Experts’ considerations on HLA‐haploidentical stem cell transplantation

Recently, novel strategies to control graft‐versus‐host disease and facilitate engraftment have allowed an increasing number of human leukocyte antigen (HLA)‐haploidentical hematopoietic stem cell transplantation (haploHSCT) to be performed. A meeting was convened to review the biological rationale and the clinical results of various T‐cell‐depleted (TCD) and T‐cell‐replete (TCR) HLA‐haploidentical ‘transplant platforms’. The objective of the meeting was to promote discussion and consent among leading researchers in the field on three main crucial issues for haploHSCT: (i) eligibility criteria, (ii) choice of the most suitable donor, and (iii) choice of the most appropriate transplant platform. The experts in attendance agreed that a patient who is eligible for an allogeneic transplant and lacks an HLA‐identical sibling or an HLA‐matched unrelated donor should be considered for an alternative donor transplant. Together with the experience of the individual center, the most important decision criteria in choosing an alternative donor source should be the rapidity of transplantation so as to avoid disease relapse/progression. The choice of the mismatched donor should be driven by younger age, ABO blood group compatibility, and Cytomegalovirus status. If a TCD transplant is planned, NK‐alloreactive donors and/or the mother should be preferred. Prospective comparative studies are needed to establish the relative efficacy of different transplant platforms. However, expertise in stem cell manipulation and in adoptive immunotherapy is essential if a TCD transplant platform is chosen.     

Management of post‐transplant lymphoproliferative disorders

The post‐transplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of neoplasms that are one of the most serious complications of bone marrow and solid organ transplants. Because these disorders are rare, there are no randomized trials from which to derive optimal treatment. Management can be challenging and must balance the goal of PTLD eradication with the risks of graft rejection, graft‐versus‐host disease, further delays in immune reconstitution and life‐threatening infections, among others. This paper will provide a comprehensive review of PTLD following solid organ transplant and haematopoietic stem cell transplant with a focus on management. Included is a discussion of novel agents that are being studied in clinical trials and, when combined or sequenced with conventional therapy, have the potential to improve outcomes.     

Biopsy‐proven adenoviral diarrhea responding to low‐dose cidofovir

Abstract: We present a case of diarrhea secondary to biopsy‐proven adenovirus (ADV) infection after autologous peripheral hematopoietic stem cell transplant for multiple myeloma. The patient had a negative plasma polymerase chain reaction for ADV and a dramatic clinical response to low‐dose cidofovir. To our knowledge, this is the first report in an adult hematopoietic stem cell recipient of the use of low‐dose cidofovir to treat proven ADV gastrointestinal infection.     

Severe COVID‐19 in a patient with chronic graft‐versus‐host disease after hematopoietic stem cell transplant successfully treated with ruxolitinib

Graft‐versus‐host disease (GVHD) is a common complication of hematopoietic stem cell transplant, which is known to be mediated by cytotoxic T‐cell effectors and dysregulated inflammatory cytokines. Similarly, the lung injury observed in severe COVID‐19 cases appears to be related to a massive production of pro‐inflammatory cytokines. The selective JAK1/2 inhibitor ruxolitinib has shown promising results in the context of GVHD, and different trials are currently underway in patients with severe COVID‐19; nevertheless, no clinical observation of safety or efficacy of treatment with ruxolitinib in this context has been published yet. We describe a first case of severe COVID‐19 developed after hematopoietic stem cell transplantation in a patient with a concomitant chronic GVHD (cGVHD), in which a treatment with ruxolitinib was administered with good tolerance and positive outcome.     

Substantial variation in post‐engraftment infection prophylaxis and revaccination practice in autologous stem cell transplant patients

There is a paucity of evidence supporting the necessity or duration of Pneumocystis jirovecii and antiviral prophylaxis as well as revaccination following autologous stem cell transplant (ASCT). A survey aimed at evaluating these policies was distributed to 34 ASCT centres across Australasia. The 26 survey respondents demonstrated significant heterogeneity in their infection prophylaxis and revaccination strategy post‐transplant despite the availability of consensual guidelines.     

Trimethoprim–sulfamethoxazole‐induced rhabdomyolysis in an allogeneic stem cell transplant patient

P.J. Kiel, N. Dickmeyer, J.E. Schwartz. Trimethoprim–sulfamethoxazole‐induced rhabdomyolysis in an allogeneic stem cell transplant patient.
Transpl Infect Dis 2010: 12: 451–454. All rights reserved Abstract: Rhabdomyolysis is a serious, potentially life‐threatening complication diagnosed when creatine phosphokinase levels exceed 1000 U/L. Although many drugs are associated with rhabdomyolysis, the previous reports of trimethoprim–sulfamethoxazole (TMP/SMX)‐induced rhabdomyolysis have involved patients with human immunodeficiency virus/acquired immunodeficiency syndrome. This is the first report, to our knowledge, of TMP/SMX‐induced rhabdomyolysis in an allogeneic stem cell transplant patient.     

Rescue haploidentical peripheral blood stem cell transplantation for engraftment failure: a single‐centre case series

Graft failure affects approximately 5% of allogeneic stem cell transplants, with a poor prognosis. Salvage second allogeneic stem cell transplantation (alloSCT2) is limited by high rates of transplant‐related mortality from infection and graft‐versus‐host disease. We report on five adult patients receiving rescue alloSCT2 using haploidentical peripheral blood stem cells. All patients achieved neutrophil engraftment, two subsequently died from sepsis and disease relapse, respectively. Three patients remain alive up to 2 years post‐transplant. We suggest consideration of haploidentical alloSCT2 for patients with graft failure.     

Pulmonary Arteriovenous Malformations Presenting as Platypnea‐Orthodeoxia in Graft‐Versus‐Host Disease

This case highlights the utility of agitated saline studies during transesophageal echocardiography (TEE) for detection of pulmonary arteriovenous malformations (PAVM) as a viable alternative to contrast‐enhanced imaging studies. By carefully studying each pulmonary vein individually during saline contrast studies, TEE is able to demonstrate and localize PAVM. In addition, this report represents the first documentation of PAVM arising as a complication of graft‐versus‐host disease after allogeneic hematopoietic stem cell transplant.     

Acanthamoeba infection in a patient with chronic graft‐versus‐host disease occurring during treatment with voriconazole

Abstract: We report a case of disseminated infection with Acanthamoeba in a patient with graft‐versus‐host disease after hematopoietic stem cell transplant (HSCT) for acute lymphocytic leukemia. The infection involved the brain, skin, and lungs and occurred despite treatment with voriconazole for mold prophylaxis, and did not respond to treatment with multiple other agents reported to have activity against Acanthamoeba. To our knowledge, infection with Acanthamoeba has been reported in 4 other patients after HSCT or bone marrow transplant, and our case is the first to be diagnosed ante‐mortem.     

Diversity of antiviral‐resistant human cytomegalovirus in heart and lung transplant recipients

J.M. Iwasenko, G.M. Scott, Z. Naing, A.R. Glanville, W.D. Rawlinson. Diversity of antiviral‐resistant human cytomegalovirus in heart and lung transplant recipients.
Transpl Infect Dis 2011: 13: 145–153. All rights reserved Abstract: Immunocompromised transplant recipients are at high risk for human cytomegalovirus (CMV)‐related infection and disease. Antiviral prophylaxis and treatment have reduced CMV morbidity and mortality, but at times promote development of antiviral‐resistant CMV strains that can significantly contribute to adverse clinical outcomes in transplant recipients. We have investigated CMV genotypes in transplant recipients (bone marrow, stem cell, kidney, heart, lung, and liver) receiving antiviral prophylaxis or preemptive therapy or treatment, to determine the viral characteristics and clinical impact of antiviral‐resistant CMV in these different groups. Antiviral‐resistant CMV strains were detected by polymerase chain reaction sequencing of the CMV protein kinase (UL97) and viral DNA polymerase (UL54) genes from clinical specimens. A trend toward more frequent detection of multidrug resistance and co‐circulation of multiple resistant strains was seen in heart and lung transplant recipients compared with other transplantation types. A greater diversity and number of UL97 and UL54 mutations were observed in heart and lung transplant recipients; whereas antiviral‐resistant CMV infections in other transplant recipients were predominantly the result of a single mutant genotype. Furthermore, 43% (6/14) of CMV‐positive heart and lung transplant recipients were infected with CMV strains containing UL54 mutations conferring multidrug resistance compared with only 6% (1/18) of CMV‐positive recipients of other transplanted organs or stem cells. Emergence of CMV strains containing previously unrecognized UL54 mutations (F412S and D485N) also occurred in 1 lung and 1 heart transplant recipient. The development of these mutations under antiviral selective pressure, and clinical outcome of infection suggests these mutations are likely to confer antiviral resistance. Emergence of CMV antiviral resistance remains a significant issue in immunocompromised patients treated with antiviral agents, and emphasizes the relevance of regular antiviral resistance testing when designing optimal patient‐management strategies.     

New ways to separate Graft‐versus‐Host Disease and Graft‐versus‐Tumour effects after allogeneic haematopoietic stem cell transplantation

A major challenge to transplant immunologists and physicians remains the separation of harmful graft‐versus‐host disease (GvHD) and beneficial graft‐versus‐tumour (GvT) effects after allogeneic haematopoietic stem cell transplantation. Recent advances in our understanding of the allogeneic immune response provide potential new opportunities to achieve this goal. Three potential new approaches that capitalize on this new knowledge are considered in depth; the manipulation of organ‐specific cytokines and other pro‐inflammatory signals, the selective manipulation of donor effector T cell migration, and the development of cell‐mediated immunosuppressive strategies using donor‐derived regulatory T cells. These new approaches could provide strategies for local control of allogeneic immune responses, a new paradigm to separate GvHD and GvT effects. Although these strategies are currently in their infancy and have challenges to successful translation to clinical practice, all have exciting potential for the future.     

Non‐toxigenic Vibrio cholerae in an autologous stem cell and renal transplant recipient

A patient with a renal transplant after an autologous stem cell transplant for multiple myeloma developed non‐toxigenic Vibrio cholerae diarrhea after travel to Mexico. This is a rare cause of diarrhea in transplant recipients, and the patient had not had pre‐travel counseling. This case reflects the lack of referral of transplant recipients for travel infectious disease review before overseas travel and the role of the live attenuated cholera vaccine.     

Epstein‐Barr virus post‐transplant lymphoproliferative disease (PTLD) after hematopoietic stem cell transplantation

Epstein‐Barr virus (EBV) viremia and post‐transplant lymphoproliferative disease (PTLD) are severe complications after hematopoietic stem cell transplantation (HSCT). A series of risk factors have been found to predict EBV viremia and PTLD, including the T‐cell depletion, reduced intensity conditioning, and alternative donor. The rituximab pre‐emptive therapy could improve PTLD prognosis significantly, but the trigger of initiating rituximab pre‐emptive therapy has not been well established. Additionally, EBV‐specific cytotoxic T cell (CTL) is a promising approach to treat EBV‐PTLD.     

The fludarabine,cytarabine, and granulocyte colony‐stimulating factor (FLAG) chemotherapy regimen is an alternative to anthracycline‐based therapy for the treatment of acute myeloid leukemia for patients with pre‐existing cardiac disease

We conducted a retrospective study assessing FLAG (fludarabine, cytarabine, and granulocyte colony‐stimulating factor) as first‐line treatment in 56 newly diagnosed acute myeloid leukemia patients considered ineligible for anthracycline‐based treatment due to advanced age, significant comorbidities, or pre‐existing cardiac disease. The median age was 69 (21–80); 46% received FLAG for pre‐existing cardiac disease and others due to age (32%), non‐cardiac comorbidities (20%), or previous anthracycline exposure (2%). The induction mortality was 16% and, among evaluable patients, 48% achieved a complete remission after the first induction course with an additional patient achieving a remission after a second course for a total complete remission rate of 50%. Four patients proceeded to an allogeneic stem cell transplant including two with pre‐existing cardiac disease. Among non‐transplanted patients, the relapse rate (RR) was 47%. When censored at time of stem cell transplant, the median relapse‐free survival was 14.7 months. The median overall survival was 9.3 months with 1‐ and 2‐yr survivals of 44% and 22%, respectively. There was no difference in clinical outcomes between patients treated with FLAG for cardiac reasons vs. other reasons. In conclusion, FLAG is a useful alternative to anthracycline‐based induction for Acute myeloid leukemia in those with significant comorbidities including pre‐existing cardiac disease.     

Strongyloides hyperinfection following hematopoietic stem cell transplant in a patient with HTLV‐1‐associated T‐cell leukemia

Strongyloides stercoralis has the potential to cause accelerated autoinfection in immunocompromised hosts. Screening tests for strongyloidiasis may be falsely negative in the setting of immunosuppression. We report a case of Strongyloides hyperinfection syndrome in a patient with human T‐lymphotropic virus type 1‐associated T‐cell leukemia early after hematopoietic stem cell transplant. The diagnosis was made by stool ova and parasite examination, despite a negative screening enzyme‐linked immunosorbent assay. Because of anticipated prolonged neutropenia, an extended course of treatment was utilized.     

Listeria grayi : vancomycin‐resistant,gram‐positive rod causing bacteremia in a stem cell transplant recipient

H. Salimnia, D. Patel, P.R. Lephart, M.R. Fairfax, P.H. Chandrasekar. Listeria grayi: vancomycin‐resistant, gram‐positive rod causing bacteremia in a stem cell transplant recipient
Transpl Infect Dis 2010: 12: 526–528. All rights reserved Abstract: We report the first case of Listeria grayi bacteremia in a stem cell transplant recipient. The patient developed bacteremia with a gram‐positive rod that was initially thought to be Corynebacterium species and a skin contaminant. The organism grew in multiple blood cultures and therapy with vancomycin was initiated. The API Coryne (version 3.0) identified the organism as L. grayi. Susceptibility testing by Etest suggested that the organism was resistant to vancomycin, but susceptible to ampicillin. After therapeutic change from vancomycin to ampicillin, the bacteremia cleared. Empiric therapy with vancomycin for all gram‐positive bacterial infections is not appropriate. Accurate identification and antibiotic susceptibility is important, particularly in those with persistent bacteremia.     

Late relapses following reduced intensity allogeneic transplantation in patients with multiple myeloma: a long‐term follow‐up study

We analysed the long‐term outcomes of 60 multiple myeloma patients who underwent reduced intensity allogeneic stem cell transplantation between August 2000 and March 2008. Regimens included fludarabine and melphalan conditioning (flu‐mel regimen) for allogeneic haematopoietic cell transplant (HCT) or a planned tandem regimen consisting of high‐dose melphalan conditioning for autograft followed by low‐dose total body irradiation conditioning for allogeneic HCT (auto‐allo regimen). Donors included human‐leucocyte‐antigen‐matched siblings (n = 55) or matched unrelated donors (n = 5). With a median follow‐up of 9·8 years, 7‐year overall survival (OS) and progression‐free survival (PFS) were 60% and 31%, respectively. By multivariate Cox regression analysis, disease status of complete response (CR) or partial response (PR) at transplant and the presence of chronic graft‐versus‐host disease were significantly associated with improved OS. Only disease status was significantly associated with improved PFS. We noted a surprising number of very late relapses, with six patients (10%) relapsing between 6 and 12 years post‐transplant. Among the six late relapse patients, all were transplanted within 14 months of diagnosis, five had normal karyotypes, and five were in CR/PR. Our data provide additional evidence that, while survival may be extended by reduced intensity allogeneic transplant, ultimately, it may not offer a cure.     

Safety and efficacy of upfront plerixafor + G‐CSF versus placebo + G‐CSF for mobilization of CD34+ hematopoietic progenitor cells in patients ≥60 and <60 years of age with non‐Hodgkin's lymphoma or multiple myeloma

The efficacy and safety of plerixafor + G‐CSF in enhancing hematopoietic stem cell mobilization and collection has been demonstrated in two phase III studies involving patients with NHL or MM. In these pivotal studies, plerixafor + G‐CSF significantly increased the proportion of patients achieving target stem cell yields, compared to placebo + G‐CSF. In this analysis, we compare the efficacy and safety of plerixafor + G‐CSF versus placebo + G‐CSF in patients enrolled in the two phase III studies, stratified by age: ≥60 years of age and <60 years of age. The proportion of older patients who achieved target stem cell yields was significantly higher in the plerixafor group than in placebo group (NHL: 50.9 vs. 25.4%, P < 0.001; MM: 69.6 vs. 23.7%, P < 0.001). In this older cohort, the median times to neutrophil and to platelet engraftment following autologous stem cell transplant were comparable between the plerixafor and placebo groups. Similar efficacy findings were observed in the younger age group. The most common adverse events (all grades) reported among older patients in the plerixafor group included diarrhea (41.3%), nausea (38.9%), fatigue (30.2%), and injection‐site reaction (29.4%). The frequency of adverse events was similar between the older and the younger age groups. Taken together, our subanalysis demonstrate that plerixafor + G‐CSF can be safely and effectively used in adult patients of all ages, including those ≥60 years, to support optimal stem cell mobilization for autologous stem cell transplantation. Am. J. Hematol. 88:1017–1023, 2013. © 2013 Wiley Periodicals, Inc.     

Outcomes of primary refractory diffuse large B‐cell lymphoma (DLBCL) treated with salvage chemotherapy and intention to transplant in the rituximab era

Rituximab‐containing salvage chemotherapy followed by high‐dose therapy and autologous stem cell transplant (ASCT ) in chemosensitive patients remains the standard of care for patients with relapsed and refractory diffuse large B‐cell lymphoma (DLBCL ). However, its role in those patients achieving less than a complete response to first‐line therapy (primary refractory disease) in the rituximab era is not well defined. We reviewed the outcomes of 82 transplant‐eligible patients with primary refractory DLBCL who underwent salvage therapy with the intent of administering high‐dose therapy and ASCT to patients achieving chemosensitive remission. The estimated 3‐year overall and progression‐free survival for all patients was 38% and 29%, respectively, and 65% and 60% respectively for patients proceeding to stem cell transplant. Long‐term remission was achieved in 45% of patients achieving a partial response (PR) to initial induction therapy and <20% of patients with stable or progression of disease following initial therapy. These results suggest that salvage chemotherapy with the intent of subsequent high‐dose therapy and ASCT remains a feasible strategy in certain patients with primary refractory DLBCL , particularly for those achieving a PR to frontline therapy. The primary barrier to curative therapy in patients with primary refractory disease is resistance to salvage therapy, and future studies should be aimed towards increasing the response rate in this population.     

RB but not R‐HCVAD is a feasible induction regimen prior to auto‐HCT in frontline MCL: results of SWOG Study S1106

Aggressive induction chemotherapy followed by autologous haematopoietic stem cell transplant (auto‐HCT ) is effective for younger patients with mantle cell lymphoma (MCL ). However, the optimal induction regimen is widely debated. The Southwestern Oncology Group S1106 trial was designed to assess rituximab plus hyperCVAD /MTX /ARAC (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone, alternating with high dose cytarabine and methotrexate) (RH ) versus rituximab plus bendamustine (RB ) in a randomized phase II trial to select a pre‐transplant induction regimen for future development. Patients had previously untreated stage III , IV , or bulky stage II MCL and received either 4 cycles of RH or 6 cycles of RB , followed by auto‐HCT . Fifty‐three of a planned 160 patients were accrued; an unacceptably high mobilization failure rate (29%) on the RH arm prompted premature study closure. The estimated 2‐year progression‐free survival (PFS ) was 81% vs. 82% and overall survival (OS ) was 87% vs. 88% for RB and RH , respectively. RH is not an ideal platform for future multi‐centre transplant trials in MCL . RB achieved a 2‐year PFS of 81% and a 78% MRD negative rate. Premature closure of the study limited the sample size and the precision of PFS estimates and MRD rates. However, RB can achieve a deep remission and could be a platform for future trials in MCL .