Abstract
Outcomes of haploidentical hematopoietic cell transplantation (haplo-HCT) have recently improved. In the past, limitations in expanding this form of transplant were related to profound in vivo and ex vivo T-cell depletion to avoid both primary graft rejection (PGF) and lethal graft-versus-host disease (GvHD). Consequently, T-lymphocyte reconstitution was markedly hindered leading to significant rates of lethal infections associated with high rates of non-relapse mortality (NRM) and relapse of the malignant disease, limiting this strategy only to patients with no suitable donor in place. Recent developments during the last 5 years have changed this scenario dramatically. Novel strategies allowing the add-back of manipulated and selected depletion of T-lymphocytes and post-transplant alloreactive T-cell depletion (TCD) by high-dose cyclophosphamide after unmanipulated bone marrow (BM) or peripheral blood (PB) hematopoietic cell transplantation reach out to almost similar outcomes known from transplants from HLA-matched related and HLA-matched unrelated donors.
Here, we summarize the unique complications of haplo-HCT related to the immunological consequences of crossing the major histocompatibility barrier and potent immunosuppression required during the process of transplantation, such as PGF, genomic loss of HLA-mismatched human leukocyte antigen and viral reactivation, and a consequence of delayed or incomplete immune reconstitution.
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1 Introduction
Allogeneic hematopoietic cell transplantation (allo-HCT) from an one human leukocyte antigen (HLA) haplotype matched first-degree relative donor (haploidentical donor) is increasingly applied to treat patients with advanced and high-risk hematological malignancies who lack an HLA-matched related and unrelated donor [1]. Historically, infectious complications and high relapse rates of the malignant disease were the main limitations after haplo-HCT leading to a highly compromised overall survival (OS) [2]. Complications such as acute GvHD (aGvHD) and primary graft failure (PGF) were significantly reduced by profound in vivo and ex vivo T-cell depletion (TCD) of the allograft [3] providing the basis of principle feasibility of this approach.
However, this strategy of recalled as “historical,” “standard,” or “naked” haploidentical stem cell transplantation came with significant drawbacks: first is the delayed immune reconstitution with an increased and long-term risk of infectious complications. Second, due to the rather advanced stage of the disease at the time of haploidentical transplantation and the delayed immune reconstitution, a significant risk of disease relapse remains. The relapse of acute leukemia especially after haplo-HCT is often associated with loss of the mismatched HLA on the leukemic cell. Finally, with delayed immune reconstitution in place, intense alloreactivity also in host-versus-graft (HvG) direction is associated with an increased risk of graft loss and higher risks of infectious complications.
2 Graft Failure After “Standard” Haploidentical Transplant
Engraftment failure is observed in approximately 1–4% of patients following allo-HCT using HLA-matched related and unrelated donors and about 20% in umbilical cord blood (UCB) or TCD haplo-HCT [4, 5]. The most common cause of graft failure is the immunologic reaction of the residual host immune effector cells against donor cells, the so-called graft rejection. Graft rejection following haplo-HCT is largely caused by HvG reaction mediated by host T- and/or NK cells that survived the conditioning regimen [1].
However, antibody-mediated graft rejection (otherwise known as humoral rejection) has been increasingly recognized as a mechanism of primary graft failure (PGF).
2.1 Graft Rejection Mediated by T- and/or NK Cell Reactivity
The resistance to engraftment of an allogeneic hematopoietic graft was thought to be mediated primarily by residual recipient T-lymphocytes, which is increased if there is a genetic disparity between the donor and the recipient. In addition, the graft failure depends on the status of the host anti-donor reactivity. This makes recipients of an HLA-mismatched and haploidentical cell transplantation more susceptible to the development of graft rejection when compared with HLA-matched allo-HCT.
In clinical studies, especially in patients with severe aplastic anemia (SAA), a higher risk of graft failure was found due to the presence of resistant anti-donor cytotoxic T-cell populations sensitized to donor MHC antigens through repeated blood transfusions. A high number of transfusions of blood products were identified to be associated with a higher incidence of graft rejection and death [6].
In haplo-HCT the use of myeloablative conditioning (MAC) chemotherapy and high-dose post-transplant cyclophosphamide (PTCy), now commonly used to prevent GvHD, can diminish these cellular-mediated immune reactions as both human T-cells and NK cells are highly sensitive to cyclophosphamide [7]. In addition to T- and NK cell-mediated graft rejection (cellular rejection), antibody-mediated rejection (humoral rejection) occurring either by antibody-dependent cell-mediated cytotoxicity or complement-mediated cytotoxicity has been described.
2.2 Antibody-Mediated Graft Rejection
Antibody-mediated graft rejection has been a major obstacle and well-recognized cause of rejection and organ dysfunction in solid organ transplants. The risk of antibody-associated graft rejection following allo-HCT depends on antigen density on the target cell and capacities of the antibody Fc domain. While many types of preformed antibodies can be detected in alloimmunized stem cell transplant recipients, only antibodies against donor HLA antigens have been shown to have clinical significance [8,9,10].
Allosensitization is a common problem in both solid organ and allo-HCT [11, 12]. Approximately 50% of all patients requiring a transplant can become allosensitized and develop anti-HLA antibodies, and up to 30% of the patients might have donor-specific anti-HLA antibodies, which can mediate organ rejection or graft failure [13, 14]. A clear association between anti-HLA antibodies and graft failure in recipients of an allogeneic hematopoietic cell graft in particular HLA-mismatched transplantations has been demonstrated. Different mechanisms by which anti-HLA antibodies may cause graft failure are discussed [15].
The activation of the complement cascade has been shown in allosensitized recipients of solid organ transplantation and has been also described in animal models of allo-HCT [16, 17]. The classical pathway of the complement cascade is activated when the antigen-antibody complex binds C1q and initiates activation of other complement components resulting in the formation of membrane attack complex, which in turn induces lysis of the target cell with apoptosis [18].
The anti-HLA antibodies that target donor HLA antigens present on the surface of the donor-derived hematopoietic progenitor cells and antigen-antibody complexes can bind C1q and thus activate the complement cascade and cause destruction of the donor cells resulting in allograft rejection. C1q testing was developed to assess complement cascade activation in allosensitized recipients of solid organ transplants [19, 20]. In allo-HCT setting, Ciurea and coworkers showed that anti-HLA antibodies are associated with engraftment failure (see Chap. 9). This group analyzed 122 haploidentical transplant recipients tested prospectively for anti-HLA antibodies. Retrospective C1q testing was done on 22 allosensitized recipients. Twenty-two of 122 patients (18%) had donor-specific anti-HLA antibodies, 19 of which were females (86%). Seven patients with donor-specific anti-HLA antibodies (32%) rejected the graft [15]. Of the nine patients, who tested positive for C1q in the initial samples, five patients remained C1q positive at time of transplant [all with high anti-HLA antibodies levels (median 15,279, range 6487–22,944)] and experienced engraftment failure, while four patients became C1q negative pre-transplant and all engrafted the donor cells [15]. In conclusion, patients with high donor-specific anti-HLA antibodies levels and complement-binding antibodies (C1q positive) appear to be at much higher risk of primary graft failure. They concluded that C1q should be assessed in patients with donor-specific anti-HLA as prior to transplant and that reduction of anti-HLA antibodies to non-complement binding levels might prevent engraftment failure.
2.3 Documentation of Anti-HLA Antibodies
Preformed donor-specific anti-HLA antibodies (DSA) circulating in the peripheral blood (PB) at the time of transplant have been shown to be correlated with graft rejection and decrease survival in solid organ transplantation [13, 21,22,23]. Therefore, lymphocyte crossmatch tests have been developed for prediction of graft rejection [24, 25] and became mandatory in solid organ transplant according to the American Society for Histocompatibility and Immunogenetics (ASHI). In setting of allo-HCT, there has been reported that a positive crossmatch for anti-donor lymphocytotoxic antibody associated strongly with graft failure, mainly in HLA-mismatched or HLA-haploidentical transplantation patients [12, 26]. Although a lymphocyte crossmatch is an effective tool to evaluate alloimmunization and potential donor-recipient incompatibility, the procedure is labor intensive and may detect non-HLA antibodies, which may not be associated with transplant outcome since there is no data to confirm the importance of these antibodies to date [1]. More recently, DSA have been reliably detected using single antigen beads in a Luminex assay. Sensitivity and specificity have increased significantly and allowed a more effective screening of allosensitized recipients. This has been particularly useful in screening haploidentical donors especially for multiparous middle-aged females who are at higher risk of becoming allosensitized through pregnancies. Detection of DSA in this setting has allowed early treatment of these patients to prevent primary graft failure, a dreaded complication of transplantation.
2.4 Prevention of Donor-Specific Anti-HLA Antibody-Mediated Graft Failure in Haploidentical Transplant Setting
Preformed antibodies present at the time of graft infusion are unaffected by standard transplantation conditioning regimens or T-cell or B-cell immunosuppressive or modulatory strategies given in the peri-transplantation period. To reduce the risk of graft failure, a number of studies have reported beneficial effects of a variety of interventions used to reduce total anti-HLA antibody load, predominantly by using a combined approach [27]. Each procedure on its own, plasmapheresis, intravenous immunoglobulin (IVIg), cyclophosphamide, polyclonal anti-lymphocyte antibodies, monoclonal antibodies to CD20+ B lymphocytes (rituximab), and proteasome inhibitor directed against allo-antibody-producing plasma cells, has been described in recipients of a solid organ transplant. Their effectiveness as a single agent is modest [14, 28,29,30,31]. These treatment modalities also have been used to desensitize anti-HLA antibodies before haplo-HCT and HLA-mismatched allo-HCT [1].
Maruta and coworkers confirmed that repeated high-volume plasmapheresis does not effectively eliminate preformed anti-HLA antibodies [32]. Ciurea and coworkers for the first time used a combined approach using plasmapheresis, IVIg, and rituximab with some success: out of the first four patients treated with this approach, successful engraftment could be induced in 50% of the patients (two out of four), but graft failure due to persistence of anti-HLA antibodies occurred in the other two patients. In the two successfully treated patients, a significant reduction in the antibody levels could be achieved followed by successful engraftment of the donor cells, whereas the other two patients maintained high levels of anti-HLA antibodies and experienced PGF (see Chap. 9) [33].
Another strategy, which has been successfully applied also in a small number of patients, was the combination of plasmapheresis, rituximab, antibody adsorption with platelets, and administration of the proteasome inhibitor, bortezomib. Reduction of anti-HLA antibodies was achieved in one of two patients, however, both engrafted. Some of the most impressive reductions of the levels of anti-HLA antibodies were achieved by the application of 40 units of platelet transfusion from healthy donors selected to express the HLA antigens corresponding to the anti-HLA antibodies [34]. The MD Anderson group used an irradiated buffy coat, in addition to plasma exchanged, rituximab and IVIg, to desensitized patients especially with C1q positive, deemed to have highest risk [35]. A different approach was developed by the Johns Hopkins group from solid organ transplants, using a combination of repeated plasmapheresis, IVIg, and immunosuppressive medications. This group treated 15 patients who received an allo-HCT from a HLA-mismatched donor including 13 patients who received their graft from a HLA-haploidentical donor. These patients received every alternate day a single volume plasmapheresis followed by IVIg, tacrolimus, and mycophenolate mofetil starting 1–2 weeks before the beginning of transplant conditioning, depending on patient’s starting anti-HLA antibodies levels. Reduction of anti-HLA antibodies was seen in 14 of 15 patients, all of these 14 patients engrafted with donor cells [36]. Even though a small number of patients have been treated so far, taken together the experience from these reports suggests that a reduction of anti-HLA antibodies to lower levels is possible and can permit successful engraftment [1].
3 Genomic Loss of HLA-Mismatched Human Leukocyte Antigen and Leukemia Immune Escape from Haploidentical Graft-Versus-Leukemia Effect
The therapeutic advantage of allo-HCT results not only from the ability to deliver more intensive chemotherapy but also from antineoplastic effects mediated mostly by alloreactive T-cells in the graft. It has become increasingly clear that donor T-cell alloreactivity against host minor HLA antigens as well as tumor specific antigens plays a major role in disease control in a traditional HLA-matched transplants [37]. In the context of haplo-HCT, the large number of alloreactive T-cell targets encoded by the fully HLA-mismatched haplotype can allow a stronger graft-versus-tumor (GvT) effect and better prevention of disease relapse post-transplant [2]. Disease relapse post-haplo-HCT can still occur via various mechanisms. One of the important mechanisms of relapse recognized after haplo-HCT is loss of heterozygosity (LOH) in the HLA gene region on chromosome 6p of tumor cells. Tumor cells without mismatched HLA expression may be predisposed to selective expansion through in vivo escape from immune surveillance by alloreactive T-cells. Even though, this phenomenon is commonly observed in untreated solid tumors, in which the incidence can be up to 70–90% [38, 39], it is rare in leukemia at presentation. However, the LOH has been identified as a mechanism of leukemia immune escape and disease relapse after haplo-HCT [2, 40].
3.1 Mechanisms of Loss of Heterozygosity and Leukemia Immune Escape
LOH as a possible mechanism of leukemia immune escape after haplo-HCT has been described by several groups. Vago and coworkers have studied the genomic rearrangements in mutant variants of leukemia by using genomic HLA typing, microsatellite mapping, and single-nucleotide polymorphism (SNP) arrays. They identified the mutant variant of leukemia cells with HLA that differed from the donor’s haplotype which had been lost because of acquired uniparental disomy (aUPD) of chromosome 6p in 5 of 17 patients with leukemia relapse after haploidentical transplantation. This mutation resulted in leukemic cell evasion from donor T-cell recognition, whereas the original leukemic cells taken at the time of diagnosis were efficiently recognized and killed. They hypothesized that HLA loss may reflect alloimmune pressure mediated by donor T-cells toward the HLA mismatches [41]. This phenomenon was also confirmed in a report by Villalobos and coworkers, describing two cases of HLA loss by chromosome 6p aUPD resulted in total loss of the mismatched HLA haplotype among three pediatric patients with AML who relapsed after haplo-HCT [42]. The molecular events that form the basis of this type of genomic abnormality remain uncertain, but it has been postulated that aUPD may derive either from mitotic homologous recombination events or from an attempt to correct for the unbalanced loss of chromosomal material by using the remaining alleles as a template resulting in copy number neutral-LOH (CNN-LOH) without a concurrent change in the copy number; therefore, standard cytogenetic methods fail to detect this phenomenon.
Another mechanism of LOH has been described by McCurdy and coworkers in a study of two high-risk AML patients who relapsed after haplo-HCT using PTCy. In this report, the authors demonstrated the absence of mismatched recipient HLA haplotype on the isolated leukemic blasts in both cases. Interestingly, both cases represent distinct mechanisms of HLA loss. SNP array for recipient 1 demonstrated aUPD at 6p, which is the mechanism as previously described [41, 42]. However, the karyotype and SNP array for recipient 2 revealed a deletion of chromosome 6p that encompassed the mismatched HLA locus. The later represents a different, but similar, genomic mechanism and supports that the leukemic cells may lose the mismatched HLA haplotype through multiple means, resulting in evasion of the donor immune system [43].
Another mechanism causing downregulation of mismatched HLA class I antigens was described by Tamaki and colleagues. In this study, this group found a lack of mismatched HLA-A despite a retaining of both HLA haplotypes on the leukemic cell surface of the AML patient who relapsed after haplo-HCT by using flow cytometric analysis. They speculated that this finding might be associated with impaired epigenetic regulation of the gene causing downregulation of HLA class I on unshared alleles, which are preserved on shared alleles [44].
3.2 Incidence, Risk Factors, and Clinical Outcomes of Mismatched HLA Loss
While SNP arrays may detect a copy neutral LOH of chromosome 6p, this test is not routinely performed on samples from patients who relapse after allo-HCT, and its sensitivity is limited in early relapse. Moreover, assays to distinguish donor from patient-specific alleles are not clinically available at present. Therefore, the incidence of which HLA loss contributes to relapse is only documented in some small studies with limited number of patients [40,41,42,43]. The only large retrospective study to determine the incidence and outcome of HLA loss relapses after allo-HCT and to address the clinical, genetic, and immunologic factors associated with the selection of mutant leukemic variants was done by the investigators from Italy. The investigators retrospectively collected clinical and immunogenetic data from 233 consecutive allo-HCT recipients of partially HLA-incompatible donors (with 162 patients with haplo-HCT). These transplants were performed for myeloid malignancies. At 4 years after HLA-mismatched related transplantation, incidence of HLA loss relapses was 14%, whereas the incidence of the remaining cases of relapse (classical relapses) was 27%. Timing since transplantation was significantly different between the two relapse subtypes: HLA loss relapses mostly occurred late after transplant (median 307 days, range 56–784), whereas “classical” relapses occurred much earlier (median 88 days, range 12–579; P < 0.0001). Interestingly, the investigators could not identify cases of HLA loss relapses after HLA-mismatched unrelated (MMUD) transplantation, while incidence of “classical” relapse in HLA-MMUD allo-HCT was 22% at 4 years. In multivariable analysis, active disease at transplant was associated with an increased risk of HLA loss. Conversely, older patient age appeared to significantly decrease the risk. The OS of patients who relapsed in this study was poor and was not different between both types of relapse. The median OS was 94 and 78 days after LOH and classical relapse, respectively [45].
3.3 Targeted Therapy of HLA Loss Relapses
It becomes crucial to document the HLA loss in patients who have leukemia relapse after haplo-HCT because it has relevant clinical consequences: not only it demonstrates that the donor-derived T-cells circulating in the patient at the time of relapse become inefficient bystanders but also that any attempt to induce remission by infusion of donor T-lymphocytes is expected to be ineffective against the leukemic cells and potentially harmful to the patient due to the conserved risk of inducing GvHD. Based on the net result of the genomic alteration, two possible alternative immunotherapeutic strategies can be considered for these variants of leukemia relapse. The first is a second transplantation from a different HLA-haploidentical donor, selected for being mismatched against the HLA haplotype retained by leukemic blasts. Theoretically, the advantage of this method is that the donor and leukemia cells would have a full immunologic incompatibility that can help increase GvT effect, while an incompatibility between the donor and patient’s healthy tissues is only 50%. The second treatment option is an infusion of high-dose purified donor NK cells. It is based on an observation that leukemic cells that undergo genomic loss of one HLA haplotype in several cases also lose the ligands for donor inhibitory KIRs, becoming in principle susceptible to NK cell alloreactivity [46]. Even though, the effectiveness of this strategy is limited in overt leukemia relapse, it might help in preemptive treatment of impending leukemia recurrence, guided by molecular markers of minimal residual disease and early detection of HLA loss relapse.
4 Viral Reactivations After Haploidentical Transplants
Although promising survival has been achieved with the establishment of many haplo-HCT protocols, viral reactivation resulting from the impaired immune reconstitution owing to the method of TCD and extensive immunosuppression necessary to overcome HLA disparity remains one of the most important causes of morbidity and mortality.
Graft composition and conditioning may be of great impact on the immune reconstitution after haplo-HCT (see Chaps. 5, 7, and 18). Various approaches have been evaluated to deplete the host and the recipient T-cells in order to prevent graft failure and GvHD. However, extensive TCD can cause slow immune reconstitution and leads to various serious infections [3, 47]. Initial studies in TCD haplo-HCT using “megadose” CD34+ allograft have shown that PB counts of NK cells returned to normal within 2–4 weeks after transplantation, while CD4+ T-cell counts were below 100 and 200 cells/mm3 for as long as 10 and 16 months, respectively, and led to high rate of treatment-related mortality (TRM) (40%) primarily due to serious infections (see Chaps. 1 and 2) [3].
Even though various graft manipulation strategies have been investigated to partially deplete T-cells from the graft with the goal to preserve immunity and GvT effects and selectively eliminate the cells mostly responsible for GvHD, a high success rate was seen mainly in pediatric patients whose thymic function is still active, while outcomes in adult patients remain poor due to prolonged immune deficiency resulting in high rates of infectious complications [47,48,49,50,51].
Using the new platform for T-cell replete haplo-HCT using PTCy as GvHD prevention method showed a low TRM and high feasibility with an acceptable safety profile. This type of haplo-HCT seems to compare favorably with TCD methods, in terms of infectious complications [52]. Ciurea and coworkers have shown the better reconstitution of T-cell subsets including memory and naïve T-cells in patients received unmanipulated haploidentical transplantation with PTCy as compared with TCD haplo-HCT. This group also found a significant lower incidence of viral and fungal infections and a trend for a lower probability of developing any infection in the critical first 6 months post-transplant [53]. In terms of viral infection, Tischer and coworkers compared the incidence of viral infection and outcome of patients treated with a combined T-cell replete and TCD haplo-HCT and with T-cell replete haplo-HCT PTCy. This group found a significantly lower incidence of herpes virus infection as well as viral infection-related mortality in T-cell replete group suggesting that TCR haplo-HCT using PTCy can better preserve antiviral immunity and allow fast immune recovery of T-cell subset [54]. Nonetheless, it remains unclear how T-cell replete haplo-HCT with PTCy will compare with other in vivo and ex vivo methods of partial TCD [55].
4.1 Common Viral Infections in Recipients of Haploidentical Transplant
Infections from various viral pathogens have been reported in a setting of haplo-HCT. The incidence of viral infection depends on graft type and degree of immune suppression by conditioning and GvHD prophylaxis regimens. Tischer and coworkers have reported 139 occurrences of viral infection in 46 out of 55 patients, 68 of them were symptomatic and 20 associated with disease. The most frequently observed viral pathogens in this study were HHV-6; polyomavirus JC/BK, EBV, CMV, and HSV; and adenovirus (ADV) [54].
4.2 Cytomegalovirus Reactivation and Infection
Incidence and Risk Factors: Infection from cytomegalovirus (CMV) remains one of the most important complications after haplo-HCT. CMV infection can appear as reactivation, primary infection, or reinfection. It can also cause multiorgan disease including pneumonia, hepatitis, gastroenteritis, retinitis, and encephalitis, and the disease can develop both early and late transplantation period [56]. Donor and/or recipient seropositivity for CMV is a major risk factor for CMV reactivation and CMV disease during and post-transplant [57, 58]. A retrospective study by investigators from MD Anderson Cancer Center showed that of 178 patients treated with unmanipulated haplo-HCT using PTCy for GvHD prophylaxis, CMV reactivation was observed in 103 patients (63%) with a median time to reactivation of 39 days. Ten patients (approximately 10%) developed CMV disease (two had pneumonia, three had colitis, two had upper respiratory infections, one had esophagitis, and two had retinitis). The highest incidence was seen when both the patient and donor had CMV IgG seropositive before transplant. Moreover, they found that a low CD8+ T-cell count at day +90 correlated with a higher incidence of CMV reactivation [58]. Same results were found in a recent study of 138 patients treated with T-cell replete haploidentical transplantation and PTCy by Goldsmith and coworkers. In this study, 80 patients (58%) had post-transplant CMV viremia, and 23 patients (29%) progressed to CMV disease. After adjusted for “very-high” disease risk index, CMV viremia was associated with poor OS [59]. CMV reactivation seems to be more common in TCD transplantation than in transplantation using unmanipulated allograft with PTCy [60]. Mulanovich and coworkers found that CMV infection affected most patients and recurred 1–2 times on average in affected patients. In this study, 30 episodes of CMV infection were reported in 28 TCD haplo-HCT recipients [61].
Prevention and Treatment of CMV Infection: CMV serologic status should be assessed as early as possible when a patient is being considered for haplo-HCT. If a patient is CMV seronegative, CMV-negative blood products should be used during the whole transplant process. Moreover, a CMV serology negative donor is preferable for a CMV serology negative recipient. If only a CMV-seropositive donor is available for a CMV-seronegative patient, the risk of transmission of CMV by the graft to the recipient is approximately 20–30% [62]. The incidence of CMV transmission from TCD haplo-HCT has never been clarified.
Preemptive treatment is preferable over prophylaxis strategy to avoid the unnecessary treatment of patients who will not develop CMV infection or disease. Diagnostic surveillance of patients at risk of acquiring CMV infection is important to guide preemptive therapy. The common tests used include pp65 antigenemia and the CMV DNA PCR [63]. Patients must be screened for CMV viremia at least once a week in the first 100 days post-transplant. However, late CMV viremia and disease can occasionally occur in haplo-HCT setting often in patients on steroids as treatment for GvHD and/or due to poor or delayed recovery of CMV-specific T-cells and are associated with poor outcome. In most cases, it occurs between 4 and 12 months post-transplant [56]. Intravenous ganciclovir is most commonly used to treat both CMV viremia and CMV disease followed by foscarnet and cidofovir [64, 65]. The use of ganciclovir can be associated with myelotoxicity and secondary graft failure. Consequently, we recommend the use of foscarnet as first line therapy in patients with normal kidney function who are early post-haploidentical transplant.
4.3 Polyomavirus Reactivation
Incidence and Risk Factors: BK virus (BKV) is a human polyomavirus typically acquired in early childhood and becomes latent in urothelial cells of the urinary tract [66]. BKV reactivation after allo-HCT is associated with manifestations ranging from asymptomatic viruria to severe hemorrhagic cystitis (HC), ureteral stenosis, and interstitial nephritis. The incidence of BK viruria is similar in allogeneic (range 46–53%) and autologous (range 39–54%) hematopoietic cell transplantation [67, 68]. A retrospective study by Rorije and coworkers showed that 16% of allo-HCT recipients developed BKV disease (an incidence rate of 0.47/1000 patient-days), while 5.5% had severe disease [69]. Haplo-HCT with PTCy is associated with uroepithelium damage, which may enhance the BKV replication in the bladder. Besides the use of PTCy, impaired immune reconstitution after haplo-HCT may result in an increase in risk for developing a higher BK viral load in urine, enhancing the urothelial mucosal damage and a higher incidence of cystitis [70]. Ruggeri and colleagues reported as high as 62% cumulative incidence of HC at day 180 of T-cell replete haplo-HCT recipients using PTCy, and BKV was positive in blood and urine of 91% of patients at HC onset [71]. Another study by Solomon and coworkers in a series of 20 haploidentical recipients receiving PTCy showed an overall incidence of 75% of BKV-associated cystitis, with 35% of patients requiring hospitalization [72]. In the MAC setting, using the thiotepa, busulfan, and fludarabine (TBF) regimen and PTCy, Raiola and coworkers reported an incidence of HC of 40%, mainly associated with BKV reactivation [73], while the MD Anderson group reported a incidence of HC of approximately 40% with 25% severe HC requiring hospitalization, bladder irrigation, and occasional nephrostomy tube placement [58]. In haplo-HCT setting, busulfan-based conditioning has also been associated with higher incidence of BKV HC (see Chap. 5).
Diagnosis and Treatment: The diagnosis of BKV-associated HC is considered when gross hematuria or other urinary symptoms occur in the first 90 days post-transplant. Other clinical features include dysuria, frequency, urgency, suprapubic pain, and later on due to complications of urinary tract obstruction and/or renal failure if bleeding and clot formation are severe. The modality of choice for detecting viral DNA in the urine is PCR. However, it does not have high disease specificity because stem cell transplant patients without HC can excrete BKV in urine. Viral culture is not used for detection of BKV replication because growth of the virus in tissue culture can take weeks. Cytologic examination of urine can detect characteristic polyomavirus-infected cells, decoy cells, with enlarged nuclei containing a single large basophilic intranuclear inclusion. However, this feature can also be caused by other viruses, like JC or adenovirus [74]. In general, treatment of BKV-associated HC is supportive including pain and bleeding control. To date, no antiviral drug with proven efficacy against BKV replication has been licensed. Cidofovir, the antiviral drug licensed for the treatment of CMV retinitis in AIDS patients and is a second-line drug for the treatment of ganciclovir-resistant CMV infections, has been used with some success for treatment of BKV-associated HC in allo-HCT recipients [75,76,77]. Intra-bladder cidofovir has been used with variable success and avoid systemic toxicity. The BKV CTLs are a promising more effective treatment for this common complication.
4.4 Adenovirus Infection
Adenovirus (ADV) infection is a well-described complication after allo-HCT, especially in pediatric patients, and is closely associated with delayed immune reconstitution [78]. It can appear as asymptomatic viremia, localized infection, or multiorgan disease. The reported incidence of ADV infection and disease after allo-HCT varies from 8% to 47% and has become increasingly frequent in recent years [79,80,81]. The progression to a disseminated disease has been suggested in approximately 10–20% of patients and resulting in high mortality rate of up to 80% [82, 83]. Taniguchi and coworkers retrospectively examined the incidence of ADV infection in patients undergoing unmanipulated haplo-HCT. Following 121 transplantations in 110 patients, three had asymptomatic adenovirus viremia, three had localized disease (hemorrhagic cystitis), and seven had disseminated disease. The median time from transplantation to the onset of ADV-associated HC was 15 days (range, 4–39 days), and the median time to the onset of disease was 23 days (range, 7–38 days). The cumulative incidence of ADV-associated HC was 8.3%, and for ADV disease was 5.8% [84]. Several factors increase the risk of ADV infection, almost always related to a lack of cellular antiviral reactivity that is inherent to the first 100 days after transplantation such as the development of GvHD and use of anti-thymocyte globulin (ATG) or alemtuzumab or a TCD allograft [85,86,87,88,89].
Due to a high rate of mortality in patients who have disseminated ADV disease, it is imperative to monitor patients at high risk (i.e., all patients after HLA-mismatch transplants and patients with in vivo or ex vivo TCD) using sensitive monitoring tools of subclinical ADV infection. Weekly monitoring of the adenoviral load by quantitative ADV PCR in the PB is the most preferable and sensitive method for early detection of ADV disease [90, 91]. Rapidly increasing or sustained adenoviremia can predict the occurrence of severe disease both in children and in adults [91, 92]. Earlier detection of ADV at the infection site such as nasopharyngeal aspiration or stool could be associated with earlier therapeutic intervention and improved outcomes.
Treatment options for ADV infection and disease include antiviral drugs, adoptive immunotherapy, and viral-specific donor lymphocyte infusion (experimental). Ribavirin and cidofovir are commonly used agents in the treatment of ADV, which can be used as prophylaxis, preemptive treatment led by viral load cutoff values, or as therapeutic treatment in case of ADV disease which depends on risk of developing severe disease and institutional guidelines [88, 93].
5 Key Points
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Unique complications after haploidentical transplantation consist of viral reactivation and infections, graft rejection related to DSA and relapse related to LOH
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Monitoring, prevention and early treatment of viral infections, as well as detection of DSAs and treatment of allosensitized recipients represent priorities for haploidentical transplant recipients
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Einsele, H., Mielke, S., Hermann, M. (2018). Unique Complications and Limitations of Haploidentical Hematopoietic Cell Transplant. In: Ciurea, S., Handgretinger, R. (eds) Haploidentical Transplantation. Advances and Controversies in Hematopoietic Transplantation and Cell Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-54310-9_20
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