Transplant versus no transplant in myelodysplastic syndrome and acute myeloid leukemia with TP53 mutation; a referral center experience.

A remarkably high rate of post-transplant relapse in patients with TP53-mutated myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) calls to question the utility of allogeneic stem cell transplant (HSCT). We, therefore, performed a retrospective analysis to compare the outcomes between HSCT (N = 38) versus non-HSCT (N = 45) approaches. Patients in the HSCT cohort were younger (median age 63 vs. 72) while patients in the non-HSCT cohort more commonly had complex karyotype with chromosome 17 aberrancy and 5q deletion (p < .01). A total of 69 TP53 variants including 64 pathogenic variants, and 5 variants of undetermined significance were detected. Nine patients (4 in HSCT and 5 in non-HSCT) had multi-hit TP53 variants. After induction: 57.9% versus 56.6% in the HSCT versus non-HSCT cohort achieved morphologic complete remission. Median time to HSCT was 6 months and median follow-up was 15.1 months for HSCT and 5.7 months for non-HSCT. Median disease-free survival (DFS) and overall survival (OS) were 11.7 and 15.9 months for HSCT, and 4.1 and 5.7 months for non-HSCT cohorts, respectively. Non-relapse mortality at 12 months was 22% versus 44% for HSCT versus non-HSCT. In the HSCT cohort, the rate of grade II-IV acute and chronic graft-versus-host disease (GVHD) was 55% and 18%, respectively. None of the patients from the non-HSCT cohort were alive while four patients from the HSCT cohort were alive, in remission, and without GVHD (GRFS) at the time of abstraction. Better treatment strategies for patients with TP53-mutated MDS/AML remain an area of unmet clinical need.

Serious Adverse Events in Related Donors: A Report from the Related Donor Safe Study.

The incidence and risk factors for severe adverse events (SAEs) in related donors (RD) of hematopoietic cell transplants is unknown. The Related Donor Safe study is a prospective observational cohort of 1680 RDs and represents an opportunity to examine characteristics of SAEs in RDs. In this cohort, we found that SAEs were reported in a total 12 (0.71%) RDs. Of these, 5 SAEs occurred in bone marrow donors (5/404, 1.24%), and 7 (7/1276, 0.55%) were in donors of peripheral blood stem cells. All of the SAEs were considered to be related (definite, probable, or possible) to the donation process. There were no donor fatalities. Of the 12 RDs who experienced an SAE, 10 were either overweight or obese. Five of the 12 RDs had predonation medical conditions that would have resulted in either possible or definite ineligibility for donation were they being assessed as unrelated donors. These SAE data will be useful in the counseling of prospective RDs before planned donation and may be helpful in identifying donors who should be considered medically unsuitable for donation.

Repeat Endoscopy Affects Patient Management in Gastrointestinal Graft-Versus-Host Disease.

Graft versus host disease (GVHD) of the gut is associated with significant morbidity and mortality after allogeneic hematopoietic cell transplant (allo-HCT). No guidelines exist regarding repeat endoscopy after failure of first-line treatment with steroids. We aimed to study if repeat endoscopic biopsy can be helpful in these patients to guide treatment decisions. We retrospectively reviewed medical records of all patients who underwent repeat endoscopy for clinical suspicion of gastrointestinal (GI) GVHD after allo-HCT. Of the 318 patients, 24 underwent endoscopy twice after allo-HCT. At first endoscopy, 20 patients (80%) showed abnormal findings: 16 with GVHD alone, 1 with GVHD plus cytomegalovirus (CMV), and 3 with GVHD plus infectious colitis. On repeat endoscopy in these 20 patients with GVHD, 6 showed improvement leading to de-escalation of therapy, 8 showed worsening of GVHD including detection of CMV in 2 patients, and 2 had no histological changes. One patient with simultaneous GVHD and CMV diagnosed on first biopsy, displayed significant improvement leading to de-escalation of therapy. Three patients with GVHD along with infectious colitis on biopsy subsequently showed improvement on repeat biopsy leading to de-escalation of therapy. Among 4 patients with normal findings on first endoscopy, 3 had GVHD and 1 had epstein-barrvirus-associated post-transplant lymphoproliferative disorder (EBV-PTLD) on repeat procedures. This study supports the usefulness of repeat endoscopy in persistently symptomatic patients when there is no improvement after the initial treatment based on the results of the first endoscopy. Repeat endoscopy may guide therapy without significant complications.

Higher Risks of Toxicity and Incomplete Recovery in 13- to 17-Year-Old Females after Marrow Donation: RDSafe Peds Results.

Although donation of bone marrow (BM) or peripheral blood stem cells (PBSCs) from children to family members undergoing allogeneic transplantation are well-established procedures, studies detailing levels of pain, symptoms, and long-term recovery are lacking. To address this lack, we prospectively enrolled 294 donors age <18 years at 25 pediatric transplantation centers in North America, assessing them predonation, peridonation, and at 1 month, 6 months, and 1 year postdonation. We noted that 71% of children reported pain and 59% reported other symptoms peridonation, with resolution to 14% and 12% at 1 month postdonation. Both older age (age 13 to 17 years versus younger) and female sex were associated with higher levels of pain peridonation, with the highest rates in older females (57% with grade 2-4 pain and 17% with grade 3-4 pain). Multivariate analyses showed a 4-fold increase in risk for older females compared with males age <13 years (P <.001). At 1 year, 11% of 13- to 17-year-old females reported grade 2-4 pain, compared with 3% of males age 13 to 17 years, 0% of females age <13 years, and 1% of males age <13 years (P = .01). Males and females age 13 to 17 years failed to return to predonation pain levels at 1 year 22% and 23% of the time, respectively, compared with 3% and 10% in males and females age <13 years (P = .002). Our data show that females age 13 to 17 years are at increased risk of grade 2-4 pain at 1 year and >20% of females and males age 13 to 17 years do not return to baseline pain levels by 1 year after BM donation. Studies aimed at decreasing symptoms and improving recovery in older children are warranted.

Related peripheral blood stem cell donors experience more severe symptoms and less complete recovery at one year compared to unrelated donors.

Unlike unrelated donor registries, transplant centers lack uniform approaches to related donor assessment and deferral. To test whether related donors are at increased risk for donation-related toxicities, we conducted a prospective observational trial of 11,942 related and unrelated donors aged 18-60 years. Bone marrow (BM) was collected at 37 transplant and 78 National Marrow Donor Program centers, and peripheral blood stem cells (PBSC) were collected at 42 transplant and 87 unrelated donor centers in North America. Possible presence of medical comorbidities was verified prior to donation, and standardized pain and toxicity measures were assessed pre-donation, peri-donation, and one year following. Multivariate analyses showed similar experiences for BM collection in related and unrelated donors; however, related stem cell donors had increased risk of moderate [odds ratios (ORs) 1.42; P<0.001] and severe (OR 8.91; P<0.001) pain and toxicities (OR 1.84; P<0.001) with collection. Related stem cell donors were at increased risk of persistent toxicities (OR 1.56; P=0.021) and non-recovery from pain (OR 1.42; P=0.001) at one year. Related donors with more significant comorbidities were at especially high risk for grade 2-4 pain (OR 3.43; P<0.001) and non-recovery from toxicities (OR 3.71; P<0.001) at one year. Related donors with more significant comorbidities were at especially high risk for grade 2-4 pain (OR 3.43; P<0.001) and non-recovery from toxicities (OR 3.71; P<0.001) at one year. Related donors reporting grade ≥2 pain had significant decreases in Health-Related Quality of Life (HR-QoL) scores at one month and one year post donation (P=0.004). In conclusion, related PBSC donors with comorbidities are at increased risk for pain, toxicity, and non-recovery at one year after donation. Risk profiles described in this study should be used for donor education, planning studies to improve the related donor experience, and decisions regarding donor deferral. Registered at clinicaltrials.gov identifier:00948636.

Effect of Aging and Predonation Comorbidities on the Related Peripheral Blood Stem Cell Donor Experience: Report from the Related Donor Safety Study.

The development of reduced-intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RDs) of peripheral blood stem cells (PBSCs). The effects of age on donation efficacy, toxicity, and long-term recovery in RDs are poorly understood. To address this we analyzed hematologic variables, pain, donation-related symptoms, and recovery in 1211 PBSC RDs aged 18 to 79 enrolled in the Related Donor Safety Study. RDs aged > 60 had a lower median CD34+ level before apheresis compared with younger RDs (age > 60, 59 × 106/L; age 41 to 60, 81 × 106/L; age 18 to 40, 121 × 106/L; P < .001). This resulted in older donors undergoing more apheresis procedures (49% versus 30% ≥ 2 collections, P < .001) and higher collection volumes (52% versus 32% > 24 L, P < .001), leading to high percentages of donors aged > 60 with postcollection thrombocytopenia <50 × 109/L (26% and 57% after 2 and 3days of collection, respectively). RDs aged 18 to 40 had a higher risk of grades 2 to 4 pain and symptoms pericollection, but donors over age 40 had more persistent pain at 1, 6, and 12 months (odds ratio [OR], 1.7; P = 0.02) and a higher rate of nonrecovery to predonation levels (OR, 1.7; P = .01). Donors reporting comorbidities increased significantly with age, and those with comorbidities that would have led to deferral by National Marrow Donor Program unrelated donor standards had an increased risk for persistent grades 2 to 4 pain (OR, 2.41; P < .001) and failure to recover to predonation baseline for other symptoms (OR, 2.34; P = .004). This information should be used in counseling RDs regarding risk and can assist in developing practice approaches aimed at improving the RD experience for high-risk individuals.

Toxoplasma Encephalitis following Tandem Autologous Hematopoietic Stem Cell Transplantation: A Case Report and Review of the Literature.

Infection with Toxoplasma gondii is a rare but often fatal complication in hematopoietic stem cell transplantation (HSCT) recipients. Most cases have been reported in allogeneic (allo-) HSCT recipients, with only narrative reports following autologous HSCT (ASCT). We report the case of a 58-year-old Caucasian male presenting with toxoplasma encephalitis following tandem ASCT for myeloma and successfully treated with diagnosis by polymerase chain reaction analysis of cerebrospinal fluid. He was treated with sulfadiazine and pyrimethamine (with leucovorin) followed by pyrimethamine and atovaquone as secondary prophylaxis while receiving subsequent therapy for progressive multiple myeloma. Toxoplasmosis is a potential complication in allo-HSCT as well as ASCT recipients and should be considered in any post-HSCT patient with neurological dysfunction. Rapid diagnosis and immediate antimicrobial treatment are essential to avoid morbidity and mortality.

Outcome of allogeneic stem cell transplantation in myelodysplastic syndrome patients: prognostic implication of monosomal karyotype.

OBJECTIVE: Monosomal karyotype (MK) is defined as the presence of two or more autosomal monosomies or a single monosomy associated with a structural abnormality. It was first described as a high-risk cytogenetic abnormality for acute myeloid leukemia and more recently in myelodysplastic syndromes (MDS). However, allotransplant outcome in MDS with MK has not been described. PATIENTS AND METHODS: We retrospectively reviewed data of 79 patients with MDS who underwent allotransplant at the University of Iowa from 1990 to 2009. We recorded patients' cytogenetic data, clinical characteristics and evaluated outcome following allogeneic stem cell transplant stratified by cytogenetic classification. RESULTS: Of 79 patients, 37 (47%) had unfavorable karyotypes (23 complex karyotype, 25 abnormal chromosome 7). Twenty-four patients (30%) had MK. Twenty-four patients (30%) relapsed and 59 (74.7%) died during study period. Patients with MK had higher 2-yr relapse incidence (RI) (51% vs. 29%; P = 0.01), lower 2-yr event-free survival (EFS) (8% vs. 40%; P = 0.02), and lower 2-yr overall survival (OS)(6% vs. 41%; P = 0.02) than patients without MK. We further analyzed the effect of MK in each unfavorable karyotype composite. Although the outcome was not statistically different, unfavorable karyotypes with patients with MK showed a trend toward higher 2-yr RI [hazard ratio (HR), 1.7; P = 0.34], lower 2-yr EFS (HR, 1.5; P = 0.29), and lower 2-yr OS (HR, 1.5; P = 0.28) compared to unfavorable karyotypes without MK. CONCLUSION: Cytogenetic abnormalities remain an important prognostic factor for allotransplant outcome of MDS. Our results suggested poor allotransplant outcomes with high RI and low OS in MDS with MK.

Treatment with plerixafor in non-Hodgkin's lymphoma and multiple myeloma patients to increase the number of peripheral blood stem cells when given a mobilizing regimen of G-CSF: implications for the heavily pretreated patient.

We investigated the efficacy and toxicity of combining granulocyte-colony stimulating factor (G-CSF) at standard doses with plerixafor, a CXCR4 inhibitor, to mobilize stem cells in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). Patients with NHL and MM underwent mobilization with G-CSF (10 microg/kg/day) for up to 9 days and plerixafor (240 microg/kg/day), which started on the evening of day 4. Apheresis began on day 5 and continued daily until either >or= 5 x 10(6) CD34/kg were collected or to a maximum of 5 aphereses. Toxicities, increase in circulating CD34 cells/microL before and after the first dose of plerixafor, percentage of patients collecting >or= 5 x 10(6) CD34/kg, total CD34 cells/kg collected, engraftment, and exploratory efficacy analyses in heavily pretreated patients were examined. Six sites enrolled 49 patients (NHL, 23; MM, 26). All completed mobilization and 47 of 49 (96%) underwent transplant. Circulating CD34 cells/microL increased by 2.5-fold (1.3-6.0-fold) after the first plerixafor dose. The median CD34 cells/kg collected was 5.9 x 10(6) (1.5-22.5) in 2 (1-5) days of aphereses. Median days to neutrophil and platelet engraftment were 11 (8-16) and 14.5 (7-39) days, respectively. Adverse events primarily were mild nausea and diarrhea (n=24). Twenty-eight (57%) were identified as heavily pretreated patients. Their median fold increase in circulating CD34 cells/microL was 2.5 (1.4-5.0) after plerixafor, similar to minimally pretreated patients. Plerixafor and G-CSF increased circulating CD34 cells/microL and led to the adequate collection of stem cells for autotransplant in 96% of the patients. This combination may have particular value in heavily pretreated patients.

Invasive zygomycosis in hematopoietic stem cell transplant recipients receiving voriconazole prophylaxis.

We report 4 cases of invasive zygomycosis in hematopoietic stem cell transplant recipients, all occurring after May 2003, when voriconazole began to be used as antifungal prophylaxis. No cases of zygomycosis had been detected in this population in the 3 years prior to May 2003. All 4 patients were receiving immunosuppressive therapy for presumed graft-versus-host disease. Profoundly immunosuppressed patients receiving voriconazole prophylaxis remain at risk for less-common pathogens that are intrinsically resistant to this agent.

A fatal case of West Nile virus infection in a bone marrow transplant recipient.

West Nile virus (WNV) can cause severe, potentially fatal neurological illnesses, which include encephalitis, meningitis, Guillain-Barré syndrome, and anterior myelitis. Because of the short viremic phase, WNV infection is most commonly diagnosed by detection of immunoglobulin M antibody to WNV in serum or cerebrospinal fluid (CSF). We describe a patient with T cell lymphoma who had undergone a T cell-depleted bone marrow transplantation and developed fatal WNV infection. The results of serological tests of blood samples and of CSF tests were negative. Diagnosis was made postmortem by a positive result of reverse-transcriptase polymerase chain reaction (ABI 7700; TaqMan) for WNV in stored CSF and serum samples.

Outcomes of renal transplantation following bone marrow transplantation.

This single center retrospective study was undertaken to determine the outcome of kidney transplantation (KT) after bone marrow transplantation (BMT) and also to determine the need for immunosuppressive therapy after KT when the BMT marrow donor is the KT donor. Kidney transplantation was performed in 10 patients with BMT nephropathy (BMTN). In six patients, the KT donor was the BMT donor; these individuals were given no long-term immunosuppression. Four other patients received KT from donors who were not the marrow donor (two living donors, two cadaveric donors). After median follow up of 34 months, no patient had an episode of acute rejection. All graft losses (n = 4) resulted from patient death. Three were because of infectious processes, including two infectious deaths in patients not on immunosuppression. Median estimated actuarial patient and graft survival (Kaplan-Meier) was 105 months. We conclude that patients with BMTN who receive KT from their marrow donor do not require immunosuppression. Whether immunosuppressive therapy is given or not, outcome appears to be determined largely by BMT-related immune dysfunction.