Background/Objectives: Allogeneic hematopoietic stem cell transplantation (alloSCT) is a curative treatment for myeloid diseases, yet relapse remains the major cause of post-transplant mortality. To reduce the risk of recurrence, we evaluated the addition of 400 cGy total body irradiation (TBI) to conditioning with fludarabine-busulfan (Flu/Bu4). Methods: In this prospective study, 46 patients with myeloid diseases were randomized to Flu/Bu4 or Flu/Bu4/TBI conditioning group. The Flu/Bu4 conditioning regimen consisted of fludarabine 40 mg/m² on days -6 to -3 followed by busulfan 130 mg/m² on days -6 to -3. Flu/Bu4/TBI conditioning regimen added 400 cGy TBI on day -1 to the FluBu4 regimen. Results: Among 34 acute myeloid leukemia (AML) patients, relapse was numerically lower in those who received Flu/Bu4/TBI (25%) versus Flu/Bu4 (44.4%) at three years (HR = 0.58, 95% CI 0.19 to 1.81, p = 0.35). Flu/Bu4/TBI appeared to increase the risk of non-relapse mortality (NRM) vs. Flu/Bu4 in AML patients at three years (25.0% versus 11.1%; HR = 2.11, 95% CI 0.51 to 8.83, p = 0.65). Overall survival (OS) was similar in AML patients undergoing conditioning with Flu/Bu4 (72.2%) versus Flu/Bu4/TBI (62.5%) at one year (p = 0.4). Conclusions: In conclusion, the addition of 400 cGy TBI to Flu/Bu4 reduced the risk of relapse but did not improve OS as a consequence of higher regimen-related mortality. Clinicaltrials.gov identifier: NCT01366612.

Background: Disease relapse is a primary cause of treatment failure after hematopoietic stem cell transplantation in the treatment of malignancy. Consolidation therapy early after transplantation may reduce this risk, but it is difficult to administer in the setting of various post-transplant complications. We proposed that testing donor cell chimerism and for persistent minimal residual disease (MRD) with next-generation sequencing (NGS) of plasma cell-free DNA (cfDNA) early after transplantation would identify those patients at higher risk of relapse who would possibly benefit from consolidation therapy. Methods: We enrolled 20 subjects with known tumor-associated somatic mutations into this prospective pilot study, testing plasma samples before and at 28, 56, and 84 days after transplantation. Pre- and post-transplant bone marrow samples were also analyzed. All samples were subjected to an agnostic, commercially available panel covering 302 genes. Results: Significantly more mutations (p < 0.0001) were detected in the plasma cfDNA than in the bone marrow cells in pre-transplant testing (92 versus 61 mutations, respectively), most likely reflecting sampling variation when bone marrow was used. Two subjects were negative for MRD in staging studies immediately before transplants. Most (19/20) subjects had intermittent or sustained MRD detected in post-transplant plasma cfDNA testing, albeit with much lower average variant allele frequencies (VAFs). Six out of 20 subjects suffered relapses within 12 months after transplantation, and all 6 could be identified by adverse-risk driver mutations that persisted after transplantation. No patients who cleared the adverse-risk mutations relapsed. Donor chimerism using cfDNA fell for all relapsed patients and contributed to the identification of patients at early risk for relapse. Conclusions: These data demonstrate that testing plasma cfDNA for persistent leukemia-associated somatic mutations and donor chimerism as early as 28 days after transplantation will identify a subset of patients with high-risk mutations who are at high risk of relapse. This early assessment of relapse risk may facilitate modifications to the treatment plan, reducing the risk of treatment failure.

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Background: Fluoroquinolone prophylaxis during autologous stem cell transplantation (aSCT) reduces the risk of fever but raises the risk of bloodstream infection (BSI) with fluoroquinolone-resistant Enterobacterales (FRE). We performed a prospective cohort study to detect the presence and potential gain or loss of colonic FRE colonization using serial sampling before and after aSCT in a uniform population of patients with a diagnosis of multiple myeloma. Methods: Eligible subjects underwent aSCT after conditioning with dose-intense melphalan, 200 mg/m². Peri-anal swabs were obtained before aSCT, upon hospital discharge, and 12–16 weeks after transplantation. Samples were cultured in tryptic soy broth supplemented with either ciprofloxacin or ceftriaxone with subsequent plating onto selective chromogenic agar designed to facilitate recovery and differentiation of Enterobacterales. Results: FRE colonization on pre-transplant sampling was detected for 23 of 117 subjects (19.7%) and 29 of 98 (29.6%) subjects at hospital discharge after a course of fluoroquinolone (116/117 subjects) prophylaxis (p < 0.001) and 28 of 92 (30.4%) subjects at 12–16 weeks. Including all three sampling time points, 48 of 117 subjects (41.0%) tested positive for FRE colonization. In total, 58 of the 90 FRE isolates (64.4%) from 48 subjects expressed extended-spectrum beta-lactamase (ESBL). Three FRE-colonized subjects developed FRE BSI. Bloodstream isolates for two subjects were identical to the organisms identified on pre-transplant sampling. Conclusions: We hypothesize that fluoroquinolone prophylaxis of subjects with undetected low levels of FRE colonization allows the expansion of the FRE population, placing subjects at risk of BSI with fluoroquinolone-resistant (and ESBL-expressing) Enterobacterales. Pre-transplant testing for FRE colonization permits patient-specific design of prophylactic and empiric antibiotic regimens.