Matched Sibling Donor Bone Marrow Research Articles

Isolated Optic Nerve Relapse in a Pediatric Patient With T-Cell Lymphoblastic Leukemia: A Brief Report.

Isolated optic nerve (ON) relapse is a rare occurrence in lymphoblastic leukemia (LBL). A 10-year-old boy with T-LBL presented 8 months after diagnosis with blurred vision and thickening of right ON on magnetic resonance imaging consistent with relapse. Cerebrospinal fluid and bone marrow were negative for leukemia. He received reinduction chemotherapy (including nelarabine and craniospinal radiation) followed by a myeloablative matched sibling donor bone marrow transplant. He remains in remission 2 years post-transplant with normal vision. We also review the literature for reports of isolated ON relapse in patients with LBL. Our patient's clinical course demonstrates that disease control can be achieved with early detection of ON relapse before disease progression.

Reduced toxicity matched sibling bone marrow transplant results in excellent outcomes for severe congenital neutropenia.

Severe congenital neutropenia (SCN) is caused by germline mutations, most commonly in ELANE, impacting neutrophil maturation and leading to high risk of life-threatening infections. Most patients with ELANE-mutant SCN can achieve safe neutrophil counts with chronic Granulocyte-Colony Stimulating Factor (G-CSF). However, up to 10% of patients have neutropenia refractory to G-CSF and require allogeneic stem cell transplant. Traditional conditioning for these patients includes busulfan and cyclophosphamide which is associated with significant toxicities. We present five patients with SCN without myeloid malignancy transplanted using a reduced toxicity regimen of busulfan, fludarabine and thymoglobulin. 5 pediatric patients with SCN underwent matched sibling donor bone marrow transplant (MSD-BMT) between 2014-2022 on or per CHP14BT057 (NCT02928991), a prospective, single center trial testing elimination of cyclophosphamide from conditioning in pediatric patients with single lineage inherited BMF syndromes. All patients had MSDs and no evidence of MDS. Conditioning consisted of PK-adjusted busulfan, fludarabine, and thymoglobulin, with calcineurin inhibitor and mycophenolate mofetil GVHD prophylaxis. With median follow-up of 48.4 months, overall and event-free survival were 100%. There was no acute GVHD and one instance of chronic limited GVHD. Patients exhibited >95% donor myeloid chimerism at 5 years post-BMT. Two patients experienced CMV reactivation without end-organ disease, and no other viral reactivation or significant infections occurred. MSD-BMT with reduced toxicity myeloablation for SCN provides excellent outcomes while minimizing toxicity. These data suggest that busulfan, fludarabine, and ATG can be considered an efficacious, low-toxicity standard of care regimen for patients with SCN undergoing MSD-BMT.

222 - Matched Sibling Donor Bone Marrow Transplant with Busulfan + Fludarabine Conditioning Results in Excellent Outcomes for Severe Congenital Neutropenia

222 - Matched Sibling Donor Bone Marrow Transplant with Busulfan + Fludarabine Conditioning Results in Excellent Outcomes for Severe Congenital Neutropenia

Patient and Caregiver Attitudes Towards Gene Therapy for Sickle Cell Disease: A Need for Partnership and Education

Background:Fewer than 20% of patients with sickle cell disease (SCD) have access to curative matched sibling donor bone marrow transplantation (MSD-BMT). Development of novel therapies to ameliorate the serious morbidity and early mortality caused by SCD is a National Institute of Health research priority. Gene therapy for SCD has emerged as a promising approach in early-stage clinical trials approach with the potential to reach greater numbers of patients than MSD-BMT. Knowledge and attitudes of individuals with SCD towards this investigational new therapy and their willingness to participate in early-stage clinical trials have not been systematically described.Methods:Patients with SCD at least 13 years of age (n=66) and caregivers of children with SCD (n=38) were surveyed about knowledge, attitudes, and beliefs regarding gene therapy for SCD. Most questions utilized a 5-item Likert response scale while The Newest Vital Sign was used to assess health literacy. To explore attitudes around gene therapy in further detail, we identified a regionally diverse focus group comprised of 12 patients/caregivers with SCD from across the United States. We audio-recorded, transcribed verbatim, and analyzed five focus group discussions using thematic content analysis to identify salient themes related to attitudes towards gene therapy for SCD. Our goal was to identify the educational needs and preferences of this patient / caregiver stakeholder group.Results:Survey: Of the 104 survey respondents 96% identified as Black and 4% as Hispanic. Respondents were between 13-64 years (mean 29.6, Std Dev 11.9 years). HbSS and HbSC were the most common genotypes (61.5% and 24%, respectively). Only 4.8% of participants (N=5) felt “extremely knowledgeable” about gene therapy for SCD while most (63.4%) reported no/slight knowledge. We found no association between health literacy levels and gene therapy knowledge (p=0.361). Nearly 30% of participants reported that the risk of cancer as a potential side effect would “probably not prevent their enrollment” on a gene therapy trial while 48% said it “definitely/probably would preclude their participation”. Most respondents had a neutral attitude regarding the safety of gene therapy for SCD and how good of a treatment it was (56.7% and 58.6%, respectively). Only a few respondents endorsed the idea that gene therapy was “unsafe” or “not a good treatment for SCD” (5.8% and 4.8% respectively). There was an association between increasing knowledge about gene therapy and agreement that it is safe (p=0.012) and a good treatment for SCD (p=0.031).Focus Groups: Among the focus group participants, there was consensus that communication about gene therapy is suboptimal. Participants noted that clinicians frequently use medical jargon, do not tailor their approach to the individual patient/caregiver, and fail to adequately disclose important details. Focus group members desired more information about side effects and risks associated with conditioning chemotherapy, immunosuppression, risk of infertility, and hair loss. Participants, particularly parents of children with SCD, were worried about future unknown risks and described the enormity of the decision to enroll in an early-phase trial. Focus group members verbalized the need for inclusion of patients with SCD as partners during the informed consent/assent process and ideally, at the outset of the clinical trial design.Conclusion:Very few patients with SCD described feeling knowledgeable about gene therapy for SCD; a majority have neutral feelings about the safety and utility (“good treatment for SCD”) of this new approach. Patient/caregiver-centered education about gene therapy in a manner that meets stakeholder informational needs is urgently needed. Given the temporary hold on lentiviral gene therapy trials for SCD (after some participants developed a myeloid neoplasm on an industry sponsored trial in February 2021) and the risk of cancer as a probable or definite barrier to enrollment in a gene therapy trial for many patients, transparency of information about these risks is essential. For the successful execution of novel trials in SCD, a community-based participatory research approach is vital. DisclosuresSharma: Medexus Inc: Consultancy; Spotlight Therapeutics: Consultancy; Novartis: Other: Salary support paid to institution; Vertex Pharmaceuticals/CRISPR Therapeutics: Other: Salary support paid to institution; Vindico Medical Education: Honoraria; CRISPR Therapeutics: Other, Research Funding. Johnson: CRISPR Therapeutics: Research Funding.

Long Term Followup of Sickle Cell Disease Post Hematopoietic Stem Cell Transplant from Uganda

Introduction: Sickle cell disease (SCD) remains associated with high risk of morbidity and early death. Many patients in sub-Saharan Africa continue to experience severe complications despite best supportive care. Hematopoietic stem cell transplant (HSCT) can be considered for a select group of patients. When successful, HSCT is economical and improves quality of life. We report the experience from our south-south partnership whereby Ugandan patients with SCD have undergone HSCT at the Bone Marrow Transplant Center in Gurgaon, IndiaMaterial and methods: 23 consecutive patients suffering from SCD who underwent HSCT between June 2014 and July 2017 were included in the study. Eleven underwent matched sibling donor bone marrow transplant (BMT) using busulfan 3.2 mg/kg/day for 4 days, cyclophosphamid 50mg/kg/day for 4 days, and hATG (PfizerATGAM) 30mg/kg/day for 3 days. Two adult patients underwent matched sibling donor HSCT using reduced intensity conditioning with busulfan 3.2 mg/kg/day for 4 days, cyclophosphamid 60mg/kg/day for 2 days, and ATG (PfizerATGAM) 30mg/kg/day x 3 days. Immune suppression for for HSCT patients was cyclosporine 3mg/kg/day in 2 divided doses starting D-4 and methotrexate 10mg/m2 on D+1 followed by 7mg/m2 on day 3, 6 and 11 post HSCT. Ten patients underwent haploidentical HSCT using hypertransfusion (target Hb 11-13gm/dl), hydroxyurea (20mg/kg/day) and azathioprine (2mg/kg/day) from day -45, conditioned with Thiotepa 10mg/kg in two divided doses (D-7), fludarabine 30mg/m2 (D-6 to D-2), cyclophosphamide 14.5 mg/kg (D-5, D-4), TBI 2Gy with thymic shielding (D-1), rATG (Genzyme Thymoglobulin) 1.5 mg/kg (D-9 to D-7). GVHD prophylaxis included PTCy 50 mg/kg/day on D3 and 4, tacrolimus (target level 5-15 ng/ml) or sirolimus (target levels 10-15ng/ml) (till 6 months post HSCT) and MMF (till D35) starting from D5.Results: The median patient age was 8 years (range 10 months-31 years). Before transplantation all patients had repeated episodes of SCD complications warranting a transplant. All were non-responsive to hydroxyurea. Of the 23 patients, 18 survived without sickle cell disease with Lansky/Karnofsky scores of 100. One had a primary graft failure another secondary graft failure with recurrence of disease. At median follow up of 479 days (range 51-1204) the probabilities of survival, SCD-free survival, and transplant-related mortality after transplant were 87%, 78%, and 13%, respectively. Three children who underwent haploidentical HSCT died. One died due to PRES with intracranial hemorrhage at day 86 post BMT, another one due to primary graft failure with Klebsiella sepsis with shock. The third child died due to complicated falciparum malaria and possible invasive fungal infection at day 24 post HSCT. He had full donor chimerism.Conclusion: Outcomes of HSCT in SCD have improved significantly. With better conditioning regimens and improved supportive care, alternative donor transplant and adult HSCT have become viable therapeutic options. HSCT should be strongly considered as a curative modality for selected patients suffering from SCD. DisclosuresNo relevant conflicts of interest to declare.

Paediatric severe aplastic anaemia treatment: where to start?

Paediatric severe aplastic anaemia treatment: where to start?

Eculizumab to Treat Posterior Reversible Encephalopathy Syndrome Due to Underlying Transplant-Associated Thrombotic Microangiopathy in Patients Receiving Allogeneic Hematopoietic Cell Transplant for Sickle Cell Disease

Pre-existing endothelial dysfunction and vascular injury sustained during allogeneic hematopoietic stem cell transplantation (HCT) increases risk for endothelial injury-related complications like posterior reversible encephalopathy (PRES) and transplant-associated thrombotic microangiopathy (TA-TMA) in patients with sickle cell disease (SCD). Herein, we report two SCD HCT recipients in whom PRES-related symptoms resolved only after eculizumab therapy was initiated for underlying TA-TMA. Case 1 25-year-old male with SCD developed PRES-related seizures and headaches on Day+30 following matched sibling donor bone marrow transplant (BMT) and reduced-intensity conditioning (RIC) with fludarabine/melphalan/alemtuzumab and graft-versus-host disease (GvHD) prophylaxis with tacrolimus and methotrexate (MTX). Symptoms initially resolved after discontinuing tacrolimus. However, on Day+60, he presented with hypertension (HTN), status epilepticus, and right intracranial hemorrhage. Despite adequate HTN control and maximal anti-epileptic therapy, his symptoms persisted. Two weeks later, laboratory testing confirmed TA-TMA. Both PRES and TA-TMA symptoms and signs resolved after five weeks of eculizumab therapy (Figure 1). Case 2 Eight-year-old female with SCD underwent 10/10 matched unrelated BMT following RIC with fludarabine/melphalan/thiotepa/alemtuzumab and MTX/tacrolimus/abatacept for GvHD prophylaxis. She developed altered mental status, seizures, and HTN and Day+74 MRI brain confirmed PRES. Her symptoms also persisted despite tacrolimus cessation and effective HTN control. One week later, laboratory testing confirmed TA-TMA. Complete resolution of neurological symptoms occurred after three weeks of eculizumab therapy. (Figure 2). Conclusion Our cases highlight maintaining a high level of clinical suspicion for TA-TMA in SCD patients presenting with PRES post-HCT and consideration for eculizumab therapy in such patients.

Stem Cell Transplantation in Advanced Stage Sickle Cell Disease with Haploidentical T-Cell Depleted PBSC Yields Comparable Outcomes to Matched Sibling Donor Bone Marrow: Results of a Pilot Study

Background: Sickle cell disease (SCD) is an inherited disorder with an estimate of 300,000 affected newborns per year worldwide. Despite improvements in preventive measures and conventional therapy, substantial morbidity and mortality, resulting in a reduced life expectancy persist. Allogeneic hematopoietic stem cell transplantation (HSCT) with a matched sibling donor (MSD) is currently the curative standard of care. However, matched donor availability is <20% and unrelated donor (MUD) HSCT is associated with unacceptably high rates of severe graft-versus-host disease (GvHD). A T-cell depleted HSCT from a haploidentical relative (T-haplo-HSCT) expands donor availability while exhibiting low GvHD rates and thus could offer cure to the remaining 80% of SCD patients (pts).Methods: We report the results of 29 pts with advanced stage SCD transplanted with either a T-cell depleted haploidentical regimen (20 pts, median age 13 years, range 3-31 years) or with bone marrow from a matched family donor (MSD, 9 pts, median age 14, range 9-25 years). Indication for HSCT was advanced stage SCD related complications. Pts with a MSD received a bone marrow (BM) graft. Pts requiring an alternative donor were transplanted with an αß/CD19 (n=5) or CD3/CD19 (n=15) depleted graft from a haploidentical family donor. The conditioning regimen for both groups was identical except that antithymoglobulin (ATG-Neovii®) was given upfront on day -10 to -8 in T-haplo-HSCT and on day -3 to -1 in MSD. Chemotherapy consisted of thiotepa 2 x 5 mg/kg, fludarabine 4 x 40 mg/m2 and treosulfan 3 x 14 g/m2, given between days -10 and -2. Post-HSCT immunosuppression consisted of mofetil mycophenolate and tacrolimus or cyclosporine A for a duration >6 months in T-haplo-HSCT and <6 months in MSD, depending on chimerism. The MSD group received a graft containing a median of 2.4 x 108 cells/kg body weight (BW). The T-haplo-SCT group received a peripheral stem cell allograft with a median of 13.1 x 106 CD34+ cells/kg BW.Results: The conditioning regimen was well tolerated in all pts with no high-grade transplant related toxicity. The overall (OS) and disease-free survival (DFS) with a median follow-up of 17 months in 20 advanced stage mostly adolescent and adult T-haplo-HSCT pts and 22 months in 9 MSD HSCT pts was 90% vs. 100%, respectively. Engraftment was achieved in most pts with stable chimerism over 90%, except for 4 pts with a stable MC in the T-haplo SCT group and 1 patient in the MSD group off immunosuppression. All pts presented a complete BM engraftment of red cell precursors. Only one patient in the T-haplo-HSCT group with a mixed chimerism is still under immunosuppression.The post-HSCT bacterial infectious complications were comparable in both groups and the most common observed viral infections were systemic cytomegaly virus (CMV), adenovirus (ADV), polyomavirus (BKV) and Epstein Barr virus (EBV) reactivations which were successfully treated with intravenous antiviral drugs or virus specific T-cells.Two patients in the T-haplo-HSCT group achieved a DFS off immunosuppression but succumbed to post-HSCT complications. One developed a rotavirus gastroenteritis and an uncontrolled CMV pneumonitis. The other a late graft failure and succumbed to a macrophage activation syndrome.None of our pts developed a Glucksberg Grade III-IV acute GvHD and in the T-haplo SCT group 4 pts (20%) and in the MSD group 2 pts (22%) developed a steroid sensitive mild to moderate cGvHD (fasciitis/oral as well as mild cutaneous GvHD). No extensive cGvHD was observed.To our knowledge this is the largest group of advanced stage SCD pts transplanted with either a T-haplo-HSCT or a MSD approach, according to donor availability, with an almost identical regimen in a direct comparative design. These preliminary results demonstrate increasing evidence for the feasibility, safety and efficacy of a T-haplo-HSCT using CD3/CD19 or αβ/CD19 depleted grafts, in order to offer a curative option to the majority of pts with SCD. A prospective, stratified non-inferiority trial is in preparation (EudraCT number 2018-002652-33) in order to confirm these preliminary results in a large prospective cohort. DisclosuresCorbacioglu:Gentium: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria.

Assessment of Calcineurin Inhibitor-Associated Neurotoxicity in Patients with Sickle Cell Disease Receiving a Matched Sibling Donor or T-Cell Depleted Haploidentical Hematopoietic Stem Cell Transplantation

Introduction: Sickle cell disease (SCD) is one of the most prevalent monogenic hematological disorders leading to progressive multi-organ damage and reduced life expectancy despite a significant improvement of conventional and supportive care. Allogeneic hematopoietic stem cell transplantation (HSCT) with a matched sibling donor (MSD) represents currently the only curative treatment option, limited by a donor availability <20%. In a pilot study, we compared α/β/CD19 and CD3/CD19, respectively T-cell depleted haploidentical HSCT (T-haplo-HSCT) with MSD HSCT in patients (pts) with advanced stage SCD, using almost identical HSCT regimens for both donor groups.Neurotoxicity (NT) contributes significantly to HSCT-associated morbidity and mortality. Calcineurin inhibitor (CNI) related NT after HSCT is mostly caused by cyclosporine A (CsA) and tacrolimus (FK506) with an overall frequency between 4.2% - 28.8%, and severe NT in 4% - 11%, such as posterior reversible encephalopathy syndrome (PRES), seizures, visual disturbance, cortical blindness, aphasia or ataxia.Particularly in hemoglobinopathies (thalassemia, SCD) the reported incidence is around 30%, possibly also due to impaired hepatic metabolization of CsA and FK506 based on iron overload. However, also infusion modalities might impact on NT, since it was more frequently reported after 4-hours bolus injections (10.3%) than continuous infusion (3.3%). However, the excessive NT observed in SCD might be also related to the systemic vasculopathy, increasing with age and pro-inflammatory triggers after allo-HSCT.Methods: A total of 30 pts aged 3 to 31 years with homozygous SCD or HbS 0/+ ß-Thal were treated between 2012 and 2018. Nine pts received a MSD bone marrow (BM) graft, 21 pts received T-haplo-HSCT from a relative (1 second T-haplo-HSCT due to graft rejection) with a α/β CD19 or CD3/CD19 depleted graft. Post-HSCT immunosuppression consisted of either CsA in 6 MSD and 16 T-haplo-HSCT pts or FK506 in 3 MSD and 6 T-haplo-HSCT pts, both mostly in combination with mycophenolate mofetil (MMF). FK506 was administered as a 20-hours continuous infusion, while CsA was given as 4-hours bolus injections. Dosage was adjusted according to usual target levels (CsA: 120ng/ml; FK506: 7ng/ml). Duration of immunosuppression was >6 months in T-haplo-SCT and <6 months in MSD, depending on chimerism. All pts developing neurological symptoms indicative for severe CNI-related NT underwent neuroradiological imaging (MRI/CT) with consecutive symptomatic treatment as indicated.Results: Overall CNI-related NT was observed in 32.3% of our HSCT pts. Severe NT such as PRES and visual disturbance combined with aphasia was present in 16.1% (Table 1). Overall, NT was more prevalent in MSD (n=5, 55.5%) than in T-haplo-HSCT pts (n=5, 22.7%). The majority of NT events was observed under CsA prophylaxis (8/10; 80%) and in only 22% (2/9) pts with FK506. All 5 cases of severe NT, particularly all PRES, occurred on CsA. Complete recovery of neurologic symptoms was achieved in all pts spontaneously or after switching CsA to FK506 or everolimus (Table 1). Moreover, 60% of pts with NT was >18 years, and 90% >12 years suggesting an increasing risk with age while a third of patients with pre-existing NT experienced no post-HSCT NT. Of note, 4 of 5 pts with severe NT also experienced a mild acute GvHD (Table 1). The overall (OS) and disease-free survival (DFS) with a median follow-up of 17 months in T-haplo-HSCT pts and 22 months in 9 MSD HSCT pts was 90% vs. 100%, respectively.Conclusions: Our data confirm an elevated risk for NT in SCD pts following allo-HSCT. Importantly, the incidence of NT events seems to be related to age (90% of pts with NT were >12years), donor source (MSD vs. T-Haplo; 55.5% vs 22.7%) and CsA rather than FK506 (CSA 80% vs. FK506 20%). All severe NT (particularly all PRES) were observed in pts with CsA prophylaxis, while the continuous infusion of FK506 might have levelled concentration peaks. Nevertheless, the NT observed with CsA post-HSCT could be the consequence of predominantly CsA-related vascular complications inflicting systemically pre-damaged vessels of SCD pts. The mechanism of action could be similar to other systemic endotheliopathies such as sinusoidal obstruction syndrome (VOD/SOS), transplant-associated microangiopathy (TAM) and acute GvHD which was observed in 4/5 pts with severe NT, compared to an overall GvHD rate of 29%. [Display omitted] DisclosuresCorbacioglu:Gentium: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria.

Influence of Age on Acute and Chronic GVHD in Children Undergoing HLA-Identical Sibling Bone Marrow Transplantation for Acute Leukemia: Implications for Prophylaxis

Relapse remains the major cause of mortality after hematopoietic cell transplantation (HCT) for pediatric acute leukemia. Previous research has suggested that reducing the intensity of calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis may be an effective strategy for abrogating the risk of relapse in pediatric patients undergoing matched sibling donor (MSD) HCT. We reasoned that the benefits of this strategy could be maximized by selectively applying it to those patients least likely to develop GVHD. We conducted a study of risk factors for GVHD, to risk-stratify patients based on age. Patients age <18 years with leukemia who received myeloablative, T cell-replete MSD bone marrow transplantation and calcineurin inhibitor-based GVHD prophylaxis between 2000 and 2013 and were entered into the Center for International Blood and Marrow Transplant Research registry were included. The cumulative incidence of grade II-IV acute GVHD (aGVHD) was 19%, that of grade II-IV aGVHD 7%, and that of chronic GVHD (cGVHD) was 16%. Compared with age 13 to 18 years, age 2 to 12 years was associated with a lower risk of grade II-IV aGVHD (hazard ratio [HR], .42; 95% confidence interval [CI], .26 to .70; P = .0008), grade II-IV aGVHD (HR, .24; 95% CI, .10 to .56; P = .001), and cGVHD (HR, .32; 95% CI, .19 to .54; P < .001). Compared with 2000-2004, the risk of grade II-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR, .36; 95% CI, .20 to .65; P = .0007) and in 2009-2013 (HR, .24; 95% CI. .11 to .53; P = .0004). Similarly, the risk of grade III-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR, .23; 95% CI, .08 to .65; P = .0056) and 2009-2013 (HR, .16; 95% CI, .04 to .67; P = .0126) compared with those doing so in 2000-2004. We conclude that aGVHD rates have decreased significantly over time, and that children age 2 to 12 years are at very low risk for aGVHD and cGVHD. These results should be validated in an independent analysis, because these patients with high-risk malignancies may be good candidates for trials of reduced GVHD prophylaxis.

Outcomes of matched sibling donor bone marrow transplantation in children using single-agent calcineurin inhibitors as prophylaxis for graft versus host disease.

Optimal graft versus host disease (GVHD) prophylaxis prevents severe manifestations without excess immunosuppression. Standard prophylaxis includes a calcineurin inhibitor (CNI) with low-dose methotrexate. However, single-agent CNI may be sufficient prophylaxis for a defined group of patients. Single-agent CNI has been used for GVHD prophylaxis for human leukocyte antigen (HLA)-matched sibling donor (MSD) bone marrow transplants (BMTs) in young patients at the Children's Hospital of Philadelphia for over 20 years. Here, we describe outcomes using this prophylactic strategy in a recent cohort. We performed a single-institution chart review and retrospective analysis of consecutive children undergoing MSD BMT who received single-agent CNI for GVHD prophylaxis between January 2002 and December 2014. Fifty-two children with a median age of 6.1 years (interquartile range [IQR] 2.5-8.3) and donor age of 6 years (IQR 3-10), with malignant and nonmalignant diseases (n = 35 and 17, respectively) were evaluated. Forty-three (82.6%) received oral prophylaxis with single-agent tacrolimus after initial intravenous therapy. Rates of GVHD were consistent with reported rates on dual prophylaxis: the overall incidence of grades 2-4 acute GVHD was 25.5%, grades 3-4 GVHD 9.8%, and chronic GVHD 10.4%. The cumulative incidence of relapse among children with malignancy was 20% at a median of 237 days (IQR 194-318) post-transplant. Two-year overall survival was 82.7% (95% confidence interval [CI]: 69.4-90.6%) and event-free survival was 78.9% (95% CI: 65.1-87.7%). No patient experienced graft failure. Single-agent CNI is a safe, effective approach to GVHD prophylaxis in young patients undergoing HLA-identical sibling BMT. Additionally, single-agent oral tacrolimus is a reasonable alternative to cyclosporine in this population.

Influence of Age on Risk for Acute and Chronic Graft Versus Host Disease in Children Receiving HLA Identical Sibling Bone Marrow Transplantation

Introduction: In adult HLA matched sibling donor (MSD) hematopoietic cell transplantation, both recipient and donor age have been shown to be a risk factors for graft versus host disease (GVHD). While it is widely recognized that pediatric patients are at lower risk for GVHD than adults, the importance of age within the pediatric age group in MSD transplantation has not been examined. We, therefore, assessed the impact of age on GVHD risk after MSD bone marrow transplantation (BMT) in 477 pediatric patients with acute leukemia.Methods: This is a Center for International Blood and Marrow Transplantation registry study. Patients younger than 18 years with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) in 1st or 2nd complete remission (CR), who received myeloablative conditioining, T cell-replete HLA MSD BMT and calcineurin inhibitor based GVHD prophylaxis between 2000-2013 were included. Patients who received a lymphocyte depleting antibody were excluded. Because donor and recipient ages were highly correlated, their effects could not be independently assessed. We, therefore, assessed only recipient age.Results: The transplants were drawn from 101 centers. The median age of the recipients was 10.1 years. 21% had ALL in 1st CR, 24% ALL in 2nd CR, 47% AML in 1st CR and 8% AML in 2nd CR. 73% received cyclosporine and Methotrexate for GVHD prophylaxis. In a preliminary model, using grade 3-4 acute GVHD as the endpoint, we identified two cut points, 2 years and 13 years using the likelihood ratio test. In all final models, three age groups were used to define recipient age: < 2 years (n=60), 2 to 12.99 (n=255) years and 13-17.99 years (n=162). The cumulative incidence of grade 2-4 acute GVHD at 100 days post-transplant was 19% (95% confidence interval, CI, 16-23%); 24% (95% CI 14-35%), 13% (95% CI 9-18%) and 28% (95% CI 21-35%) for recipients <2 years, 2-12.99 years, and 13-17.99 years of age, respectively (p-value=0.001). For grade 3-4 acute GVHD, the cumulative incidence estimate at 100 days was 8% (95% CI 3-17%), 3% (95% CI 1-6%) and 14% (95% CI 9-20%) (p <0.001) and the cumulative incidence estimate for chronic GVHD at 1 year was 15% (95% CI 7-25%), 10% (95% CI 7-14%) and 27% (95% CI 20-34%) (p <0.001) for recipients <2 years, 2-12.99 years, and 13-17.99 years of age, respectively (Figures 1-3). In the multivariate analyses, using age 13-17.99 as the baseline and .01 as the threshold for significance, age 2-12.99 years (HR 0.43, 95% CI 0.26-0.71, p=0.001), but not age < 2 years (HR 0.59, 95% CI 0.3-1.18, p=0.14), was associated with a lower risk for grade 2-4 acute GVHD (after adjustment for GVHD prophylaxis, performance score and year of transplant). For grade 3-4 acute GVHD, again age 2-12.99 years (HR 0.24, 95% CI 0.1-0.56, p=0.001), but not age < 2 years (HR 0.75, 95% CI 0.29-1.94, p=0.55), was associated with a lower risk, after adjustment for year of transplant. For chronic GVHD (after adjustment for donor-recipient birth order, and GVHD prophylaxis), age 2-12.99 years (HR 0.32, 95% CI 0.19-0.54, p<0.001) was associated with lower risk; the effect was similar in age < 2 years, but did not reach significance (HR 0.36, 95% CI 0.16-0.82, p=0.016). Year of transplant had a strong effect on acute, but not chronic GVHD. Its effect did not appear to be mediated by changes in GVHD prophylaxis. Using 2000-2004 as the baseline, the HR for grade 2-4 acute GVHD was 0.38 (95% CI 0.20-0.64, p=0.0006) and 0.28 (95% CI 0.13-0.59, p=0.0008) for 2005-2008 and 2009-2013, respectively. For grade 3-4 acute GVHD, they were 0.23 (95% CI 0.08-0.65, p=0.0057) and 0.23 (95% CI 0.07-0.78, p=0.0183) for these periods, respectively. There was no difference in overall survival, leukemia-free survival or transplant related mortality between the age groups.Conclusion:Our results indicate that children 2-12.99 years have a lower risk for acute and chronic GVHD than those 13 years and older. Children less than 2 years may also have a reduced risk for chronic GVHD, but this possibility needs to be re-examined in a larger sample. It is plausible that pubertal changes underlie the rise in risk for GVHD during adolescence. An important limitation of our study was that we were unable to examine the impact of donor age because of the strong correlation between donor and recipient age. A study with a larger sample is also needed to further investigate this matter. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

No Effect of Birth Order on Relapse, Graft-Versus-Host Disease or Transplant Related Mortality in Matched Sibling Donor Bone Marrow Transplant in Pediatric Patients with Leukemia

Introduction: The impact of birth order of patient and donor in matched sibling hematopoietic stem cell transplantation (HSCT) has not been fully defined. It has been postulated that as a result of fetomaternal trafficking donors who are younger than the transplant patient may develop in utero tolerance to patient cells. A large registry study of adult and pediatric patients found that using a donor younger than the recipient (R>D) was associated with decreased acute GVHD; single center studies found this to be correlated with decreased relapse and improved overall survival as well. We hypothesized that in pediatric patients with hematologic malignancies and a presumed low incidence of acute GVHD that birth order would not have an impact on relapse incidence.Methods: We performed an IRB -approved retrospective chart review of consecutive patients with acute leukemia undergoing matched sibling transplant bone marrow transplantation at Dana Farber/ Boston Children’s Hospital between 1/1/2001 and 10/31/ 2013. All patients were conditioned ablatively with a Busulfan or TBI based regimen. No product underwent T cell depletion. Patients with twin donors or with secondary leukemia were excluded. Basic patient demographics were collected including development of Grade II-IV acute GVHD, relapse and transplant-related mortality (TRM). Patients were assigned a Low Risk (HSCT in 1st remission) or High Risk (all others) disease status. Patients were then divided into 2 groups: those with donor older than recipient (D>R) and those with donor younger (R>D). Chi-Square test was used to assess for significant differences in relapse between patients.Results:We reviewed 91 patients with AML or ALL. Age range was 7 months to 24 years (median 11 years). 43 patients were D>R and 48 were R>D. The overall incidence of acute GVHD (Grade II-IV) was 16 % and TRM 4%; neither was significantly different between the two cohorts. Only 1 patient experienced graft rejection (R>D/ALL). For the population as a whole the relapse incidence was not statistically different - 35% in the R>D cohort vs 25% in the D>R cohort (p=0.46). There was also no difference detected in relapse rate when AML and ALL were evaluated separately (p=0.45 and p=0.57 respectively). We also compared the relapse rate by disease risk status. While previous data (Dobbelstein, ASH abstract 2008) suggested fewer relapses in R>D patients, our data revealed a similar trend but only in high risk patients (24% vs 41%), and statistical significance was not achieved (p=0.25). For low risk patients birth order had no effect on relapse incidence (p=0.88).Conclusion:Previous studies, primarily involving adult patients, have demonstrated an effect of birth order in matched sibling transplants for hematologic malignancies. A decrease in acute GVHD when the donor in younger than recipient (R>D) has been the most consistent finding although single center studies have shown an effect on relapse rate and overall survival as well. In our single institution retrospective study of a similarly treated cohort of pediatric patients we saw no effect of birth order on GVHD, TRM or relapse. Perhaps in the pediatric setting when the incidence of significant GVHD and TRM is low, maternally induced donor tolerance or sensitization to patient cells has less impact and other factors including disease status or patient age predominate. Thus our results suggest that birth order need not be considered as an important factor in matched sibling donor selection for pediatric patients with acute leukemias. DisclosuresNo relevant conflicts of interest to declare.

Comparable Leukemia-Free Survival after Autologous Hematopoietic Cell Transplantation Versus HLA-Identical Sibling Hematopoietic Cell Transplantation for Adult Acute Myeloid Leukemia in First Complete Remission: A Registry Study By the Adult AML Working Group of the Japan Society for Hematopoietic Cell Transplantation

Allogeneic hematopoietic cell transplantation (HCT) from a matched sibling donor (MSD) may provide a cure for acute myeloid leukemia in first complete remission (AML/CR1), although the procedure is associated with a higher rate of treatment-related mortality (TRM) than autologous HCT, and it remains uncertain which modality is preferable as post-remission treatment. We therefore conducted a retrospective registry-based analysis to compare the outcomes of patients with AML/CR1 receiving autologous peripheral blood (PB) grafts (n=398, median age: 47, range: 17-80) and those receiving allogeneic MSD bone marrow (BM) grafts (n=633, median age: 38, range: 16-73) or allogeneic MSD PB grafts (n=475, median age: 42, range: 16-74) between 1995 and 2011. Consequently, the 5-year overall survival (OS) rates for the autologous PB, allogeneic BM and allogeneic PB recipients were 62% (95% confidence interval [CI], 57-67%), 61% (95% CI, 57-65%; P=0.90) and 54% (95% CI, 49-59%; P=0.07), respectively (Fig. 1-A), and the 5-year leukemia-free survival (LFS) rates were 57% (95% CI, 52-62%), 58% (95% CI, 54-63%; P=0.49) and 51% (95% CI, 46-56%; P=0.12), respectively(Fig. 1-B). Meanwhile, the 5-year cumulative incidence of TRM was 8% (95% CI, 5-11%), 16% (95% CI, 13-19%; P=0.009) and 19% (95% CI, 15-23%; P=0.0001), respectively, while that of relapse was 35% (95% CI, 30-40%), 26% (95% CI, 22-29%; P=0.003) and 30% (95% CI, 26-35%; P=0.08), respectively. A multivariate analysis performed with autologous PB HCT as the reference showed a hazard ratio (HR) for OS of 0.93 (95% CI, 0.73-1.18; P=0.53) for allogeneic BM HCT and 1.08 (95% CI, 0.83-1.39; P=0.57) for allogeneic PB HCT and an HR for LFS of 0.86 (95% CI, 0.69-1.09; P=0.21) and 0.98 (95% CI, 0.77-1.24; P=0.85), respectively. Stratifying the patients according to cytogenetics (favorable, intermediate and poor) and age (<50 years and ≥ 50 years) did not influence the results. Accordingly, autologous PB HCT may be a viable alternative as post-remission therapy in patients with AML/CR1 in the absence of MSD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Hematopoietic Cell Transplantation for Children with Acute Lymphoblastic Leukemia in Second Complete Remission: Similar Outcomes in Recipients of Unrelated Marrow and Umbilical Cord Blood versus Marrow from HLA Matched Sibling Donors

Transplant decisions for children with acute lymphoblastic leukemia (ALL) in second complete remission (CR2) are often based on the type of available donor. In many cases, allogeneic hematopoietic cell transplantation (HCT) is considered only if a human leukocyte antigen (HLA) matched sibling donor (MSD) is available. The role of unrelated donor (URD) HCT in this patient population is not well established. As advances in supportive care and donor selection have improved, the use of URD HCT in such patients should be reevaluated. We analyzed the outcomes of 87 consecutive children with ALL in CR2 who underwent allogeneic HCT at the University of Minnesota between 1990 and 2007. Donor sources included MSD bone marrow (n = 32), well and partially matched (M, n = 18) and mismatched (MM, n = 16) URD bone marrow and URD umbilical cord blood (UCB, n = 21). Although the incidence of neutrophil recovery was similar in all groups, the overall incidence of grades II-IV acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD) was 37% and 9%, respectively, with a higher incidence of aGVHD in recipients of URD grafts. Leukemia-free survival (LFS) at 5 years was lower in recipients of MM-URD grafts, but was comparable in all other groups. Although relapse at 5 years was highest in recipients of MSD (50%), results were not significantly different compared to recipients of M-URD (17%), MM-URD (6%), and UCB (33%) (P = .17). The development of grades II-IV aGVHD and a first remission >3 years were associated with a lower risk of relapse (relative risk [RR] 0.2, P = .03; RR 0.2. P = .01 respectively). Together, these results support the continued investigation of URD HCT for ALL in CR2, and suggest the timing of HCT in these children should be based primarily on the risk of relapse with conventional chemotherapy and not on the type of donor available.

Gloves and Socks Syndrome after bone marrow transplantation

A 17-year-old male patient with relapsed T-cell acute lymphoblastic leukaemia (T-ALL) underwent matched sibling donor bone marrow transplantation (BMT) after myeloablative conditioning with total body irradiation (TBI) and etoposide. Haematological engraftment was achieved on day +15. Ciclosporin (3 mg/kg/d) and mycophenolate mofetil were given for immunosuppression, together with antibiotics and aciclovir for infectious prophylaxis. On day +14, he developed paresthesiae, oedema and erythema of the hands and feet followed by erythematous, papular lesions that spread centripetally. There were no signs of acute graft-versus-host disease (aGvHD) involving other organ systems. Weekly polymerase chain reaction (PCR) screening for viral infections, such as cytomegalovirus, Epstein–Barr virus, human herpesvirus 6 and parvovirus B19 in the peripheral blood remained negative. As aGvHD was a differential diagnosis, the patient received prednisolone 2 mg/kg/d from days +18 to +20. A biopsy of the plantar lesion was taken on day +21. Histology showed non-specific interface dermatitis with vacuolar degeneration and perivascular inflammatory infiltrates mostly composed of lymphocytes. PCR analysis identified repetitively high parvovirus B19 DNA content in the cutaneous biopsy specimen, still without signs of viremia. In the course of a week, the lesions cleared with palmar and plantar desquamation. In summary, these data argue for manifestation of a gloves and socks syndrome post-BMT caused by parvovirus B19, which may resemble clinical features of aGvHD because of immunological phenomena accompanying parvovirus B19 infection.

Frequency and magnitude of dose adjustment of IV busulfan in targeted dosing strategy for pediatric allogeneic transplantation

Busulfan is an important therapuetic agent in pediatric allogeneic transplantation. The recent introduction of IV busulfan (IV Busulfex®, ESPpharma) has descreased the intra-and interpatient dose variations associated with oral absorption and allows for targeted therapy. Children have increased drug clearance and varying degrees of hepatic function both developmentally and associated with the underlying disorders for which they are being treated. Because of this variability, first dose pharmacokinetics were perfomed on all of our patients to ensure the targeted AUC was achieved. In a series of 85 consecutive children undergoing allogeneic transplant at Methodist Children’s Hospital/Texas Transplant Institute from June 2001 to October 2003, 45 children received myeloablative doses of busulfan (0.8 mg/kg for patients 3–10 kgs; 1 mg/kg for patients > 10 kgs till age 4 yrs; 0.8 mg/kg for patients > 4 yrs given every 6 hours for 16 doses) as part of a busulfan/cyclophosphamide, busulfan/melphalan or busulfan/fludarabine preparative regimen. 42/45 patients had their actual weight used for dosing calculations. Adjusted IBW was used in 3 patients. All patients received dilantin for seizure prophylaxis. First dose pharmcokinetics were performed by the Clinical Pharmokinetics Lab at Seattle Cancer Care Alliance, targetting an AUC of 900–1300 umol.min, with dose adjustments done starting with dose 7, if needed. Donor source was matched sibling donor bone marrow or cord blood in 10 and unrelated donor sources in 35 (2 marrow and 33 mismatched umbilical cord units). The median age was 4.7 yrs (range 1 month to 17 years). Patients underwent transplant for a variety of conditions: 12 AML, 5 CML, 1 JMML, 9 ALL, 1 lymphoma, 3 HLH, 10 primary immunodefiencies, 4 hematology disorders. No patients developed VOD. 32/33 patients of patients who received a fully myeloabalative preparative regimen engrafted. A targeted AUC (900–1300 umoles.min) was achieved with initial dosing in 50% of the patients. However, many children required dose adjustment to achieve the targeted AUC, mostly dose escalation (see table ). Given the variability of metabolism in children, first dose pharmacokintics are recommended. Additionally, the starting dose in infants is lower than the currently recommended dose.TableAge/ WeightStarting Dose (mg/kg)AUC μmol · min: Median (range)Final Dosing (mg/kg): Median (range)Percent of Patients Requiring Dose AdjustmentDose Increased/ Dose Decreased3–10 kg (n = 12)0.81167 (825–1869)0.93 (0.67–1.25)50%–6/12 pts4↑/2↓10 kg-4 years (n = 11)11142 (908–1518)1 (0.76–1.25)27%–3/112↑/1↓>4 years (n = 22)0.81089 (620–1827)0.82 (0.57–1.25)65%–15/2311↑/4↓ Open table in a new tab

Adverse outcomes in primary hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare condition characterized by abnormal proliferation of macrophages. Although the mortality rate in children diagnosed with primary HLH is high, little has been described about the nature of adverse events. This review evaluates unfavorable events in children with primary HLH to suggest methods of improving outcomes. Charts of patients who met diagnostic criteria for primary HLH at the Hospital for Sick Children between January 1985 and June 2000 were retrospectively reviewed. The primary outcome measure was an adverse event, defined as death, the subsequent diagnosis of malignancy, or developmental delay. Twenty children were diagnosed with primary HLH. The median age at diagnosis was 6.5 months (range 1-78 months). Nineteen children received chemotherapy and two underwent matched sibling donor bone marrow transplantation. Of the 20 children, 12 (60%) died. These deaths were attributed to progressive HLH in 4 cases and invasive infection in 8 cases. These infections consisted of disseminated cytomegalovirus infection (n = 1), sepsis (n = 1), and invasive fungal infections (n = 6). Eight children survived. Two were subsequently diagnosed with malignancy. Two others were found to have significant developmental delay. The overall mortality rate was 60% in our series of 20 children with primary HLH; 50% of deaths were directly attributable to invasive fungal infection. Developmental delay and the diagnosis of malignancy are important events in this cohort.

Equivalent outcomes in patients with chronic myelogenous leukemia after early transplantation of phenotypically matched bone marrow from related or unrelated donors

PURPOSE: To determine if the favorable outcomes after transplantation of matched sibling donor bone marrow in patients with chronic myelogenous leukemia can be achieved using bone marrow from an HLA-A,B/DRB1–matched unrelated donor. SUBJECTS AND METHODS: Between April 1983 and December 1997, 141 patients with chronic myelogenous leukemia in its first chronic phase received a bone marrow transplant from a matched sibling donor (n = 96) or an HLA-A,B/DRB1–matched unrelated donor (n = 45). The median age of matched sibling donor recipients was 38 years (range, 8 to 56 years) and of unrelated donor recipients was 35 years (range, 3 to 53 years; P = 0.03). The median follow-up was 6 years (range, 1 to 15 years) in matched sibling donor recipients and 5 years (range, 2 to 10 years) in unrelated donor recipients. RESULTS: There was no significant difference in the 5-year survival rates of matched sibling donor recipients [58%; 95% confidence interval (CI), 48% to 68%] and unrelated donor recipients (53%; 95% CI, 39% to 67%; P = 0.4). Among patients who underwent transplantation within 1 year after diagnosis, the 5-year survival rate of matched sibling donor recipients (76%; 95% CI, 65% to 87%) was not significantly different ( P = 0.5) from that of unrelated donor recipients (70%; 95% CI, 52% to 88%). In multiple regression analysis, longer time from diagnosis to transplantation, T-cell depletion, and grades III or IV graft versus host disease were independently associated with poorer survival. Transplantation of unrelated donor bone marrow was not associated with mortality (relative risk, 1.1; 95% CI, 0.6 to 2.1; P = 0.7). CONCLUSIONS: Transplantation of bone marrow from a matched sibling donor or an HLA-A,B/DRB1–matched unrelated donor produces equivalent outcomes in patients with chronic myelogenous leukemia, particularly if the transplant takes place within 1 year after diagnosis.