Second malignancies after allogeneic hematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (allo-HCT) may prolong life and cure patients suffering from otherwise fatal diseases. However, the growing population of long-term survivors has led to the realization of multiple long-term complications, including the risk of second malignancies. Compared to the autologous setting, allo-HCT carries a much higher risk of posttransplant lymphoproliferative disorder (PTLD), which usually occurs within the first year after allo-HCT and is strongly associated with the Epstein-Barr virus (EBV). Treatment-related myelodysplastic syndromes (tMDS) and second leukemias are extremely rare. Both autologous and allo-HCT carry increased risks for second solid malignancies (SSM). The cumulative incidence of SSM continues to increase in each of the largest studies with as much as 20 years of follow-up, likely related to the long latency of radiation-related SSM. Systematic, prospective monitoring, vigilant screening processes, and well-maintained survivorship clinics and databases are absolute necessities, and should be included in the infrastructure of individual transplant centers and networks, with mandatory periodic reporting of second malignancy incidences. Primary care and transplant physicians alike must be aware of the risk of second malignancies after allo-HCT. Most importantly, guidelines should be developed in regard to screening and prevention of second malignancies, so that physicians can provide state-of-the-art counsel and care for the benefit of our patients.     

Prediction and prevention of transplant-related mortality from pulmonary causes after total body irradiation and allogeneic stem cell transplantation.

Between July 1997 and August 2004, 146 consecutive patients with hematologic malignancies received a T cell-depleted peripheral blood stem cell transplant from an HLA-identical sibling by using total body irradiation (TBI) and cyclophosphamide conditioning regimens. Eighty-five patients received 13.6 Gy of TBI with no lung shielding, and 61 received lung shielding (total lung dose, 6-12 Gy). Ninety-four patients (65.5%) had standard-risk disease; the remainder had more advanced disease or unfavorable diagnoses. Of the 21 transplant-related deaths, 14 were from pulmonary causes (10 idiopathic pulmonary syndromes and 4 from infection) that occurred at a median of 90 days (range, 23-238 days) after transplantation. Independent risk factors for pulmonary transplant-related mortality (PTRM) were pretransplantation diffusion capacity for carbon monoxide (relative risk, 5.7 for diffusion capacity for carbon monoxide <85%), smoking (relative risk, 5.0), and CD34 cell dose (relative risk, 9.4 for a CD34 dose of <5 x 10(6) cells per kilogram). Patients receiving lung shielding had significantly lower PTRM (3.3% versus 14.1%; P = .02) and better overall survival (70% +/- 6% versus 52% +/- 5%; P = .04), but lung shielding was not a significant independent factor for determining PTRM. These results suggest that pulmonary mortality after TBI-based preparative regimens is predictable and that higher CD34 cell doses can reduce the risk.     

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.     

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.     

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.     

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.     

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.     

异基因造血干细胞移植后的相关并发症及危险因素

背景：有效预防和治疗异基因造血干细胞移植后并发症是提高患者存活率的重要因素。 目的：分析异基因造血干细胞移植后相关并发症的发生和危险因素。 方法：应用文献检索的方法获取异基因造血干细胞移植后相关并发症研究的文献,对符合研究标准的文献进行深入的数据分析,文章选取异基因造血干细胞移植后极易发生的并发症进行分析,如肺部并发症、真菌性败血症、巨细胞病毒感染以及中枢神经系统并发症等。 结果与结论：异基因造血干细胞移植后易出现肺部并发症,而且死亡率较高,肺部并发症的发病机制可能与移植物抗宿主病和巨细胞病毒抗原血症相关。异基因造血干细胞移植后真菌性败血症病原菌以假丝酵母菌属为主,死亡率较高,应二级预防性和早期经验性抗真菌治疗。更昔洛韦、膦甲酸钠对异基因造血干细胞移植后巨细胞病毒感染的治疗有效。中枢神经系统并发症在异基因造血干细胞移植后发生率较低,但在治疗过程也不容忽视。异基因造血干细胞移植后相关并发症的发生与多种危险因素有关,在临床治疗过程中要对相关因素采取预防措施,减少并发症的发生,提高患者的存活率。     

Erythrocyte transfusion practices after allogeneic hematopoietic stem cell transplantation]

Allogeneic peripheral blood hematopoietic stem cell transplantation is being evaluated in a randomized French study comparing the use of peripheral blood stem cells vs. bone marrow graft stem cells. In order to standardize immunohematological (IH) assessment and transfusion practices within our protocol, we made suggestions to 25 allo-transplantation French centers on the following elements: pre-inclusion IH assessment, IH exclusion criteria, transfusion rules, post-transplantation IH surveillance and treatment of hemolysis. The analysis of their responses to our suggestions led us to elaborate recommendations which were approved and implemented by the French Bone Marrow Transplantation Society (SFGM). These recommendations concern the transfusion practice in the general framework of allogeneic hematopoietic stem cell transplantation and can therefore be considered as referential.     

Varicella zoster virus meningoencephalitis after allogeneic hematopoietic stem cell transplantation

Although the reactivation of varicella zoster virus (VZV) is a common complication after allogeneic hematopoietic stem cell transplantation (HSCT), VZV meningoencephalitis is a rare life-threatening infectious disease after HSCT. We describe here a patient who developed VZV meningoencephalitis 2 years after human leukocyte antigen-matched unrelated HSCT for acute myeloblastic leukemia. She developed chronic graft-versus-host disease, and cyclosporine (CSA) was continued until 17 months after HSCT. Low-dose acyclovir (ACV) at 200 mg/day was administered to prevent the reactivation of VZV from day -7 to the termination of CSA. At 22 months, she suddenly developed fever, loss of consciousness, and seizure, with generalized skin rash. A high level of VZV DNA was detected in her cerebrospinal fluid (CSF). She was diagnosed to have VZV meningoencephalitis. Intravenous ACV at 30 mg/kg/day was given for 2 months. Although loss of consciousness was quickly resolved, some neurologic symptoms persisted. She did not have any known risk factors for VZV reactivation. Therefore, we should keep in mind that any HSCT recipient may develop VZV meningoencephalitis, and examination of CSF for VZV infection with an empiric administration of ACV may be recommended for HSCT recipients with central nervous system symptoms, even in the absence of skin manifestations.     

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.     

Clinical impact of natural killer cell reconstitution after allogeneic hematopoietic transplantation

Although the optimal donor for allogeneic hematopoietic stem cell transplantation is a human leukocyte antigen (HLA)-matched sibling, 75% of patients do not have a match and alternatives are matched unrelated volunteers, unrelated umbilical cord blood units, and full HLA-haplotype-mismatched family members. This review will focus on the open issues of allogeneic hematopoietic transplantation and on the benefits of natural killer (NK) cell alloreactivity and its underlying mechanisms. Donor-versus-recipient NK cell alloreactivity derives from a mismatch between inhibitory receptors for self major histocompatibility complex (MHC) class I molecules on donor NK clones and the MHC class I ligands on recipient cells. These NK clones sense the missing expression of the self MHC class I allele on the allogeneic targets (“missing self”) and mediate alloreactions. Here, we review the translation of NK cell allorecognition into the clinical practice of allogeneic hematopoietic transplantation and discuss how it has opened innovative perspectives in the cure of leukemia.     

Cytomegalovirus management after allogeneic hematopoietic stem cell transplantation: A mini-review

Because of the high incidence of cytomegalovirus (CMV) seropositivity in the population, CMV infection is a common and severe complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Taiwan. Here we propose a CMV management strategy for patients undergoing allo-HSCT from the Taiwanese perspective, which focuses on the epidemiology, diagnosis, monitoring, prophylaxis, and treatment of CMV infection after allo-HSCT. In terms of CMV monitoring, weekly CMV monitoring with the COBAS® AmpliPrep system is the standard approach because the pp65 CMV antigenemia assay has a lower sensitivity than CMV monitoring with the COBAS® AmpliPrep system. However, pp65 CMV antigenemia assay has a better correlation with clinical symptoms in immunocompromised patients. A 14-week prophylactic course of letermovir is recommended for allo-HSCT recipients in Taiwan, especially for recipients of hematopoietic stem cells from mismatched unrelated and haploidentical donors. Preemptive ganciclovir therapy should be initiated when the CMV viral load exceeds 1000 copies/mL, and should not be discontinued until CMV DNA is no longer detected in the blood. For allo-HSCT recipients who have CMV-related diseases, ganciclovir with or without CMV-specific intravenous immunoglobulin is the standard of care. The limited availability of foscarnet, an alternative for patients who are not responsive to or cannot tolerate ganciclovir, is a crucial issue in Taiwan. For pediatric allo-HSCT recipients, more data are needed to propose a CMV management recommendation.     

Hemorrhagic cystitis following allogeneic hematopoietic cell transplantation

We conducted a retrospective study to investigate the incidence, risk factors, and clinical features of hemorrhagic cystitis (HC) following allogeneic hematopoietic cell transplantation (allo-HCT). Adult patients who developed HC after allo-HCT were identified from the HCT database of the Asan Medical Center and their medical records were reviewed. From December 1993 to August 2001, a total of 210 adult patients underwent allo-HCT. Fifty-one patients developed HC with a cumulative incidence of 25.7%. The median onset of HC was post-transplant day 24 (range, -2 to 474), and the median duration was 31 days (range, 8 to 369). Significant risk factors for HC by univariate analysis included diagnosis of chronic myelogenous leukemia (p=0.028), unrelated HCT (p=0.029), grade III-IV acute graft-versus-host disease (GVHD) (p<0.001), extensive chronic GVHD (p=0.001), and positive cytomegalovirus antigenemia between post transplant days 31 and 60 (p=0.031). Multivariate analysis showed that grade III-IV acute GVHD was the most important risk factor for the occurrence of HC after allo-HCT (odds ratio, 3.38; 95% CI, 1.36-8.39). Late-onset HC, which occurred beyond 3 weeks after allo-HCT, was more frequently associated with GVHD than early-onset HC (p=0.007). Our data suggest that a portion of late-onset HC might be a manifestation of GVHD.     

Donor chimerism does not predict response to donor lymphocyte infusion for relapsed chronic myelogenous leukemia after allogeneic hematopoietic cell transplantation.

We studied the effect of donor chimerism level on the outcome of donor lymphocyte infusion (DLI) therapy in 42 patients with persistent or relapsed hematologic malignancies after non-T cell-depleted allogeneic hematopoietic cell transplantation. Seventy-five percent of chronic myelogenous leukemia (CML) and 39% of non-CML patients entered remission after DLI therapy. Remission and survival rates were similar for CML patients irrespective of their pre-DLI donor chimerism levels; however, remission occurred sooner in patients with > or =10% pre-DLI donor chimerism. None of the non-CML patients with <10% pre-DLI donor chimerism and 47% of those with > or =10% pre-DLI donor chimerism attained remission. The 2-year survival rates after DLI were 75% for CML and 17% for non-CML patients. We conclude that a low level of donor marrow chimerism is not an adverse prognostic factor for response to DLI in CML patients, but for non-CML patients it may confer worse outcomes. Better methods to augment the response to DLI for patients with hematologic malignancies other than CML that recur after allogeneic hematopoietic cell transplantation are needed, whereas for relapsed CML patients, combination therapies including imatinib mesylate or other promising antileukemic agents may provide outcomes superior to those with DLI alone.     

Risk factors for moderate-to-severe chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Among 810 consecutive hematopoietic stem cell transplantation (HSCT) patients, 679 survived more than 3 months and were evaluated for chronic GVHD. The aim of this study was to find predisposing factors increasing the risk of development of moderate-to-severe chronic GVHD. Many of the donors were HLA-identical siblings or related (n = 435), 185 were HLA-matched unrelated, and 59 were mismatched related or unrelated donors. Most of the patients had a hematological malignancy (n = 568), but 111 patients with a nonmalignant disease were included. Two hundred twenty-three patients (33%) developed mild, 41 (6%) moderate, and 15 (2.2%) severe chronic GVHD. The 5-year probability of development of moderate-to-severe chronic GVHD was 10%. We analyzed 30 potential risk factors for chronic GVHD. In the multivariate analysis, acute GVHD) grades II to IV (relative hazard [RH], 2.30; 95% CI, 1.29-4.10; P = .005), CML diagnosis (RH, 2.37; CI, 1.38-4.08; P = .002) and transplantation from an immunized female donor to a male recipient (RH, 2.16; CI, 1.14-4.11; P = .02) were independent risk factors for moderate-to-severe chronic GVHD. Recipient age also was significant (RH, 2.42; CI, 1.23-4.77; P = .01) if CML was not included in the analysis. In patients with no risk factors, the 5-year probability of development of moderate-to-severe chronic GVHD was 5%. In patients with 1 risk factor, the probability was 13%; 2 risk factors, 23%; and 3 risk factors, 45%. Among patients who developed chronic GVHD (n = 279), acute GVHD grades II to IV (RH, 2.18; CI, 1.23-3.86; P < .01) was the only predictive factor for moderate-to-severe chronic GVHD versus mild disease. Patients with previous acute GVHD grades II to IV may benefit from more aggressive initial treatment. This possibility would have to be examined in clinical trials.     

Increasingly frequent diagnosis of acute gastrointestinal graft-versus-host disease after allogeneic hematopoietic cell transplantation.

The reported incidence of grades II to IV acute graft-versus-host disease (GVHD) after hematopoietic cell transplantation with HLA-identical sibling donors has increased considerably during the past 15 to 20 years at our center. The purpose of this study was to evaluate the potential reasons for this change. We reviewed organ stages and overall grades of GVHD for 2220 patients who received a first marrow or peripheral blood cell transplant from an HLA-identical sibling or an HLA-allele-matched unrelated donor with the use of a posttransplantation immunosuppressive regimen that included both methotrexate and cyclosporine between 1985 and 2001. The most striking change was an increased incidence of stage 1 gut involvement from 10% to 20% before 1992 to 50% to 60% since 1992, both with related and unrelated donors. This change increased the incidence of grade II GVHD with sibling donors, such that the overall incidence of grade II to IV GVHD is now 60% to 70%. Among patients with chronic myeloid leukemia in chronic phase, the increasingly frequent diagnosis of acute GVHD since 1992 has not been associated with decreased survival. A high diagnostic sensitivity and increased awareness that gut GVHD can occur without skin involvement account for the increased incidence of acute GVHD at our center.     

Outcomes among patients with recurrent high-risk hematologic malignancies after allogeneic hematopoietic cell transplantation.

We retrospectively analyzed outcomes among 307 consecutive patients who had recurrent or persistent acute leukemia (n = 244), chronic myelogenous leukemia in blast phase (CML; n = 28), or advanced myelodysplastic syndromes (MDS; n = 35) after allogeneic hematopoietic cell transplantation and who received at least 1 relapse-directed intervention: withdrawal of immunosuppression, chemotherapy, or donor lymphocyte infusion (DLI). Transplants were performed at a single institution between 1995 and 2004, and outcomes were analyzed according to time intervals from transplantation to detection of malignancy: "early," <100 days (n = 111); "intermediate," 100-200 days (n = 73); and "late," >200 days (n = 123). The overall remission rate was 30%. Compared to early recurrence, intermediate recurrence and late recurrence were associated with increasing probabilities of remission (hazard ratios, 1.89 and 2.16; P = .05 and .02) and decreasing risks of overall mortality (hazard ratios, 0.73 and 0.33; P = .05 and <.0001). The 2-year overall survival (OS) estimates for patients with early, intermediate, and late recurrence were 3%, 9%, and 19%, respectively. Remission was associated with a median survival prolongation of 9.5 months. Individual types or combinations of these nonrandomly assigned relapse-directed interventions were not associated with higher or lower probabilities of remission or survival. More effective intervention strategies are needed for treatment of recurrent high-risk hematologic malignancies after hematopoietic cell transplantation. In the absence of innovative clinical trials, patients with early recurrence might wish to forego further interventions in favor of palliative care.