Multiplexed Gastrointestinal PCR panels for the Evaluation of Diarrhea in HCT Recipients.

BACKGROUND: Multiplexed gastrointestinal PCR panels (MGPP) are frequently employed as an aid in the diagnosis and management of diarrhea in HCT recipients. Many issues related to the optimal use of MGPP in HCT patients remain to be clarified. OBJECTIVE: To better define MGPP diagnostic and therapeutic stewardship in HCT recipients including indications and benefits of testing, optimal timing, and interpretation of results. STUDY DESIGN: We retrieved 463 consecutive MGPP ordered on 651 consecutive first HCT (312 allogeneic, 339 autologous) performed at our institution between June 2015 and June 2023. RESULTS: One hundred and sixteen (25%) of the 463 MGPP identified at least one and 12 (3%) more than one diarrheagenic pathogen. A positive result was more likely if the test was ordered within 48 hours of a hospital admission [32/78(41%)] or as an outpatient [46/111(41%)] as compared with evaluation of hospital onset diarrhea [38/274(14%)]. Among the positive results, the most frequent pathogens identified included C. difficile (64%), diarrheagenic E. coli (20%), norovirus (9%), and adenovirus 40/41 (5%). Thirty-eight percent of the positive C. difficile MGPP determinations were associated with a positive test for toxin. Among our allogeneic HCT cohort, 3% of MGPP for hospital onset diarrhea yielded an organism other than C. difficile. Fifty-six percent of positive and 14% of all submitted tests resulted in a change in treatment. For organisms other than C. difficile, only 1% of all tests and 5% of positive tests resulted in initiation of therapy. For patients at risk for acute graft vs. host disease (aGVHD), a positive or negative MGPP result was not predictive for a new diagnosis of aGVHD in proximity to diarrhea onset. CONCLUSIONS: MGPP testing is most useful when administered at hospital admission or as an outpatient. Since MGPP is sensitive and does not distinguish between colonization and causes of diarrhea, caution is needed in interpretation of results, especially for toxin negative C. difficile and diarrheagenic gram-negative organisms.

An Algorithm Addressing the Problem of Overdiagnosis of Clostridioides difficile Infections in Hematopoietic Stem Cell Transplantation Recipients: Effects on C. difficile Infection Rates and Patient Outcomes.

Diarrhea of other causes and Clostridioides difficile colonization are common in patients hospitalized for hematopoietic stem cell transplantation (HSCT). It has been well recognized that these issues tend to decrease the specificity of stool testing for C. difficile infection (CDI). The best way to address this problem is uncertain. In September 2018, we initiated a project with the goal of addressing the apparent problem of overdiagnosis of CDIs in our HSCT population. Using the quality improvement tool Model for Improvement, we introduced a C. difficile stool testing and CDI diagnosis algorithm with the aim of decreasing unnecessary inpatient CDI diagnoses and treatments. In this study, we examined the effects of the algorithm. We reviewed all HSCT admissions for the 2 years before introduction of the algorithm and the subsequent 3 years, recording all stool submissions for C. difficile determination and CDI. At the close of the study, we recruited our advanced practice providers (APPs) to review all CDIs following algorithm initiation and provide feedback on the ease of use of the algorithm and potential improvements to the overall process. Stool submissions for C. difficile determination decreased from 38.0/1000 to 20.6/1000 inpatient days (P < .001) and CDI diagnoses decreased from 5.5/1000 to 2.4/1000 days (P = .007). Patients admitted for a first allogeneic HSCT, first autologous HSCT, or HSCT readmission showed similar proportionate reductions. No detrimental effects on hospital length of stay, overall survival, progression-free survival, rate of readmission post-HSCT, incidence of acute graft-versus-host disease, or incidence of recurrent CDI were noted following algorithm introduction. A strategy of education, monitoring/feedback, and ease of algorithm access proved effective in inducing provider compliance. APPs rated the algorithm high on ease of use. We conclude that the use of an algorithm defining criteria for C. difficile testing, diagnosis, and treatment was associated with significantly decreased CDI diagnoses on a HSCT inpatient unit without apparent adverse effects.

Extended spectrum cephalosporin resistant enterobacteriaceae carriage and infection in patients admitted with newly-diagnosed acute leukemia.

BACKGROUND: Current information is limited on the incidence, risk factors, and consequences of extended-spectrum cephalosporin resistant Enterobacteriaceae (ESCRE) carriage in patients undergoing therapy for newly-diagnosed acute leukemia. METHODS: We monitored 300 consecutive patients who submitted a first stool within the first week of initial hospitalization for initial and hospital acquired ESCRE carriage. Selected available isolates underwent DNA sequencing for determination of strain typing and resistance genes. RESULTS: 19 (6%) patients had ESCRE in their initial stool, and there was continued risk for new acquisition throughout their multiple hospitalizations. Patients with AML had more acquired carriage during their initial hospitalization. Increased hospitalizations and male sex were risk factors for detected acquired ESCRE carriage. ESCRE stool carriage was predictive for ESCRE BSI but not for overall survival. Sequencing revealed that E. coli ESCRE isolates contained primarily ESBL, while Enterobacter spp. and Citrobacter spp. showed primarily AmpC genes. The antibiotic sensitivity patterns for ESCRE BSI isolates reflected these genome findings. DISCUSSION/CONCLUSIONS: ESCRE carriage is common in patients with acute leukemia undergoing repeated hospitalizations and increases the risk for ESCRE BSI. ESCRE genera express differing resistance genes which may be predictive for empiric antibiotic efficacy.

Transfer of Extended Spectrum Cephalosporin Resistant Enterobacteriaceae Among Patients on an HSCT Unit and the Value of Surveillance and Contact Isolation.

The mechanism(s) of acquisition of extended-spectrum cephalosporin-resistant Enterobacteriaceae (ESCRE) on inpatient hospital units dedicated to hematopoietic stem cell transplantation (HSCT) is unclear. The objectives of this study were to determine whether ESCRE organisms are transmitted among patients housed on a HSCT unit, clarify the mechanisms involved, and determine whether routine surveillance for ESCRE carriage and contact isolation for ESCRE carriers is beneficial. The study was conducted on a 30-bed inpatient unit dedicated to the care of patients with hematologic malignancies and HSCT recipients. To investigate whether ESCRE organisms may be transmitted vertically to subsequent room occupants, presumably through contamination of room surfaces, we (1) cultured 6 high touch areas in 10 rooms before and 9 rooms after terminal cleaning that had been occupied by patients with ESCRE carriage, (2) determined the in vitro survivals of our most common clinical ESCRE species, and (3) followed the subsequent room occupants of 54 consecutive ESCRE colonized patients for the development of inpatient acquired ESCRE carriage. To investigate whether ESCRE organisms are transmitted horizontally among inpatients we (1) sequenced 60 available ESCRE Escherichia coli isolates obtained from unit inpatients and searched for identities using complete-genome multisequence locus typing (cgMLST) and (2) retrospectively tabulated the cumulative rates of acquired ESCRE carriage in 356 patients admitted for a first HSCT before (200 patients) or after (156 patients) institution of universal ESCRE stool surveillance and contact isolation for carriers. No ESCRE organisms were cultured from patient rooms before or after terminal cleaning. In vitro, few, if any, ESCRE organisms survived longer than 2 hours. Nine of the subsequent occupants of a room in which a patient with ESCRE carriage had resided were detected with ESCRE carriage, only 2 of whom carried the same species as that of the prior occupant. DNA sequencing and cgMLST determination of the 60 E. coli isolates showed 53 cgMLST strains. Seven of the 53 strains were shared by 2 patients. After institution of universal ESCRE surveillance/isolation there was a significant decline in acquired ESCRE carriage among HSCT recipients. We conclude that vertical transmission of ESCRE organisms through room contamination appears to be uncommon on modern HSCT units. Conversely, our results are consistent with the horizontal spread of ESCRE organisms, probably mediated by intermediate vectors such as personnel or shared equipment. Further studies are needed to better define the magnitude of and risk factors for ESCRE horizontal transfers and the benefits of ESCRE surveillance/isolation.

Long-term Outcomes with Nonmyeloablative HLA-Identical Related Hematopoietic Cell Transplantation Using Tacrolimus and Mycophenolate Mofetil for Graft-versus-Host Disease Prophylaxis.

Nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) from HLA-identical related donors using cyclosporine (CSP) and mycophenolate mofetil (MMF) for postgrafting immunosuppression is effective therapy for hematologic cancers. However, graft-versus-host-disease (GVHD) remains a major cause of morbidity and mortality. Pilot data suggested lower acute GVHD incidence with tacrolimus/MMF compared to historical experience using CSP/MMF after nonmyeloablative HCT. In a phase II multicenter trial, we evaluated the effect of tacrolimus/MMF for GVHD prophylaxis after HLA-identical related donor peripheral blood HCT in patients with hematologic malignancies (n = 150) using conditioning with 2 Gy total body irradiation (TBI) for patients with a preceding (within 6 months) planned autologous HCT (n = 50) or combined with 90 mg/m2 fludarabine for those without recent autologous HCT (n = 100). Oral tacrolimus was given from days -3 to 56 (tapered by day +180 if no GVHD). Oral MMF was given from days 0 to 27. Patient median age was 57 (range, 20 to 74) years. The cumulative incidences (CI) of day 100 grade II to IV and III to IV acute GVHD were 27% and 4%, respectively. With median follow-up of 10.3 (range, 3.1 to 14.5) years, the 5-year CI of chronic extensive GVHD was 48%. One-year and 5-year estimates of nonrelapse mortality, relapse/progression, survival, and progression-free survival were 9% and 13%, 35% and 50%, 73% and 53%, and 56% and 37%, respectively. GVHD prophylaxis with tacrolimus/MMF resulted in a low risk of acute GVHD and compared favorably with results from a concurrent trial using CSP/MMF. A randomized phase III trial to investigate tacrolimus/MMF versus CSP/MMF in nonmyeloablative HCT is warranted.

Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: Improved outcomes over two decades.

We have used a non-myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation for the past twenty years. During that period, changes in clinical practice have been aimed at reducing morbidity and mortality from infections, organ toxicity, and graft-versus-host disease. We hypothesized that improvements in clinical practice led to better transplantation outcomes over time. From 1997-2017, 1,720 patients with hematologic malignancies received low-dose total body irradiation +/- fludarabine or clofarabine before transplantation from HLA-matched sibling or unrelated donors, followed by mycophenolate mofetil and a calcineurin inhibitor ± sirolimus. We compared outcomes in three cohorts by year of transplantation: 1997 +/- 2003 (n=562), 2004 +/- 2009 (n=594), and 2010 +/- 2017 (n=564). The proportion of patients ≥60 years old increased from 27% in 1997 +/- 2003 to 56% in 2010-2017, and with scores from the Hematopoietic Cell Transplantation Comborbidity Index of ≥3 increased from 25% in 1997 +/- 2003 to 45% in 2010 +/- 2017. Use of unrelated donors increased from 34% in 1997 +/- 2003 to 65% in 2010-2017. When outcomes from 2004 +/- 2009 and 2010-2017 were compared to 1997 +/- 2003, improvements were noted in overall survival (P=.0001 for 2004-2009 and P <.0001 for 2010-2017), profression-free survival (P=.002 for 2004-2009 and P <.0001 for 2010 +/- 2017), non-relapse mortality (P<.0001 for 2004 +/- 2009 and P <.0001 for 2010 +/- 2017), and in rates of grades 2 +/- 4 acute and chronic graft-vs.-host disease. For patients with hematologic malignancies who underwent transplantation with non-myeloablative conditioning, outcomes have improved during the past two decades. Trials reported are registered under ClinicalTrials.gov identifiers: NCT00003145, NCT00003196, NCT00003954, NCT00005799, NCT00005801, NCT00005803, NCT00006251, NCT00014235, NCT00027820, NCT00031655, NCT00036738, NCT00045435, NCT00052546, NCT00060424, NCT00075478, NCT00078858, NCT00089011, NCT00104858, NCT00105001, NCT00110058, NCT00397813, NCT00793572, NCT01231412, NCT01252667, NCT01527045.

Are Clostridioides difficile infections being overdiagnosed in hematopoietic stem cell transplant recipients?

BACKGROUND: Because both diarrhea due to other causes and gastrointestinal colonization with toxigenic Clostridioides difficile are common in HSCT, there is a possibility of false-positive diagnoses of C difficile infections (CDI). METHODS: We estimated the probability of a patient being colonized by toxigenic C difficile by testing non-diarrheal surveillance stools from 223 HSCT recipients and the probability that a specimen submitted for C difficile testing was not CDI by determining the number of clinical tests that returned negative from this cohort. The number of expected false-positive CDI was estimated using these probabilities and compared with observed clinical test results. RESULTS: The expected false-positive and the observed numbers of positive clinical results were similar. The 20 patients diagnosed with CDI were also similar to 142 patients with diarrhea and C difficile-negative stools in number of stools on day of testing, associated symptoms, and the recorded number of days to formed stools. C difficile colonization was most commonly detected during the first week and CDI during the second. Retrospective analysis of 837 patients showed that 18 stools were submitted for each diagnosis of CDI. Ribotyping of the surveillance samples showed 17 ribotypes. CONCLUSIONS: Although several assumptions could impact the accuracy of our false-positive CDI estimates, it appears that many HSCT recipients diagnosed with CDI may actually represent colonized status and an alternative cause of diarrhea. Diagnostic stewardship, including limiting CDI diagnoses to patients with positive toxin and restricting stool submissions to patients with more severe symptoms, may decrease the number of false-positive diagnoses.

Clostridioides difficile colonization and infection in patients admitted for a first autologous transplantation: Incidence, risk factors, and patient outcomes.

BACKGROUND: More data are needed regarding the incidence, risk factors, and outcomes for Clostridioides difficile infection (CDI) and colonization in patients undergoing an autologous hematopoietic stem cell transplantation (AHSCT). METHODS: We studied 472 consecutive patients admitted for a first AHSCT and conducted a prospective C difficile stool surveillance and ribotyping analysis in a subset of 94 patients. RESULTS: Clostridioides difficile infection was diagnosed in 7% of patients for an incidence of 3.4 CDI/1000 inpatient days, recurrent/reinfection CDI was rare. CDI was increased in patients who were colonized on admission, had required a recent pre-admission inpatient stay for fever and/or serious infection, or received empiric therapy with a carbapenem or extended-spectrum penicillin. CDI was associated with a longer length of stay and higher hospital costs. Twelve of 94 patients (13%) were found to have colonization on admission; CDI was diagnosed in 27% of these vs 1% in those with initial negative stools. Colonization in the hospital for those negative on admission was infrequent. C difficile ribotyping showed a predominance of 014/020. CONCLUSIONS: Clostridioides difficile infection is a significant infection in patients receiving a first AHSCT. The risk factors identified may be useful in designing preventive interventions.

Decrease in vancomycin-resistant Enterococcus colonization associated with a reduction in carbapenem use as empiric therapy for febrile neutropenia in patients with acute leukemia.

OBJECTIVE: To compare the effects of empiric carbapenems versus cycling cefepime and piperacillin/tazobactam on the rates of vancomycin-resistant Enterococcus (VRE) colonization, bloodstream infections, and outcomes of patients admitted with acute leukemia. DESIGN: Retrospective clinical study with VRE molecular strain typing and gastrointestinal microbiome comparison. SETTING: A regional referral center for acute leukemia. PATIENTS: 342 consecutive patients admitted with newly diagnosed acute leukemia. METHODS: In September 2015, we changed our empiric antibiotic of choice for neutropenic fever from a carbapenem to the cycling regimen. We studied 214 consecutive patients during the carbapenem period and 128 during the cycling period. Surveillance for VRE stool colonization was conducted weekly. Representative stool samples were analyzed for VRE MLST types and changes in the composition and diversity of the fecal microbiota. RESULTS: The change in empiric antibiotics was associated with a significant decrease in VRE colonization (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.27-0.66), a switch in the dominant VRE MLST types on the unit, and some modifications in the gastrointestinal microbiome. There were no differences in total gram-positive or gram-negative BSIs. During the carbapenem period, we observed higher absolute numbers of Candida spp and fewer ESBL BSIs, but these did not reach statistical significance. Patients during the carbapenem period had longer lengths of stay and durations of severe neutropenia and 10% higher hospital cost. CONCLUSIONS: Carbapenem-sparing empiric antibiotic regimens may have advantages related to VRE ecology, gastrointestinal dysbiosis, duration of neutropenia, cost and length of stay.

Clostridioides difficile colonization and infection in patients with newly diagnosed acute leukemia: Incidence, risk factors, and patient outcomes.

BACKGROUND: The frequency, risk factors, and outcomes for Clostridioides difficile infection (CDI) in patients with newly diagnosed acute leukemia (AL) admitted for induction therapy are unclear. METHODS: We studied 509 consecutive patients with AL admitted between 2006 and 2017 and conducted a prospective C difficile surveillance and ribotyping analysis in a subset of these. RESULTS: The incidence of CDI was 2.2/1,000 inpatient days during induction, and CDI was rare after discharge. CDI was highest in patients with acute myelogenous leukemia. A hospitalization shortly before admission and administration of a greater number of antibiotics increased the risk for CDI. No single class of antibiotics conveyed an increased risk. All cases were successfully treated, and CDI was not associated with an increase in length of stay, costs, or mortality. In a subgroup analysis, 16% of patients with acute myelogenous leukemia and 4% with other leukemia types were colonized on admission. Colonization was associated with a higher risk of CDI. Ribotyping of available isolates showed 27 different strain types with 014/020 and 027 being the most frequent. CONCLUSIONS: The number of antibiotics administered are a major risk factor for CDI in patients with AL. However, CDI appears to have minimal clinical impact in this population.

Genomic analysis of adult B-ALL identifies potential markers of shorter survival.

B lymphoblastic leukemia (B-ALL) in adults has a higher risk of relapse and lower long-term survival than pediatric B-ALL, but data regarding genetic prognostic biomarkers are much more limited for adult patients. We identified 70 adult B-ALL patients from three institutions and performed genome-wide analysis via single nucleotide polymorphism (SNP) arrays on DNA isolated from their initial diagnostic sample and, when available, relapse bone marrow specimens to identify recurring copy number alterations (CNA). As B-cell developmental genes play a crucial role in this leukemia, we assessed such for recurrent deletions in diagnostic and relapse samples. We confirmed previous findings that the most prevalent deletions of these genes occur in CDKN2A, IKZF1, and PAX5, with several others at lower frequencies. Of the 16 samples having paired diagnostic and relapse samples, 5 showed new deletions in these recurrent B-cell related genes and 8 showed abolishment. Deletion of EBF1 heralded a significant negative prognostic impact on relapse free survival in univariate and multivariate analyses. The combination of both a CDKN2A/B deletion and an IKZF1 alteration (26% of cases) also showed a trend toward predicting worse overall survival compared to having only one or neither of these deletions. These findings add to the understanding of genomic influences on this comparably understudied disease cohort that upon further validation may help identify patients who would benefit from upfront treatment intensification.

Phase 2 study of intensified chemotherapy and allogeneic hematopoietic stem cell transplantation for older patients with acute lymphoblastic leukemia.

BACKGROUND: Outcomes among older patients with acute lymphoblastic leukemia remain poor. This study sought to determine the efficacy of an intensified, multi-agent approach derived from a Dana-Farber consortium trial in younger adults for patients older than 50 years (trial identifier NCT00973752). METHODS: The primary endpoint was overall survival (OS) at 1 year. Patients received induction chemotherapy with vincristine, prednisone, doxorubicin, and pegylated asparaginase. Imatinib was incorporated for Philadelphia chromosome-positive disease. After induction, the first consolidation incorporated clofarabine. Patients in remission could proceed to allogeneic hematopoietic cell transplantation (HCT) after induction and consolidation I. Those not receiving HCT went on to receive central nervous system, consolidation II, and continuation phases of treatment. RESULTS: Thirty patients were enrolled: 19 achieved a complete remission (CR) after induction and 1 achieved CR after consolidation I for a CR rate of 67%. Sixteen patients underwent HCT. The proportion surviving at 1 year was 63%, and this met the primary endpoint. The 2-year OS rate was 52% (n = 30), and the 2-year disease-free survival rate was 52% for patients achieving CR (n = 20). There was no survival advantage among those undergoing HCT. Therapy-related hyperbilirubinemia prompted adjustments and limitations to asparaginase dosing. CONCLUSIONS: Intensified chemotherapy can result in improved outcomes in comparison with historical data. Additional studies of similarly intensive regimens are warranted in this population. Cancer 2016;122:2379-2388. © 2016 American Cancer Society.

Frequency, risk factors, and outcomes of vancomycin-resistant Enterococcus colonization and infection in patients with newly diagnosed acute leukemia: different patterns in patients with acute myelogenous and acute lymphoblastic leukemia.

OBJECTIVE To determine the frequency, risk factors, and outcomes for vancomycin-resistant Enterococcus (VRE) colonization and infection in patients with newly diagnosed acute leukemia. DESIGN Retrospective clinical study with VRE molecular strain typing. SETTING A regional referral center for acute leukemia. PATIENTS Two hundred fourteen consecutive patients with newly diagnosed acute leukemia between 2006 and 2012. METHODS All patients had a culture of first stool and weekly surveillance for VRE. Clinical data were abstracted from the Intermountain Healthcare electronic data warehouse. VRE molecular typing was performed utilizing the semi-automated DiversiLab System. RESULTS The rate of VRE colonization was directly proportional to length of stay and was higher in patients with acute lymphoblastic leukemia. Risk factors associated with colonization include administration of corticosteroids (P=0.004) and carbapenems (P=0.009). Neither a colonized prior room occupant nor an increased unit colonization pressure affected colonization risk. Colonized patients with acute myelogenous leukemia had an increased risk of VRE bloodstream infection (BSI, P=0.002). Other risk factors for VRE BSI include severe neutropenia (P=0.04) and diarrhea (P=0.008). Fifty-eight percent of BSI isolates were identical or related by molecular typing. Eighty-nine percent of bloodstream isolates were identical or related to stool isolates identified by surveillance cultures. VRE BSI was associated with increased costs (P=0.0003) and possibly mortality. CONCLUSIONS VRE colonization has important consequences for patients with acute myelogenous leukemia undergoing induction therapy. For febrile neutropenic patients with acute myelogenous leukemia, use of empirical antibiotic regimens that avoid carbapenems and include VRE coverage may be helpful in decreasing the risks associated with VRE BSI.

The impact of involved field radiation therapy in the treatment of relapsed or refractory non-Hodgkin lymphoma with high-dose chemotherapy followed by hematopoietic progenitor cell transplant.

BACKGROUND: Patients with refractory/relapsed non-Hodgkin lymphoma (NHL) often receive high-dose chemotherapy (HDCT) followed by hematopoietic progenitor cell transplant (HPCT) as salvage therapy. We examined the role of involved field radiation therapy (IFRT) in this setting. METHODS: The records of 167 patients with refractory/relapsed NHL who underwent HDCT followed by HPCT between February 1990 and November 2003 were reviewed. Fifty-three patients received IFRT and 114 did not receive IFRT in the peritransplant period. RESULTS: Eighty patients were alive at the time of analysis with a median follow up for alive patients of 4.5 years in the no IFRT group and 4.2 years in the IFRT group (P = 0.53). Patients undergoing IFRT were more likely to have bulky (P = 0.02) and extranodal (P= 0.04) disease at initial diagnosis. There was no significant difference between the treatment groups regarding mortality in the first 100 days after HPCT (P = 0.31). Five-year overall survival rates were 46.7% for the no IFRT group and 40.0% for the IFRT group (P= 0.15). Disease-free survival was significantly worse for patients receiving IFRT (P = 0.02); however, when considering local control, the addition of IFRT resulted in a 5-year rate similar to that for patients who did not receive IFRT (68.6% vs. 72.0% respectively, P= 0.73). CONCLUSIONS: Although disease-free survival was inferior in patients who received IFRT, despite more adverse clinical features the use of IFRT resulted in similar rates of local control and overall survival compared with those who did not receive IFRT. The use of IFRT was not associated with an increase in the risk of acute mortality or late events.

The impact of involved field radiation therapy for patients receiving high-dose chemotherapy followed by hematopoietic progenitor cell transplant for the treatment of relapsed or refractory Hodgkin disease.

OBJECTIVES: Patients with refractory/relapsed Hodgkin disease (HD) often receive high-dose chemotherapy (HDCT) followed by hematopoietic progenitor cell transplant (HPCT) as salvage therapy. This study sought to determine if involved field radiation therapy (IFRT) in this setting improves patient outcomes. METHODS: The records of 65 patients with refractory/relapsed HD who underwent HDCT followed by HPCT between September 1988 and October 2003 were retrospectively reviewed. Forty-four patients did not receive IFRT and 21 received IFRT. RESULTS: Thirty-eight patients were alive at the time of analysis with a median follow-up of 3.4 years in the no IFRT group and 1.8 years in the IFRT group (P = 0.38). IFRT patients were more likely to have bulky disease at initial diagnosis (P = 0.05). Progression-free survival (PFS) was similar in the 2 groups (P = 0.83). Twenty-two patients in the no IFRT group and 5 in the IFRT group have died (P = 0.06). Five-year overall survival rates were 55.6% for the no IFRT group and 73.3% for the IFRT group (P = 0.16). There was no significant difference between the treatment groups regarding mortality in the first 100 days after HPCT (P = 0.41), late events (P = 0.26), or failure in sites previously involved with disease (P = 0.76). CONCLUSIONS: Although the current study did not demonstrate an improvement in PFS with the addition of IFRT to HDCT and HPCT, there was a trend toward improved overall survival. The potential benefit of IFRT may be underestimated because of the heterogeneity of the treatment groups. The use of IFRT was not associated with an increase in the risk of acute mortality or late events.

Malignant infantile osteopetrosis and primary pulmonary hypertension: a new combination?

Malignant infantile osteopetrosis (MIOP), a rare genetic disorder of the osteoclast, is fatal without hematopoietic stem cell transplantation. Primary pulmonary hypertension (PPH), a rare progressive disorder of the pulmonary circulation, is predominantly fatal in the absence of successful therapy. A clinical association between these two disorders has not been recognized and a pathophysiologic link between osteoclast function and pulmonary vascular pressure as a rationale for such an association is not readily apparent. Here, we report five infants with MIOP, without cardiac abnormalities, who were found to have PPH after undergoing stem cell transplantation. We suggest that PPH may be linked to a specific variant of MIOP and recognizing the potential for pulmonary hypertension in children with MIOP may lead to a more rapid diagnosis and life-saving intervention.