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We have initiated a single center phase I study in patients with hematologic malignancies progressively substituting day +4 posttransplant cyclophosphamide (PT-CY) with bendamustine (PT-BEN) following myeloablative conditioning (MAC) and T-cell replete haploidentical bone marrow transplantation (haplo-BMT). We report herein our interim analysis of our first three cohorts PT-CY (mg/kg)/PT-BEN (mg/m

Myeloid sarcoma is a rare variant of acute myeloid leukemia (AML) which presents as an extramedullary soft tissue mass. Due to the rarity of this disease, along with nonspecific presenting symptoms, diagnosis can be delayed or missed without a high index of suspicion. In this case, we discuss a patient diagnosed with AML relapse in the form of myeloid sarcoma two years after allogeneic hematopoietic stem cell transplant (alloHSCT) for myelodysplastic syndrome (MDS) with the initial presentation for back pain misdiagnosed as spinal stenosis. This case report aims to help healthcare providers in recognizing the early signs and symptoms of this disorder as well as provide information in regards to treatment options and risk assessment.

Background Myelofibrosis (MF) is a chronic hematologic malignancy with poor prognosis for which the only curative therapy is allogeneic stem cell transplant (alloHSCT). It is suggested that eligible patients with Intermediate-2 and high-risk disease proceed to transplant. Frequency of transplant for MF is increasing, given the advent of reduced intensity conditioning regimens and earlier identification of high-risk disease with mutation testing. Patients with MF are at high risk of regimen related toxicities and poor transplant outcomes due to increased risk of prolonged engraftment and graft failure. These concerns may contribute to a greater reluctance to embrace alternative donor source allografts such as haploidentical (haplo) donors. Herein, we report a case series of patients with MF undergoing alloHSCT. Methods A retrospective analysis was performed on all patients having received a haploidentical HSCT at our institution. Results Three patients were identified as having received haplo HSCT for MF. All received a bone marrow graft. Median age was 57 (range 46-61). One patient had primary MF, one post-PV MF, and one post-ET MF. Risk category at time of transplant by DIPSS was Intermediate -2 in two patients, and high in one. Two of the three patients had a major ABO mismatch. All patients and donors were positive for CMV IgG. Mean cell dose was 2.07 × 10^6 CD34+/kg recipient body weight (range 1.65 × 10^6 to 3.19 × 10^6). All patients received busulfan/fludarabine/melphalan conditioning (one myeloablative dosing, two reduced intensity). Post-transplant cyclophosphamide on days +3 and +4, tacrolimus, and mycophenolate mofetil were used for GvHD prophylaxis in all cases. Median time to neutrophil engraftment was Day +22 (range 20-24), median time to platelet engraftment was 67 days (range 37 - > 70). All patients had complete donor chimerisms at Day +30. Recovery of marrow cellularity was delayed in all patients. All patients had CMV reactivation by PCR, one patient had CMV esophagitis. Infectious complications were common, including BK virus, C. difficile colitis, invasive pulmonary aspergillosis, and klebsiella bacteremia Two patients developed chronic GvHD; one with cGVH of eyes & mouth not requiring systemic therapy, one with cGVH of upper GI tract/mouth. All patients are currently off immunosuppression. All patients are alive at a median follow up of 1.5 years post-transplant (range 456-656 days). Discussion Our case series using a haploidentical donor source and busulfan/fludarabine/melphalan conditioning along with post-transplant cyclophosphamide for patients with MF demonstrates outcomes at least comparable to conventional donor source transplants for MF. While infectious complications and slightly prolonged engraftment were noted in the early transplant period, these can be overcome with aggressive supportive care.

Globoid cell leukodystrophy (GLD) is a progressive neurodegenerative disorder caused by the deficiency of galactocerebrosidase (GALC), resulting in accumulation of toxic metabolites in neural tissues. Clinically variable based on age of onset, infantile GLD is generally a rapidly fatal syndrome of progressive neurologic and cognitive decline, whereas later-onset GLD has a more indolent, protracted clinical course. Animal models, particularly the twitcher mouse, have allowed investigation of both the pathophysiology of and the potential treatment modalities for GLD. Cellular therapy for GLD, notably hematopoietic cell transplantation (HCT; transplantation of bone marrow, peripheral blood stem cells, or umbilical cord blood cells) from a normal related or unrelated allogeneic donor provides a self-renewing source of GALC in donor-derived cells. The only currently available treatment option in human GLD, allogeneic HCT, can slow the progression of the disease and improve survival, especially when performed in presymptomatic infants. Because persistent neurologic dysfunction still occurs after HCT in GLD, preclinical studies are evaluating combinations of HCT with other treatment modalities. © 2016 Wiley Periodicals, Inc.

Background Transplant-associated thrombotic microangiopathy (TA-TMA) is a rare, potentially lethal complication of allogeneic stem cell transplant. It is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction. Endothelial injury and terminal complement activation contribute to the pathogenesis of TA-TMA. Several risk factors have been identified including certain conditioning regimens, acute graft versus host disease (GvHD) and/or calcineurin inhibitors (CNI), and viral infections. Eculizumab, a monoclonal antibody directed against C5 which prevents the formation of the C5b-9 membrane attack complex, is effective in treatment of TA-TMA, but with significant infection risk. Here, we review our institution's experience with TA-TMA treated with eculizumab. Methods A retrospective review was performed on all adult and pediatric patients with TA-TMA treated at our institution with eculizumab since 2015. Results Five patients with TA-TMA ages 4.5, 8.5, 11.4, 33, and 37 years (2 female) were treated with eculizumab. All patients received myeloablative conditioning, three TBI-based. Donor source was haploidentical (n=2), matched-unrelated (n=2), and cord (n=1). All patients were on a CNI at diagnosis. TA-TMA therapy required cessation of CNI in 3 of 5 patients. Median day of diagnosis from transplant was 73 days (range 17-251). All patients had renal impairment, three requiring dialysis. Median days from TMA diagnosis to treatment with eculizumab was 3 (range 1-5). Median doses received was 6 (range 4 - >25). Resolution of hemolysis with eculizumab was brisk, ranging from 25-59 days. Figure 1 illustrates a representative trend with regards to LDH, Haptoglobin, CH50, and eculizumab dosing. Four of five patients were alive with a median follow-up of 10.3 months (range 1 - 45 months). The one death was due to Stage IV GvHD and candidemia, present before diagnosis of TMA. Infections were common, including viral and fungal. There were no deaths due to TMA. Two patients continue on dialysis 2.5 and 34.5 months after diagnosis. Discussion Our experience confirms variable clinical presentations, as our patients differed in presence and severity of acute GvHD, confounding role of CNI or triggering of TA-TMA by viral infections. All patients were started on eculizumab promptly following diagnosis, with a high awareness for and prophylaxis of potential infectious complications, which has mitigated the reported high mortality risk of TA-TMA.

Background The nearly universal donor accessibility afforded by haploidentical bone marrow transplantation (haplo-BMT) is salient for our program, as half of the patients undergoing hematopoietic cell transplantation (HCT) are ethnic or racial minorities. This highlights the need for effective haplo-BMT regimens and improvements in graft-versus-host disease (GvHD) prophylaxis. Balancing GvHD prevention with the maintenance of graft-versus-leukemia (GvL) is an ongoing challenge in the field of HCT. We have previously shown in mice that bendamustine (BEN) can safely replace cyclophosphamide (CY) as post-transplant (PT) GvHD prophylaxis following haplo-BMT, with comparable protection from GvHD and superior GvL effects. Based on our preclinical data, we have initiated a Phase I/II study to replace PT-CY (given on days +3 and +4) with PT-BEN following haplo-BMT. Methods Phase I is a standard 3 + 3 dose escalation design with six dose level cohorts. The first three cohorts (1-3) consist of a combination of sequentially reduced doses of CY and increased doses of BEN on day +4 post-BMT with the dose of CY on day +3 remaining unchanged. The next three cohorts (4-6) will involve progressive substitution of CY with BEN on day +3. We are enrolling patients ages 8-60 years with a diagnosis of acute leukemia, chronic myeloid leukemia, myelodysplastic syndrome, Hodgkin's or non-Hodgkin's lymphoma who do not have a readily available HLA-matched (10/10) donor. Myeloablative busulfan, fludarabine, and melphalan or TBI and fludarabine are used as conditioning regimens. Engraftment, immune reconstitution, T-cell receptor β (TRB) diversity, GvHD, infections, relapse, non-relapse mortality (NRM), event-free survival (EFS) and overall survival (OS) are monitored. Patients undergoing haplo-BMT (using the same conditioning regimens) who do not wish to receive PT-BEN are consented as PT-CY controls for the clinical endpoints and immune reconstitution studies. Results We have enrolled through Cohort 2 with no dose-limiting toxicities. Cohort 2 of PT-BEN had significantly earlier neutrophil engraftment than PT-CY controls (median day +13 compared to +17), with >5-fold higher neutrophil to lymphocyte ratios through day +100. PT-BEN patients displayed higher CD4 to CD8 ratio and demonstrated significantly greater TRB diversity than PT-CY only patients through 1 year following transplant. Patients receiving PT-BEN had a trend toward a lower incidence of CMV reactivation, 33% compared to 100% in PT-CY controls. No PT-BEN patient has developed grade III-IV acute GvHD or chronic GvHD. Conclusions PT-BEN has been well-tolerated, with patients demonstrating early engraftment. Preliminary data with PT-BEN indicate potential differences in immune reconstitution and TRB diversity. This may be advantageous in viral control, as well as in GvHD and GvL responses.