Background.Patients with blood disorders colonized with antibiotic-resistant bacteria (ARB) are prone to systemic infections that are difficult to treat. Reintroduction of commensal bacteria in a murine model of enterococcal colonization of the gut can lead to eradication of enterococci. We hypothesized that fecal microbiota transplantation (FMT) could be used to eradicate ARB in humans.Methods. Participants colonized with ARB were treated with intraduodenal FMT according to a prospective protocol (NCT02461199). The primary endpoint was complete ARB decolonization at 1 month after FMT. Secondary endpoints included safety assessment and partial ARB decolonization. Microbiome sequencing was performed to investigate the influence of microbial composition of the transplanted material on the outcome of FMT.Results. Twenty-five FMTs were performed in 20 participants (including 40% who had neutropenia) who were colonized by a median of 2 (range, 1-4) strains of ARB. The primary endpoint was reached in 15/25 (60%) of the FMTs and more frequently in cases in which there was no periprocedural use of antibiotics (79% vs 36%, P < .05). Among participants, 15/20 (75%) experienced complete ARB decolonization. There were no severe adverse events, and partial ARB decolonization was observed in 20/25 (80%) of the FMTs. The microbiota composition analysis revealed higher abundance of Barnesiella spp., Bacteroides, and Butyricimonas and greater bacterial richness in the fecal material, resulting in eradication of Klebsiella pneumoniae compared with nonresponders.Conclusions. FMT in patients with blood disorders is safe and promotes eradication of ARB from the gastrointestinal tract. Clinical Trials Registration. NCT02461199.

In this prospective randomized trial, we compared the efficacy and toxicity of cladribine (2-CdA) alone to 2-CdA combined with cyclophosphamide (CC) or cyclophosphamide and mitoxantrone (CMC) in untreated progressive chronic lymphocytic leukemia (CLL). Study end points were complete response (CR), overall response, minimal residual disease (MRD), progression-free survival, overall survival, and toxicity. From January 1, 1998 to December 31, 2003, 508 patients from 15 hematology departments were randomized. Compared with 2-CdA, CMC induced higher CR rate (36% vs 21%, P ‫؍‬ .004), and a trend for higher CR rate with CC was observed (29% vs 21%, P ‫؍‬ .08). Furthermore, the percentage of patients who were in CR and were MRD negative was higher in CMC compared with 2-CdA (23% vs 14%, P ‫؍‬ .042). There were no differences in overall response, progressionfree survival, and overall survival among treatment groups. Grade 3/4 neutropenia occurred more frequently in CC (32%) and CMC (38%) than in 2-CdA (20%) (P ‫؍‬ .01 and P ‫؍‬ .004, respectively). Infections were more frequent in CMC compared with 2-CdA (40% vs 27%, P ‫؍‬ .02).In conclusion, CMC used in first-line treatment of CLL results in a higher CR rate and suppresses MRD more efficiently than 2-CdA monotherapy, although associates with increased toxicity. No important differences in efficacy and toxicity were found between CC and 2-CdA regimens.

PURPOSE Little is known about comparison of the activity of different purine nucleoside analogs in chronic lymphocytic leukemia (CLL). We conducted a randomized phase III trial to compare efficacy and safety of cladribine and fludarabine, each combined with cyclophosphamide, in previously untreated progressive CLL. PATIENTS AND METHODS Patients received cladribine at 0.12 mg/kg combined with cyclophosphamide at 250 mg/m(2) for 3 days intravenously (CC regimen) or fludarabine at 25 mg/m(2) combined with cyclophosphamide at 250 mg/m(2) for 3 days intravenously (FC regimen), every 28 days for up to six cycles. The primary end point was complete response (CR) rate. Secondary end points included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related toxicity. RESULTS Of 423 randomly assigned patients (211 to CC and 212 to FC), 395 were evaluated in the final analysis. The CR and ORR reached 47% and 88% in the CC arm and 46% and 82% in the FC arm (P = .25 and P = .11, respectively). The median PFS was 2.34 years with CC and 2.27 years with FC (P = .51). OS and grade 3/4 treatment-related toxicity were also comparable. Moreover, we did not observe any significant differences in CC and FC efficacy across different patient prognostic subgroups that included patients with 17p13 (TP53 gene) deletion who had poor survival in both study arms. CONCLUSION Cladribine and fludarabine in combination with cyclophosphamide are equally effective and safe first-line regimens for progressive CLL. Both combinations have unsatisfactory activity in patients with 17p13 (TP53 gene) deletion.

Cladribine (2-chlorodeoxyadenosine, 2-CdA) treatment-associated infections may shorten potentially long-term survival in hairy cell leukemia (HCL). In search of the optimal mode of 2-CdA administration, 132 patients with untreated HCL were randomized to receive either standard 5-day 2-CdA protocol or a novel schedule of 6 weekly 2-CdA infusions suggested to be less toxic. Analysis of treatment response confirmed similar complete remission rates, overall response rates, progressionfree survival, and overall survival in both 2-CdA protocols. However, we did not observe lower toxicity in the weekly schedule. Of special interest, no significant differences were found in the rate of grade 3/4 infections (18% for daily and 26% for weekly protocol, difference ؊8.2%; 95% confidence interval [CI] ؊23.2% to 6.9%; P ‫؍‬ .28) and the rate of septic deaths (3% for daily and 2% for weekly protocol, difference 1.4%; 95% CI ؊4.3% to 7.0%; P ‫؍‬ .64). In conclusion, HCL treatment with weekly 2-CdA infusions is equally effective but no safer than the standard 5-day 2-CdA protocol. IntroductionCladribine (2-chlorodeoxyadenosine, 2-CdA) belongs to standard therapeutic options for hairy cell leukemia (HCL). In chemotherapy-naive HCL, one course of 2-CdA induces complete response (CR) and long-term survival in the vast majority of patients. [1][2][3][4][5] Given this considerable clinical efficacy, the major challenge regarding 2-CdA therapy is reduction of side effects, especially severe infections that may lead to septic death. Lauria et al 6 suggested that a novel schedule based on 6 weekly 2-hour 2-CdA infusions could be as effective as the standard 7-day and 5-day protocols but associated with less neutropenia and fewer life-threatening infections. To test the potential clinical benefit of the weekly schedule, in 1998 the Polish Adult Leukemia Group (PALG) initiated a prospective multicenter, randomized comparison with 5-day 2-CdA infusion that is the standard treatment of active HCL in Poland. Patients, materials, and methodsThe study was carried out at 14 hematology centers, with central randomization and data management performed in the Department of Hematology at the Medical University of Lodz. The study was approved by the ethics committee of the Medical University of Lodz, and all patients gave informed consent in accordance with the Declaration of Helsinki. Eligibility criteriaPatients with untreated, active HCL, World Health Organization (WHO) scale performance status better than grade 4, normal liver and renal function, without secondary neoplasm, and age 18 years or older were considered eligible. The diagnosis of HCL and the criteria of activity of disease were defined as previously reported. Preliminary results of this study were presented at 46th annual meeting of the American Society of Hematology, San Diego, CA, December 4-7, 2004, 17 and at the 48th annual meeting of the American Society of Hematology, Orlando, FL, December 9-12, 2006. 18 The publication costs of this article were defrayed in part by page...

Between January 1991 and December 1997, 103 patients, 97 with typical hairy cell leukemia (HCL) and 6 with HCL‐variant (HCL‐V) were treated with 2‐chlorodeoxyadenosine (2‐CdA) given as 2‐h infusion for 5 consecutive d at a daily dose 0.12 mg/kg. To our knowledge this is the largest cohort of HCL patients treated with this type of regimen. Median follow‐up amounted to 36 months. Fifty‐six of 97 patients with typical HCL were newly diagnosed and 41 were relapsed after previous treatment. Splenectomy as a first‐line therapy was performed in 23 patients and 18 remaining patients received prednisone, chlorambucil or interferon‐α (IFN‐α) alone or in combinations. Seventy‐five (77.3%) patients entered CR and 18 (18.6%) achieved PR, giving an overall response rate of 95.9%. The mean time of first CR duration amounting to 32 months (range 3–72) did not correlate to the number of 2‐CdA cycles. 2‐CdA was equally effective in treatment of newly diagnosed patients and patients who relapsed after previous therapeutic procedures. Relapse of the disease occurred in 20 of 75 patients who achieved CR after 2‐CdA and was usually manifested by very discrete changes in peripheral blood counts (neutropenia and/or relative lymphocytosis). The mean progression‐free survival (PFS) time in this group was 37.4 (range 10–66) months. Ten of 20 relapsed patients were retreated with 2‐CdA given an identical course to the first one. Seven patients entered second CR lasting 19+ (range 8–47) months and 3 experienced PR. This confirms the previous observations that 2‐CdA gives no resistance to leukemic clone. Ten remaining patients have not required retreatment so far and remain in a good clinical and hematological state. The results of HCL‐V treatment with 2‐CdA were poor. Only 2 patients achieved PR and 4 patients did not respond to this drug. Seven patients (5 with typical HCL and 2 with HCL‐V) died, 3 of causes unrelated to the disease. Second neoplasms were noted in 5 patients. 2‐CdA‐related side effects resulted mainly from myelosuppression and infectious complications. In conclusion we confirm the effectiveness of 2‐CdA in inducing CR in patients with typical HCL, but this drug is unable to completely eradicate the leukemic clone which results in the relapse of the disease. The real incidence of the relapse rate may be underestimated unless bone marrow biopsy is performed. The results of our study indicate that a 2‐h infusion of 2‐CdA in HCL patients is at least as effective as a 24‐h infusion but more convenient to the patients, and may be given on an outpatient basis.