11 allogeneic HSCT recipients have received 0.5-2x107 pVSTs/m2 without adverse events. Three patients received the cells prophylactically and remained infection free up to 3 months post-pVSTs. The other 8 patients were treated for one or more active infections. Based on viral load measurements a single infusion successfully controlled active infections associated with all our targeted viruses: CMV (2 CR, 1 PR); EBV (4 CR, including a frank PTLD case); Adv (1 CR); HHV6 (2 CR) and BK (4 CR, 1 PR, 1 NR). Of note, all 3 patients with BK hemorrhagic cystitis had marked improvement/disappearance of hematuria post-pVSTs. One subject had transient but severe bladder pain with inflammation, seen on cytoscopy, and a 6-log fall in urine BK viral load with detection of BK-specific T-cells in his bladder. Our only partially non-responding patient had 3 viral infections (EBV, HHV6, BK) and cleared EBV and HHV6 but not BK following the infusion of a line that lacked specificity for this virus, likely reflecting the seronegative status of the donor. Thus, infusion of pVSTs has been safe and clinically effective against up to four simultaneous/sequential infections in a single HSCT recipient. We are currently extending this platform to include other clinically relevant viruses and are planning to assess the activity of "off the shelf" 3rd party pVSTs for broader implementation.
