Anurag K. Singh

Allogeneic Stem Cell Transplantation: A Historical and Scientific Overview

The field of hematopoietic stem cell transplant (HSCT) has made ground-breaking progress in the treatment of many malignant and nonmalignant conditions. It has also pioneered the concepts of stem cell therapy and immunotherapy as a tool against cancer. The success of transplant for hematologic malignancies derives both from the ability to treat patients with intensive chemoradiotherapy and from potent graft-versus-leukemia (GVL) effects mediated by donor immunity. Additionally, HSCT has been a curative therapy for several nonmalignant hematologic disorders through the provision of donor-derived hematopoiesis and immunity. Preclinical and clinical research in the field has contributed to an advanced understanding of histocompatibility, graft-versus-host disease (GVHD), GVL effect, and immune reconstitution after transplant. Improved donor selection, tailored conditioning regimens, and better supportive care have helped reduce transplant-related morbidity and mortality and expanded access. The development of unrelated donor registries and increased utilization of cord blood and partially matched related donor transplants have ensured a donor for essentially everyone who needs a transplant. However, significant barriers still remain in the form of disease relapse, GVHD infectious complications, and regimen-related toxicities. Recent developments in the field of cellular therapy are expected to further improve the efficacy of transplant. In this review, we discuss the current science of HSCT from a historical perspective, highlighting major discoveries. We also speculate on future directions in this field. Cancer Res; 76(22); 6445-51. ©2016 AACR.

Effect of extracorporeal photopheresis on lung function decline for severe bronchiolitis obliterans syndrome following allogeneic stem cell transplantation.

Extracorporeal photopheresis (ECP) is a commonly used treatment for severe graft‐versus‐host‐disease (GVHD). We sought to evaluate the effects of ECP over a prolonged period on forced expiratory volume in 1 s (FEV1) in patients with pulmonary GVHD. We identified eight patients who developed new airflow obstruction following allogeneic stem cell transplantation and a substantial decline in FEV1 despite receiving corticosteroids and standard therapy for pulmonary GVHD. Those eight patients were treated with ECP for a period of 1 year, with a primary endpoint of FEV1 change during this treatment period. Over the first 3 months of ECP, there was no further decline in FEV1 in seven of the eight patients. However, over the 1 year period, only two of the eight patients had stability in FEV1. The rate of FEV1 decline was substantially less once ECP was initiated, though the median FEV1 continued to decline over 1 year of therapy. All patients survived through the first year of ECP therapy. There was a significant decrease in the median dose of prednisone per patient throughout the 12 months of ECP treatment. ECP shows promise in slowing rate of decline of FEV1 in pulmonary GVHD, though the effects may not be long lived. J. Clin. Apheresis 31:347–352, 2016.

Skin Recurrence of Transformed Mycosis Fungoides Postumbilical Cord Blood Transplant despite Complete Donor Chimerism

Background. Allogeneic stem cell transplant is the treatment of choice for systemic cutaneous T-cell lymphoma (CTCL) which provides graft-versus-lymphoma effect. Herein we discuss a case of recurrence of CTCL skin lesions after cord blood transplant in a patient who continued to have 100% donor chimerism in bone marrow. Case Presentation. A 48-year-old female with history of mycosis fungoides (MF) presented with biopsy proven large cell transformation of MF. PET scan revealed multiple adenopathy in abdomen and chest suspicious for lymphoma and skin biopsy showed large cell transformation. She was treated with multiple cycles of chemotherapy. Posttherapy PET scan showed resolution of lymphadenopathy. Later she underwent ablative preparative regimen followed by single cord blood transplant. Bone marrow chimerism studies at day +60 after transplant showed 100% donor cells without presence of lymphoma. However 5 months after transplant she had recurrence of MF with the same genotype as prior skin lesion. Bone marrow chimerism study continued to show 100% donor cells. Conclusion. A differential graft-versus-lymphoma effect in our case prevented lymphoma recurrence systemically but failed to do so in skin. We hypothesize that this response may be due to presence of other factors in the bone marrow and lymph node microenvironments preventing recurrence in these sites.

Retrospective evaluation of fidaxomicin versus oral vancomycin for treatment of Clostridium difficile infections in allogeneic stem cell transplant

OBJECTIVE/BACKGROUND Clostridium difficile infection (CDI) is a potential complication during hematopoietic stem cell transplantation (HSCT), and no specific recommendations exist regarding treatment of CDI in allogeneic SCT patients. Use of metronidazole and oral vancomycin has been associated with clinical failure. Fidaxomicin has previously been found noninferior to the use of oral vancomycin for the treatment of CDI, and no studies have compared the use of oral vancomycin with fidaxomicin for the treatment of CDI in allogeneic SCT. METHODS This retrospective chart review included 96 allogeneic SCT recipients who developed CDI within 100 days following transplantation. Participants were treated with oral vancomycin (n = 52) or fidaxomicin (n = 44). The primary outcome was clinical cure, defined as no need for further retreatment 2 days following completion of initial CDI treatment. Secondary outcomes were global cure, treatment failure, and recurrent disease. RESULTS No differences in clinical cure were observed between patients receiving oral vancomycin or fidaxomicin (75% vs. 75%, p = 1.00). Secondary outcomes were similar between oral vancomycin and fidaxomicin in regards to global cure (66% vs. 67%, p = .508), treatment failure (28% vs. 27%, p = .571), and recurrent disease (7% vs. 5%, p = .747). In a subanalysis of individuals that developed acute graft-versus-host disease following CDI, the difference in mean onset of acute graft-versus-host disease was 21.03 days in the oral vancomycin group versus 32.88 days in the fidaxomicin group (p = .0031). CONCLUSION The findings of this study suggest that oral vancomycin and fidaxomicin are comparable options for CDI treatment in allogeneic SCT patients within 100 days following transplant.

Utility of routine surveillance imaging for diffuse large B-cell lymphoma post autologous transplant: A single center experience

Surveillance scans after autologous stem cell transplant (auto-HCT) for patients with relapsed/refractory (RR) diffuse large B Cell lymphoma (DLBCL) have no proven survival benefit. We studied survival differences among patients with RR DLBCL post auto-HCT whose recurrences were detected clinically versus with routine surveillance imaging. Among the 139 patients with RR DLBCL that underwent auto-HCT from 2000 to 2014 at our institution, 37 relapsed: 21 clinical and 16 radiological. The median time to progression was 167 days for the clinical cohort and 565 days for the radiological cohort (p = 0.03), and median overall survival (OS) was 587 days and not reached, respectively (p = 0.006). Most patients with relapsed DLBCL after auto-HCT were diagnosed clinically and were likely to be detected earlier and have a shorter OS. Relapse in patients with aggressive disease will likely be detected when clinically apparent, and the outcome of these patients is independent of the way the relapse is diagnosed. Thus, universal scanning after auto-HCT appears to have little benefit.

Evaluation of Performance Status and Hematopoietic Cell Transplantation Specific Comorbidity Index on Unplanned Admission Rates in Patients with Multiple Myeloma Undergoing Outpatient Autologous Stem Cell Transplantation

Although outpatient autologous stem cell transplantation (ASCT) is safe and feasible in most instances, some patients undergoing planned outpatient transplantation for multiple myeloma (MM) will need inpatient admission for transplantation-related complications. We aim to evaluate the difference, if any, between outpatient and inpatient ASCT cohorts of MM patients in terms of admission rate, transplantation outcome, and overall survival. We also plan to assess whether the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) and Karnofsky Performance Status (KPS) can predict unplanned admissions after adjusting for confounding factors. Patients with MM (n = 448) who underwent transplantation at our institution between 2009 and 2014 were included in this retrospective analysis. Patients were grouped into 3 cohorts: cohort A, planned inpatient ASCT (n = 216); cohort B, unplanned inpatient admissions (n = 57); and cohort C, planned outpatient SCT (n = 175). The statistical approach included descriptive, bivariate, and survival analyses. There were no differences among the 3 cohorts in terms of type of myeloma, stage at diagnosis, time from diagnosis to transplantation, CD34 cell dose, engraftment kinetics, and 100-day response rates. Serum creatinine was higher and patients were relatively older in both the planned inpatient (median age, 62 years; range, 33 to 80 years) and unplanned (median age, 59 years; range, 44 to 69 years) admission cohorts compared with the outpatient-only cohort (median age, 57 years; range, 40 to 70 years) (P < .05). Performance status (cohort A: median, 90%; range, 60% to 100%; cohort B: 80%, 50% to 100%; cohort C: 80%, 60% to 100%) was lower (P < .05) and HCT-CI score (cohort A: median, 1.78; range, 0 to 8; cohort B: 2.67, 0 to 9; cohort C: 2.16, 0 to 7) was higher (P < .004) in both inpatient groups compared with the planned outpatient cohort. With a median follow up of 5 years, poor performance status (KPS <70%) appeared to be associated with worse survival (P < .002). HCT-CI >2 also appeared to be associated with worse outcomes compared with HCT-CI 0 to 1, the the difference did not reach statistical significance (hazard ratio, 1.41l 95% confidence interval, 0.72 to 2.76). Only 1 patient out of 448 died from a transplantation-related cause. Outpatient transplantation for myeloma is safe and feasible. In our experience, one-third of the patients undergoing outpatient transplantation needed to be admitted for transplantation-related toxicities. Patients in this group had lower preexisting KPS and higher HCT-CI scores. Whether planned admission for this group would have prevented unplanned admissions and undue stress on patients and the healthcare system should be tested in a prospective manner.

Evaluation of cytomegalovirus reactivation and tolerability in seropositive umbilical cord transplant patients after implementation of an intensive prevention strategy

OBJECTIVE/BACKGROUND Cytomegalovirus (CMV) causes significant morbidity and mortality in CMV seropositive patients undergoing umbilical cord blood transplants (UCBT). Our study aimed to describe the incidence of CMV reactivation and burden of disease, as well as the tolerability of an intensive prevention strategy as compared to historical prevention. METHODS This was a retrospective chart review of 33 CMV seropositive patients that underwent UCBT. The intensive prevention strategy in UCBT consisted of ganciclovir 5mg/kg/d intravenously or valganciclovir 900mg by mouth daily initiated at the beginning of the conditioning regimen until Day -2. Then from Day -1 to Day +100, patients received valacyclovir 2g by mouth three times daily, and from Day +101 to Day +365, acyclovir 800mg by mouth twice daily. Historical standard prevention was acyclovir 800mg by mouth twice daily initiated at the beginning of the conditioning regimen until Day +365. RESULTS Thirty-three patients were included from 2008 to 2014. There were no differences in the adverse effects experienced between the two regimens (p=.4). CMV reactivation occurred significantly later with intensive prevention (p=.003). The median CMV viral titer at reactivation was lower in the intensive versus the historic prevention (1,800copies/mL and 2,700copies/mL, respectively), but was not significantly different. CMV disease occurred significantly less often in the intensive group (p=.039). CONCLUSION The results from this study indicate that the intensive prevention strategy was well tolerated, significantly delayed CMV reactivation, and patients had less CMV disease.