Strategies to accelerate immune recovery after allogeneic hematopoietic stem cell transplantation

The interplay existing between immune reconstitution and patient outcome has been extensively demonstrated in allogeneic hematopoietic stem cell transplantation. One of the leading causes of infection-related mortality is the slow recovery of T-cell immunity due to the conditioning regimen and/or age-related thymus damage, poor naïve T-cell output, and restricted T-cell receptor (TCR) repertoires. With the aim of improving posttransplantation immune reconstitution, several immunotherapy approaches have been explored. Donor leukocyte infusions are widely used to accelerate immune recovery, but they carry the risk of provoking graft-versus-host disease. This review will focus on sophisticated strategies of thymus function-recovery, adoptive infusion of donor-derived, allodepleted T cells, T-cell lines/clones specific for life-threatening pathogens, regulatory T cells, and of T cells transduced with suicide genes.     

A phase I trial of recombinant human thrombopoietin in patients with delayed platelet recovery after hematopoietic stem cell transplantation.

Delayed platelet recovery is a significant complication after both autologous and allogeneic hematopoietic stem cell transplantation (HSCT). A multicenter, phase I dose-escalation study of recombinant human thrombopoietin (rhTPO) was conducted to assess its safety and to obtain preliminary data on its efficacy in patients with persistent severe thrombocytopenia (<20,000/microL) >35 days after HSCT. Thirty-eight patients, 37 of whom were evaluable, were enrolled in the study from April 1996 through January 1997. rhTPO was administered at doses of 0.6, 1.2, and 2.4 microg/kg as a single dose (group A) or in multiple doses every 3 days for a total of 5 doses (group B). No significant adverse effects were observed. Ten patients had recovery of platelet counts during the 28-day study period; 3 of these 10 had an increase in marrow megakaryocyte content 7 days after completing treatment with rhTPO. When all baseline marrows were compared with samples after rhTPO treatment, there was no difference in marrow megakaryocyte content (P = 0.49). This study design could not answer the question of whether the recoveries of platelet counts observed in some patients were spontaneous or influenced by rhTPO treatment; nonetheless, the authors found no correlation between the dose of rhTPO and the recovery of platelet counts. Increases in serum TPO levels were dose-dependent and remained significantly elevated for up to 72 hours after treatment. To evaluate response, further studies of treatment strategies with rhTPO in patients with delayed platelet recovery are required.     

Reimmunization after hematopoietic stem cell transplantation

Hematopoietic stem cell transplant recipients lose immune memory of exposure to infectious agents and vaccines accumulated through a lifetime, and therefore need to be revaccinated. Reimmunization protocols vary greatly among hematopoietic stem cell transplant centers. Diphtheria and tetanus toxoids, pertussis vaccine, Haemophilus influenza type B conjugate, 23-valent pneumococcal polysaccharide, inactivated influenza and polio vaccine and live attenuated measles-mumps-rubella vaccine are the currently recommended vaccines to be included in a vaccination program after hematopoietic stem cell transplant. Other variables, such as stem cell source, new adjuvants, T-cell depleted transplants, nonmyeloablative conditioning and donor immunization have recently been introduced and a constant update of current recommendations are needed. Studies recently published, the use of other vaccines and the perspectives for different vaccination protocols are discussed in this review.     

Antigen-specific immune function after hematopoietic stem cell transplantation.

Hematopoietic stem cell recipients are characterized by an immunodeficiency of varying severity and duration. The present review focuses on the antigen-specific function of recipients with the hypothesis that the acquisition of antigen-specific function is predictive of the recipient's capacity to resist lethal infection with environmental pathogens.     

Pulmonary complications after hematopoietic stem cell transplantation

Despite advanced effective prophylaxes, pulmonary complications still occur in a high proportion of all hematopoietic stem cell recipients, accounting for considerable morbidity and mortality. The aim of our study was to describe the causes, incidences and mortality rates secondary to pulmonary complications and risk factors of such complications following hematopoietic stem cell transplantation (HSCT). We reviewed the medical records of 287 patients who underwent either autologous or allogeneic HSCT for hematologic disorders from February 1996 to October 2003 at Samsung Medical Center (134 autografts, 153 allografts). The timing of pulmonary complications was divided into pre-engraftment, early and late period. The spectrum of pulmonary complications included infectious and non-infectious conditions. 73 of the 287 patients (25.4%) developed pulmonary complications. Among these patients, 40 (54.8%) and 29 (39.7%) had infectious and non-infectious conditions, respectively. The overall mortality rate from pulmonary complications was 28.8%. Allogeneic transplant, grade II-IV acute graft-versus-host disease (GVHD) and extensive chronic GVHD were the risk factors with statistical significance for pulmonary complications after HSCT. The mortality rates from pulmonary complications following HSCT were high, especially those of viral and fungal pneumonia, diffuse alveolar hemorrhage and idiopathic pneumonia syndrome.     

Psychosocial function after hematopoietic stem cell transplantation

The authors report on a prospective cohort study of patients with chronic myelogenous leukemia undergoing allogeneic hematopoietic stem cell transplantation. The purpose was to evaluate the progression of quality of life and mood, as well as patterns of alcohol consumption, a behavior with potential adverse health consequences. Of the 84 subjects who completed serial measures and other interviews at admission for hematopoietic stem cell transplantation and 6-month follow-up, 75 provided data 12 months later The main findings of this study were that quality of life improves, measures of depressive symptoms decline, and patients drink less alcohol overall. Time was the most important variable accounting for these changes.     

Clinical utility of autopsy after hematopoietic stem cell transplantation.

Autopsy is the gold standard for establishing the cause of death. We present results of the largest retrospective review of complete autopsies of subjects after hematopoietic stem cell transplantation to better define the role of the autopsy in discovering a missed diagnosis. We reviewed the medical chart and autopsy records of 111 patients who had undergone hematopoietic stem cell transplantation from July 1986 to June 2003 from a single center. We compared the cause of death as charted by the clinical team with data obtained from postmortem chart review and autopsy reports. Of 29 (26%) cases when the premortem and postmortem major diagnoses did not agree, only 4 (4%) autopsy records provided data that might have led to the initiation of new treatments, and none of these diagnoses would be missed today with more sensitive and specific diagnostics and improved supportive care. Although autopsies after transplantation can be important educational, research, and epidemiologic tools and provide an emotional benefit to patient's families, in our series they rarely provided missed diagnoses that would alter the management of subsequent patients. Improvements in noninvasive tests for relapse or occult infections may further erode the role of autopsies in discovering missed diagnoses.     

Non-myeloablative hematopoietic stem cell transplantation.

Conventional approaches to allogeneic stem cell transplantation have used toxic high-dose conditioning therapy in attempts to eradicate underlying diseases and achieve allogeneic engraftment. Preclinical studies and clinical observations have shown that to achieve engraftment conditioning regimens could be markedly reduced in intensity with reduction in treatment toxicities. The use of potent pre- and postgrafting immunosuppression facilitated stable mixed hematopoietic chimerism in a preclinical canine model. The initial clinical experiences with attenuated conditioning regimens have shown promise as a modality to achieve human stem cell transplantation with an improved safety profile. This may allow offering potentially curative hematopoietic stem cell transplantation (HSCT) to a more representative patient population (older and sicker) who are currently not eligible for such therapy. Obtaining a state of mixed hematopoietic chimerism could prove curative of the disease phenotype of various nonmalignant disturbances of the hematopoietic and immune systems. On the other hand, patients with hematopoietic malignancy will likely require conversion to full donor hematopoeisis by virtue of graft-versus-host (GVH) reactions directed against both recipient hematopoiesis and underlying malignancy. The infusion of additional donor lymphocytes has been proposed by many groups to augment graft versus tumor responses, but most likely more specific strategies will need to be developed to improve efficacy and avoid nonspecific GVH reactions.     

Optimistic expectations and survival after hematopoietic stem cell transplantation.

An optimistic attitude is hypothesized to be beneficial when facing a life-threatening medical condition. However, the actual relationship of high expectations for treatment success and medical outcome is controversial. Using a prospective cohort of 313 autologous and allogeneic hematopoietic stem cell transplant patients enrolled July 1996 through November 1999, we tested whether patient-reported expectations before transplantation were associated with survival and quality of life following the procedure. Before transplantation, patients with higher expectations that the transplant procedure would go well had better mental and emotional functioning, but similar physical status and medical condition to patients with less optimistic expectations. In the first 2 months after transplantation, optimistic expectations were associated with better survival (92% v 84%; relative risk for mortality 0.45, 95% confidence interval 0.22-0.92; P=.03) controlling for other physical and mental characteristics. However, by 6 months posttransplantation, survival and quality of life were indistinguishable between patients with initially higher and lower expectations. Our data suggest an association between more optimistic expectations and early survival following hematopoietic stem cell transplantation, but this association is not present by 6 months posttransplantation.     

Reconstitution of self-tolerance after hematopoietic stem cell transplantation

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow or hematopoietic stem cell transplantation. GVHD is thought to be primarily due to the response of mature T cells transferred along with the bone marrow graft to foreign histocompatibility antigens expressed on host tissues. Recent studies, however, have challenged this paradigm set forth in the 1960s and have suggested that self-MHC class II antigens can be recognized in GVHD. Many questions still remain unanswered particularly in regard to the role of immune reconstitution, the ability to recognize and discriminate self and the re-establishment of self-tolerance. In fact, the failure to re-establish tolerance to self can lead to systemic autoimmunity that may exacerbate or even mimic GVHD. The present review summarizes our studies in autologous GVHD characterizing the underlying immune mechanisms and their potential impact in allogeneic hematopoietic stem cell transplantation.     

Autoimmune disease after autologous hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is an effective treatment for refractory autoimmune diseases. The safety and long-term outcome have been also acceptable. Infectious diseases under immune suppressive state after autologous HSCT are common transplantation related complications whereas autoimmune diseases are uncommon. Organ specific autoimmune diseases, such as immune mediated thrombocytopenia and thyroid dysfunction, are the most common after autologous HSCT. Systemic autoimmune diseases can also develop after autologous HSCT in patients with hematological disorders with genetic predisposition to autoimmune diseases. Although the mechanism of autoimmunity after HSCT is not well-known, long-term follow-up is essential in patients with autoimmune diseases treated with autologous HSCT.     

Preemptive cellular immunotherapy after T-cell-depleted allogeneic hematopoietic stem cell transplantation.

GVHD is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is due to donor lymphocytes that are cotransplanted with donor stem cells. These donor lymphocytes are primed by histocompatibility differences between donors and recipients and activated by a cytokine storm caused by the conditioning regimen. The most efficient method for prevention of GVHD consists of T-cell depletion (TCD) of the graft. However, TCD usually leads to an increased risk of leukemia relapse because of the loss of the graft-versus-leukemia (GVL) effect. Several groups have studied the feasibility of preemptive donor lymphocyte infusion (DLI) to lessen the impact of TCD on leukemia relapse. Preemptive DLI is given several weeks to months after the transplantation, ie, after the cytokine storm and after the patient has recovered from conditioning-regimen-related toxicities. After briefly discussing various techniques of TCD of the graft and the efficacy of DLI, this article reviews the first clinical studies evaluating a strategy of TCD of the graft followed by preemptive DLI.     

Sirolimus and thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation.

Thrombotic microangiopathy (TMA) may occur after allogeneic hematopoietic stem cell transplantation (HSCT) and is related in part to calcineurin inhibitor toxicity. We observed a higher-than-expected rate of TMA when calcineurin inhibitors were combined with sirolimus. To determine the incidence of and risk factors for TMA after HSCT, we performed a retrospective cohort analysis of myeloablative allogeneic HSCT recipients between 1997 and 2003. TMA diagnosis required the simultaneous occurrence of (1) creatinine increase >2 mg/dL or >50% above baseline, (2) schistocytosis, (3) increased lactate dehydrogenase, and (4) no evidence of disseminated intravascular coagulopathy. A total of 111 sirolimus-exposed subjects were compared with 216 nonexposed subjects after HSCT. TMA occurred in 10.8% of the sirolimus group and 4.2% in the nonsirolimus group (odds ratio, 2.79; P=.03). Sirolimus exposure was associated with TMA earlier than in nonsirolimus patients (25 versus 58 days; P=.04). Only the use of sirolimus (exact odds ratio, 3.49; P=.02) and grade II to IV acute graft-versus-host disease (exact odds ratio, 6.60; P=.0002) were associated with TMA in regression analyses. Treatment of TMA varied among affected individuals. Renal recovery was complete in 92% of sirolimus-treated patients. Overall survival after TMA diagnosis was better for sirolimus subjects than for nonsirolimus subjects (58.3% versus 11.1%; P=.02). Sirolimus seems to potentiate the effects of calcineurin inhibitors on TMA after HSCT. TMA associated with sirolimus seems reversible and has a favorable prognosis when compared with TMA associated with calcineurin inhibitors alone. A careful monitoring strategy for TMA should be used with a sirolimus-containing graft-versus-host disease prophylaxis regimen.     

Chronic kidney disease after myeloablative allogeneic hematopoietic stem cell transplantation.

Because survival of recipients of allogeneic hematopoietic stem cell transplantation (HSCT) has improved, long-term complications become more important. We studied the incidence and risk factors of chronic kidney disease in these patients and evaluated associated posttransplant complications and mortality. We performed a retrospective cohort study of 266 adults who received myeloablative allogeneic HSCT and who survived for >6 months in an 11-year period at a Dutch university medical center. Primary outcome was the incidence of chronic kidney disease defined as a glomerular filtration rate (GFR) of <60 mL/min/1.73 m(2). Chronic kidney disease developed in 61 (23%) of 266 patients, with a cumulative incidence rate of 27% at 10 years. Severe kidney disease (GFR of <30 mL/min/1.73 m(2)) developed in 3% of patients. Only 6 patients developed the thrombotic microangiopathic syndrome SCT nephropathy, and 2 of them needed dialysis. Pretransplant risk factors for chronic kidney disease were lower GFR at day 0 (P < .0001, odds ratio [OR] 0.95 95% confidence interval [CI] 0.93-0.97), female gender, and higher age (P = .001 and P < .0001, respectively). The occurrence of hypertension after transplantation was associated with chronic kidney disease (P < .0001, OR 0.34 95% CI 0.18-0.62). Mortality was 39% after a mean follow-up of 5.1 years. There was no significant difference in survival between patients with and without chronic kidney disease. Chronic kidney disease is a common late complication of myeloablative allogeneic HSCT. Because of the natural decline in renal function with time there is a risk of developing end-stage renal disease in the future. SCT nephropathy seems to be a specific cause of chronic kidney disease that is typically associated with severe kidney disease.     

The problem of thrombocytopenia after hematopoietic stem cell transplantation

Thrombocytopenia after hematopoietic stem cell transplantation (HSCT) is associated with an increased risk of bleeding and utilization of significant resources. This review presents an analysis of risk factors associated with delayed platelet engraftment. The retrospective analysis included 1,468 recipients of autologous or allogeneic transplants treated between January 1, 1990 and July 1, 1995. Risk factors associated with delayed platelet engraftment after autologous HSCT included use of marrow rather than peripheral blood as the source of stem cells, being transplanted for acute myeloid leukemia rather than other diseases, positive patient serology for cytomegalovirus and the presence of infection post-transplant before engraftment. Risk factors associated with delayed platelet engraftment after allogeneic marrow transplantation included unrelated as opposed to related donor transplants, being transplanted for diseases other than chronic myelogenous leukemia, increased age, onset of acute graft-versus-host disease (AGVHD), male gender, the administration of methotrexate for GVHD prophylaxis and the presence of infection before engraftment. Delayed platelet recovery is associated with decreased survival after both autologous and allogeneic transplants. Management of delayed platelet recovery by transfusion of blood products requires significant medical resources and is of some risk to the patients. Further development of new strategies may safely reduce the need for blood products. These include peripheral blood stem cell transplants (allogeneic and autologous), new algorithms for administering routine platelet transfusions and investigative biological agents for stimulating megakaryocytopoiesis. Further studies may elucidate the cause of increased platelet consumption associated with infection and GVHD.     

Voriconazole and sirolimus coadministration after allogeneic hematopoietic stem cell transplantation.

Sirolimus is increasingly used in transplantation for prevention and treatment of graft-versus-host disease and organ rejection. Voriconazole is contraindicated when used concomitantly with sirolimus because of a substantial increase in sirolimus drug exposure with unadjusted dosing, but voriconazole is also considered the best initial treatment of invasive aspergillosis and other fungal infections. Patients who received voriconazole and sirolimus concomitantly were identified by a review of the medical records of all allogeneic hematopoietic stem cell recipients at our institution from September 1, 2002, to June 1, 2005. Data including baseline characteristics, indications for both drugs, and potential adverse effects were evaluated. Eleven patients received voriconazole and sirolimus concomitantly for a median of 33 days (range, 3-100 days). In 8 patients whose sirolimus dose was initially reduced by 90%, trough sirolimus levels were similar to those obtained before the administration of voriconazole; no obvious significant toxicity from either drug was observed during coadministration. Serious adverse events were observed in 2 patients in whom sirolimus dosing was not adjusted during voriconazole administration. Sirolimus and voriconazole may be safely coadministered if there is an empiric initial 90% sirolimus dose reduction combined with systematic monitoring of trough levels.     

Lung transplantation for bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation

Bronchiolitis obliterans (BO) is a late onset complication of allogeneic hematopoietic stem cell transplantation (HSCT), and treatment outcome is dismal if it does not respond to immunosuppressive therapy. A 21-year-old male diagnosed with acute myeloid leukemia received an allogeneic HSCT from human leukocyte antigen- identical sibling donor. Twenty one months after transplantation, he developed progressive dyspnea and was diagnosed BO. Despite standard immunosuppressive therapy, the patient rapidly progressed to respiratory failure and Novalung® interventional lung-assist membrane ventilator was applied in the intensive care unit. Three months after the diagnosis of BO, the patient underwent bilateral lung transplantation (LT) and was eventually able to wean from the ventilator and the Novalung®. Since the LT, the patient has been under a strict rehabilitation program in order to overcome a severe lower extremity weakness and muscle atrophy. Histologic findings of the explanted lungs confirmed the diagnosis of BO. Nine months after the LT, the patient showed no signs of rejection or infectious complications, but still required rehabilitation treatment. This is the first LT performed in a patient with BO after allogeneic HSCT in Korea. LT can be an effective therapy in terms of survival for patients with respiratory failure secondary to development of BO following HSCT.     

Clinical options after failure of allogeneic hematopoietic stem cell transplantation in patients with hematologic malignancies

Disease recurrence is the single most common cause of death after allogeneic or autologous hematopoietic stem cell transplantation (HSCT). Disease status and chemosensitivity at the time of transplantation, as well as the development of graft-versus-host disease (GVHD), are factors known to influence the risk of relapse post-HSCT. Both acute and chronic GVHD have been associated with decreased relapse rates; however, owing to toxicity, overall survival is not consistently improved in these patients. Furthermore, there is a transient period of immunodeficiency after HSCT, which may permit residual malignant cells to proliferate early in the post-transplant course, before the donor immune system can establish a graft-versus-tumor response. Patients who fail an initial HSCT have an extremely poor outcome; therefore, maneuvers to prevent, identify and treat recurrent disease as early as possible in these situations are necessary. Strategies to distinguish graft-versus-tumor from GVHD, to enhance both general and disease-specific immune reconstitution after transplantation, and to increase donor-mediated anti-host immune reactions are being investigated in clinical trials. Single agent nontoxic post-HSCT chemotherapy, cellular therapies and second allogeneic HSCT using reduced intensity regimens are among the modalities under investigation.     

Shortening the immunodeficient period after hematopoietic stem cell transplantation

The delayed reconstitution of the T-lymphoid compartment represents a major clinical challenge after HLA-mismatched hematopoietic stem cell transplantation. The generation of new T lymphocytes deriving from transplanted hematopoietic stem cells requires several months, a period associated with an increased risk of opportunistic infections and relapses. Recently, the early steps of human lymphopoiesis and the nature of the thymus-seeding progenitors were described. Moreover several scientific groups succeeded to generate T-cell precursors from murine and human hematopoietic stem cells in vitro by transitory exposition to Notch-ligands. Here we summarize and discuss these results and their possible usage in the development of new cell therapies to shorten the immunodeficient period following hematopoietic stem cell transplantation.