Granulocyte colony-stimulating factor(Shire Pharmaceuticals Services Ltd.)

ELK GROVE VILLAGE, Ill., Feb. 26, 2026 /PRNewswire/ -- Orsini, a leader in rare disease pharmacy solutions, has been selected by Genetix Biotherapeutics Inc. as a specialty pharmacy partner for three FDA-approved autologous hematopoietic stem cell-based gene therapies for the treatment of rare genetic diseases. With the addition of LYFGENIA™ (lovotibeglogene autotemcel), ZYNTEGLO™ (betibeglogene autotemcel) and SKYSONA™ (elivaldogene autotemcel), Orsini's Cell and Gene Therapy Center of Excellence now supports a total of 12 therapies. LYFGENIA is a first-in-class FDA-approved ex vivo gene addition therapy indicated for the treatment of patients 12 years of age or older with sickle cell disease (SCD) and a history of vaso-occlusive events. Read the full Prescribing Information here. ZYNTEGLO is the first and only FDA-approved ex vivo gene addition therapy indicated for the treatment of adult and pediatric patients with β-thalassemia who require regular red blood cell transfusions. Read the full Prescribing Information here. SKYSONA is the first and only FDA-approved ex vivo gene addition therapy indicated to slow the progression of neurologic dysfunction in boys 4-17 years of age with early, active cerebral adrenoleukodystrophy without an available human leukocyte antigen-matched donor for allogeneic hematopoietic stem cell transplant. Read the full Prescribing Information here. "As the leading independent specialty pharmacy in cell and gene therapies, Orsini is honored to support bringing these transformative treatments to patients," Brandon Tom, Orsini's CEO, said. "With our deep experience in rare conditions and our unwavering commitment to patient care, this is a powerful step forward in delivering the promise of curative therapies to those who need it most." About Orsini Providing patients with comprehensive and compassionate care since 1987, Orsini is a leader in rare diseases and gene therapies. Orsini partners with biopharma innovators, healthcare providers and payors to support patients and their families in accessing revolutionary treatments for rare diseases. Through integrated rare disease pharmacy solutions including pharmacy distribution, patient services, clinical management and convenient home infusion services, Orsini simplifies how patients connect to advanced therapies. Orsini's high-touch care model centers on experienced and trained therapy care teams that provide personalized patient care to ensure that No Patient is Left Behind™. Orsini holds accreditations with the Accreditation Commission for Health Care (ACHC), The Joint Commission, URAC and NABP. Orsini has earned URAC's Rare Disease Pharmacy Center of Excellence Designation and ACHC's Distinction in Rare Diseases and Orphan Drugs. For more information, visit . About LYFGENIA™ (lovotibeglogene autotemcel) LYFGENIA is a one-time ex-vivo lentiviral vector (LVV) gene addition therapy approved for eligible patients with sickle cell disease, in which a functional β-globin gene is added to patients' own hematopoietic (blood) stem and progenitor cells (HSPCs). This addition results in the production of adult hemoglobin with anti-sickling properties (HbAT87Q) which has a similar oxygen-binding affinity to wild-type HbA. LYFGENIA has been shown to limit sickling of red blood cells and reduce or eliminate vaso-occlusive events (VOEs). LYFGENIA is indicated for the treatment of patients 12 years of age or older with sickle cell disease and a history of VOEs. Limitations of Use Following treatment with LYFGENIA, patients with α-thalassemia trait (-α3.7/-α3.7) may experience anemia with erythroid dysplasia that may require chronic red blood cell transfusions. LYFGENIA has not been studied in patients with more than two α-globin gene deletions. IMPORTANT SAFETY INFORMATION FOR LYFGENIA (lovotibeglogene autotemcel) Boxed WARNING: HEMATOLOGIC MALIGNANCY Hematologic malignancy has occurred in patients treated with LYFGENIA. Monitor patients closely for evidence of malignancy through complete blood counts at least every 6 months and through integration site analysis at Months 6, 12, and as warranted. Hematologic Malignancy Hematologic malignancy has occurred in patients treated with LYFGENIA (Study 1, Group A). At the time of initial product approval, two patients treated with an earlier version of LYFGENIA using a different manufacturing process and transplant procedure (Study 1, Group A) developed acute myeloid leukemia (AML). One patient with α-thalassemia trait (Study 1, Group C) has been diagnosed with myelodysplastic syndrome (MDS). The additional hematopoietic stress associated with mobilization, conditioning, and infusion of LYFGENIA, including the need to regenerate the hematopoietic system, may increase the risk of a hematologic malignancy. Patients with sickle cell disease have an increased risk of hematologic malignancy as compared to the general population. Patients treated with LYFGENIA may develop hematologic malignancies and should have lifelong monitoring. Monitor for hematologic malignancies with a complete blood count (with differential) at least every 6 months for at least 15 years after treatment with LYFGENIA, and integration site analysis at Months 6, 12, and as warranted. In the event that a malignancy occurs, contact Genetix Biotherapeutics at 1-833-999-6378 for reporting and to obtain instructions on collection of samples for testing. Post-Marketing Long Term Follow-Up Study: Patients who intend to receive treatment with LYFGENIA are encouraged to enroll in the study, as available, to assess the long-term safety of LYFGENIA and the risk of malignancies occurring after treatment with LYFGENIA by calling Genetix Biotherapeutics at 1-833-999-6378. The study includes monitoring (at pre-specified intervals) for clonal expansion. Delayed Platelet Engraftment Delayed platelet engraftment has been observed with LYFGENIA. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia. Two patients (4%) required more than 100 days post treatment with LYFGENIA to achieve platelet engraftment. Patients should be made aware of the risk of bleeding until platelet recovery has been achieved. Monitor patients for thrombocytopenia and bleeding according to standard guidelines. Conduct frequent platelet counts until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise. Neutrophil Engraftment Failure There is a potential risk of neutrophil engraftment failure after treatment with LYFGENIA. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 0.5 × 109 cells/L obtained on different days by Day 43 after infusion of LYFGENIA. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with LYFGENIA, provide rescue treatment with the back-up collection of CD34+ cells. Insertional Oncogenesis There is a potential risk of lentiviral vector-mediated insertional oncogenesis after treatment with LYFGENIA. Hypersensitivity Reactions Allergic reactions may occur with the infusion of LYFGENIA. The dimethyl sulfoxide (DMSO) or dextran 40 in LYFGENIA may cause hypersensitivity reactions, including anaphylaxis. Anti-retroviral Use Patients should not take prophylactic HIV anti-retroviral medications for at least one month prior to mobilization and until all cycles of apheresis are completed. There are some long-acting anti-retroviral medications that may require a longer duration of discontinuation for elimination of the medication. If a patient is taking anti-retrovirals for HIV prophylaxis, confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells. Hydroxyurea Use Patients should not take hydroxyurea for at least 2 months prior to mobilization and until all cycles of apheresis are completed. If hydroxyurea is administered between mobilization and conditioning, discontinue 2 days prior to initiation of conditioning. Iron Chelation Drug-drug interactions between iron chelators and the mobilization process and myeloablative conditioning agent must be considered. Iron chelators should be discontinued at least 7 days prior to initiation of mobilization or conditioning. Do not administer myelosuppressive iron chelators (e.g., deferiprone) for 6 months post-treatment with LYFGENIA. Non-myelosuppressive iron chelation should be restarted no sooner than 3 months after LYFGENIA infusion. Phlebotomy can be used in lieu of iron chelation, when appropriate. Interference with PCR-based Testing Patients who have received LYFGENIA are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to integrated BB305 LVV proviral DNA, resulting in a possible false-positive PCR assay test result for HIV. Therefore, patients who have received LYFGENIA should not be screened for HIV infection using a PCR-based assay. Adverse Reactions The most common adverse reactions ≥ Grade 3 (incidence ≥ 20%) were stomatitis, thrombocytopenia, neutropenia, febrile neutropenia, anemia, and leukopenia. Three patients died during LYFGENIA clinical trials; one from sudden cardiac death due to underlying disease and two from acute myeloid leukemia who were treated with an earlier version of LYFGENIA using a different manufacturing process and transplant procedure (Study 1, Group A). Pregnancy/Lactation Advise patients of the risks associated with myeloablative conditioning agents, including on pregnancy and fertility. LYFGENIA should not be administered to women who are pregnant, and pregnancy after LYFGENIA infusion should be discussed with the treating physician. LYFGENIA is not recommended for women who are breastfeeding, and breastfeeding after LYFGENIA infusion should be discussed with the treating physician. Females and Males of Reproductive Potential A negative serum pregnancy test must be confirmed prior to the start of mobilization and re-confirmed prior to conditioning procedures and before LYFGENIA administration. Women of childbearing potential and men capable of fathering a child should use an effective method of contraception (intra-uterine device or combination of hormonal and barrier contraception) from start of mobilization through at least 6 months after administration of LYFGENIA. Advise patients of the options for fertility preservation. Please see full Prescribing Information, including Boxed WARNING and Medication Guide for LYFGENIA. About ZYNTEGLO™ (betibeglogene autotemcel) ZYNTEGLO is a first-in-class, one-time ex-vivo LVV gene addition therapy approved for eligible patients with transfusion-dependent beta-thalassemia who require regular red blood cell (RBC) transfusions, in which functional copies of a modified form of the beta-globin gene (βA-T87Q-globin gene) is added into a patient's own HSPCs. This addition results in the production of adult hemoglobin (HbAT87Q) enabling total hemoglobin to reach normal or near normal levels. ZYNTEGLO has been shown to eliminate the need for regular RBC transfusions. ZYNTEGLO is indicated for the treatment of adult and pediatric patients with beta-thalassemia who require regular RBC transfusions. IMPORTANT SAFETY INFORMATION FOR ZYNTEGLO (betibeglogene autotemcel) Delayed Platelet Engraftment Delayed platelet engraftment has been observed with ZYNTEGLO treatment. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia; 15% of patients had ≥ Grade 3 decreased platelets on or after Day 100. Patients should be made aware of the risk of bleeding until platelet recovery has been achieved. Monitor patients for thrombocytopenia and bleeding according to standard guidelines. Conduct frequent platelet counts until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise. Risk of Neutrophil Engraftment Failure There is a potential risk of neutrophil engraftment failure after treatment with ZYNTEGLO. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 500 cells/microliter obtained on different days by Day 43 after infusion of ZYNTEGLO. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with ZYNTEGLO, provide rescue treatment with the back-up collection of CD34+ cells. Risk of Insertional Oncogenesis There is a potential risk of lentiviral vector (LVV)-mediated insertional oncogenesis after treatment with ZYNTEGLO. Patients treated with ZYNTEGLO may develop hematologic malignancies and should be monitored lifelong. Monitor for hematologic malignancies with a complete blood count (with differential) at Month 6 and Month 12 and then at least annually for at least 15 years after treatment with ZYNTEGLO, and integration site analysis at Months 6, 12, and as warranted. In the event that a malignancy occurs, contact Genetix Biotherapeutics at 1 833-999-6378 for reporting and to obtain instructions on collection of samples for testing. Hypersensitivity Reactions Allergic reactions may occur with the infusion of ZYNTEGLO. The dimethyl sulfoxide (DMSO) in ZYNTEGLO may cause hypersensitivity reactions, including anaphylaxis. Anti-retroviral and Hydroxyurea Use Patients should not take prophylactic HIV anti-retroviral medications or hydroxyurea for at least one month prior to mobilization, or for the expected duration for elimination of the medications, and until all cycles of apheresis are completed. If a patient requires anti-retrovirals for HIV prophylaxis, then confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells. Interference with Serology Testing Patients who have received ZYNTEGLO are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to integrated BB305 LVV proviral DNA, resulting in a false-positive test for HIV. Therefore, patients who have received ZYNTEGLO should not be screened for HIV infection using a PCR-based assay. Adverse Reactions The most common non-laboratory adverse reactions (≥20%) were mucositis, febrile neutropenia, vomiting, pyrexia, alopecia, epistaxis, abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder, and pruritus. The most common Grade 3 or 4 laboratory abnormalities (>50%) include neutropenia, thrombocytopenia, leukopenia, anemia, and lymphopenia. Drug Interactions Drug-drug interactions between iron chelators and the myeloablative conditioning agent must be considered. Iron chelators should be discontinued at least 7 days prior to initiation of conditioning. The prescribing information for the iron chelator(s) and the myeloablative conditioning agent should be consulted for the recommendations regarding co-administration with CYP3A substrates. Some iron chelators are myelosuppressive. After ZYNTEGLO infusion, avoid use of these iron chelators for 6 months. If iron chelation is needed, consider administration of non-myelosuppressive iron chelators. Phlebotomy can be used in lieu of iron chelation, when appropriate. Pregnancy/Lactation Advise patients of the risks associated with conditioning agents, including on pregnancy and fertility. ZYNTEGLO should not be administered to women who are pregnant, and pregnancy after ZYNTEGLO infusion should be discussed with the treating physician. ZYNTEGLO is not recommended for women who are breastfeeding, and breastfeeding after ZYNTEGLO infusion should be discussed with the treating physician. Females and Males of Reproductive Potential A negative serum pregnancy test must be confirmed prior to the start of mobilization and re-confirmed prior to conditioning procedures and before ZYNTEGLO administration. Women of childbearing potential and men capable of fathering a child should use an effective method of contraception (intra uterine device or combination of hormonal and barrier contraception) from start of mobilization through at least 6 months after administration of ZYNTEGLO. Advise patients of the option to cryopreserve semen or ova before treatment if appropriate. Please see full Prescribing Information and Patient Information for ZYNTEGLO. About SKYSONA™ (elivaldogene autotemcel) SKYSONA is the first FDA-approved, one-time ex-vivo LVV gene addition therapy approved for eligible patients with early, active cerebral adrenoleukodystrophy (CALD), in which functional copies of the ABCD1 cDNA are added into a patients' own HSCs. This addition results in the production of functional adrenoleukodystrophy protein (ALDP) which can then participate in the local degradation of very long chain fatty acids (VLCFAs), which is believed to slow or possibly prevent further inflammation and demyelination resulting from the disease. SKYSONA is indicated to slow the progression of neurologic dysfunction in boys 4-17 years of age with early, active cerebral adrenoleukodystrophy (CALD) without an available human leukocyte antigen (HLA)-matched donor for allogeneic hematopoietic stem cell transplant. Limitations of Use SKYSONA does not prevent the development of or treat adrenal insufficiency due to adrenoleukodystrophy. An immune response to SKYSONA may limit the persistence of descendent cells of SKYSONA, causing rapid loss of efficacy of SKYSONA in patients with full deletions of the human adenosine triphosphate binding cassette, sub family D, member 1 (ABCD1) gene. SKYSONA has not been studied in patients with CALD secondary to head trauma. Given the risk of hematologic malignancy with SKYSONA, and unclear long-term durability of SKYSONA and human adrenoleukodystrophy protein (ALDP) expression, careful consideration should be given to the appropriateness and timing of treatment for each boy, especially for boys with isolated pyramidal tract disease since their clinical symptoms do not usually occur until adulthood. IMPORTANT SAFETY INFORMATION FOR SKYSONA (elivaldogene autotemcel) Boxed WARNING: HEMATOLOGIC MALIGNANCY Hematologic malignancies, including life-threatening cases of myelodysplastic syndrome and acute myeloid leukemia, have occurred in patients treated with SKYSONA. Patients have been diagnosed between 14 months and 10 years after SKYSONA administration, and the cancers appear to be related to treatment with SKYSONA. Monitor patients closely for evidence of malignancy through complete blood counts at least every 3 months. Monitor patients through assessments for evidence for clonal expansion or predominance at least twice in the first year and annually thereafter; consider bone marrow evaluations as clinically indicated. Hematologic Malignancy Hematologic malignancies, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have developed in patients treated with SKYSONA in clinical studies between 14 months and 10 years after SKYSONA administration. Malignancies are life-threatening. Death related to treatment for malignancy and relapse of malignancy have occurred. As of July 2025, hematologic malignancies have been diagnosed in 10/67 (15%) clinical study patients. At diagnosis of hematologic malignancy, all 10 patients had predominant integrations; 7 in proto-oncogenes, including 6 in MECOM. Pathological diagnoses ranged between MDS-unilineage dysplasia to acute myeloid leukemia. As of July 2025, 9 of the 10 patients had received allogeneic hematopoietic stem cell transplant. One of the patients with MDS relapsed 6 months after an allogenic transplant and required re-treatment of MDS. SKYSONA Lenti-D lentiviral vector genomic integration, including into the proto-oncogene MECOM, appears to have mediated the cases of hematologic malignancy. All patients treated with SKYSONA in clinical studies have integrations into MECOM; however, it is unknown which integrations into MECOM or other genes are likely to lead to malignancy. Consider consultation with hematology experts prior to SKYSONA treatment to inform benefit-risk treatment decision and to ensure adequate monitoring for hematologic malignancy. Consider performing the following baseline hematologic assessments: complete blood count with differential, hematopathology review of peripheral blood smear, and bone marrow biopsy (core and aspirate) with flow cytometry, conventional karyotyping, and next generation sequencing (NGS) with a molecular panel appropriate for age and including coverage for gene mutations expected in myeloid and lymphoid malignancies; and testing for germline mutations that are associated with hematologic malignancy. Early diagnosis of hematologic malignancy can be critically important, therefore, monitor patients treated with SKYSONA lifelong for hematologic malignancy. For at least the first fifteen years after treatment with SKYSONA, monitor via complete blood count (with differential) at least every 3 months and via integration site analysis or other testing for evidence of clonal expansion and predominance at least twice in the first year and then annually. Consider appropriate expert consultation and additional testing such as more frequent complete blood count (with differential) and integration site analysis, bone marrow studies, and gene expression studies in the following settings after treatment with SKYSONA: Delayed or failed engraftment of platelets or other cell lines (while all patients are at risk for hematologic malignancy, patients who do not achieve unsupported platelet counts of ≥ 20 × 109/L on or after Day 60 appear to be at higher risk); or New or prolonged cytopenias; or, Presence of clonal expansion or predominance (e.g., increasing relative frequency of an integration site, especially if ≥ 10% and present in MECOM or another proto-oncogene known to be involved in hematologic malignancy). If hematologic malignancy is detected in a patient who received SKYSONA, contact Genetix Biotherapeutics at 1 833 999 6378 for reporting and to obtain instructions on collection of samples for further testing. Serious Infections Severe infections, including life-threatening and fatal infections, have occurred in patients after SKYSONA infusion. Important opportunistic infections that have been diagnosed within the first 3 months after treatment with SKYSONA include BK cystitis, cytomegalovirus reactivation, human herpesvirus-6 viremia, candidiasis, and bacteremias. Opportunistic infections after the first 3 months include an atypical mycobacterium vascular device infection, pseudomonas bacteremia, and Epstein-Barr virus reactivations diagnosed as late as 18 months after treatment with SKYSONA. Serious infections involving adenovirus include a case of transverse myelitis at 6 months that was attributed to adenovirus and entero/rhinovirus infection, and a fatal adenovirus infection at 21 months in a patient with CALD progression who developed multisystem organ failure. Grade 3 or higher infections occurred in 21% of all patients (12% bacterial, 3% viral, and 6% unspecified). The most common Grade 3 or higher infections were vascular device infections (7% of patients) diagnosed as late as 6 months after treatment with SKYSONA, and bacteremias (6% of patients) diagnosed as late as 8 months after treatment with SKYSONA. Febrile neutropenia was commonly observed in clinical studies and may be a sign of a serious infection. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated. Monitor patients for signs and symptoms of infection before and after SKYSONA administration and treat appropriately. Administer prophylactic antimicrobials according to best clinical practices and clinical guidelines. Avoid administration of SKYSONA in patients with active infections. Prolonged Cytopenias Patients may exhibit cytopenias, including pancytopenia, for > 1 year following conditioning and SKYSONA infusion. Grade 3 or higher cytopenias on or after Day 60 following SKYSONA infusion occurred in 47% of patients and included low platelet count (14%), low neutrophil count (22%), low lymphocyte count (27%), and low hemoglobin (2%). Grade 3 cytopenias persisted beyond Day 100 in 15% of patients and included low platelet count (7%), low neutrophil count (9%), and low lymphocyte count (6%). Serious adverse reactions of pancytopenia occurred in two patients who required support with blood and platelet transfusions as well as growth factors (G-CSF for up to 6 months and eltrombopag for up to 14 months) after SKYSONA administration. One patient had intercurrent parvovirus infection and his pancytopenia was ongoing at least two years after SKYSONA administration. Pancytopenia in the other patient was ongoing until he was diagnosed with myelodysplastic syndrome approximately two years after SKYSONA administration. Monitor blood counts until normalization and assess patients for signs and symptoms of bleeding and/or infection prior to and after SKYSONA administration. Delayed Platelet Engraftment Delayed platelet engraftment (platelet count ≤ 50 × 109/L beyond 60 days after treatment with SKYSONA) has been observed. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia. Patients should be made aware of the risk of bleeding until platelet recovery has been achieved. Monitor patients for thrombocytopenia and bleeding according to standard guidelines. Conduct frequent platelet counts until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise. Risk of Neutrophil Engraftment Failure There is a potential risk of neutrophil engraftment failure after treatment with SKYSONA. Neutrophil engraftment failure was defined as failure to achieve 3 consecutive absolute neutrophil counts (ANC) ≥0.5 × 109 cells/L obtained on different days by Day 43 after infusion of SKYSONA. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with SKYSONA, provide rescue treatment with the back-up collection of CD34+ cells. Hypersensitivity Reactions Allergic reactions may occur with the infusion of SKYSONA. The dimethyl sulfoxide (DMSO) in SKYSONA may cause hypersensitivity reactions, including anaphylaxis which is potentially life-threatening and requires immediate intervention. Anti-retroviral Use Patients should not take anti-retroviral medications for at least one month prior to mobilization or the expected duration for elimination of the medications, and until all cycles of apheresis are completed. Anti-retroviral medications may interfere with manufacturing of the apheresed cells. If a patient requires anti-retrovirals for HIV prophylaxis, mobilization and apheresis of CD34+ cells should be delayed until HIV infection is adequately ruled out. Laboratory Test Interference SKYSONA affects polymerase chain reaction (PCR) assays for HIV due to LVV provirus insertion. A PCR based assay should not be used to screen for HIV infection in patients treated with SKYSONA as a false positive test result is likely. Adverse Reactions Most common non-laboratory adverse reactions (≥ 20%): mucositis, nausea, vomiting, febrile neutropenia, alopecia, decreased appetite, abdominal pain, constipation, pyrexia, diarrhea, headache, rash. Most common Grade 3 or 4 laboratory abnormalities (≥ 40%): leukopenia, lymphopenia, thrombocytopenia, neutropenia, anemia, hypokalemia. Vaccines Vaccination is not recommended during the 6 weeks preceding the start of myeloablative conditioning, and until hematological recovery following treatment with SKYSONA. Where feasible, administer childhood vaccinations prior to myeloablative conditioning for SKYSONA. Males of Reproductive Potential Advise patients of the risks associated with mobilization and conditioning agents. Males capable of fathering a child and their female partners of childbearing potential should use an effective method of contraception (intra uterine device or combination of hormonal and barrier contraception) from start of mobilization through at least 6 months after administration of SKYSONA. Data are available on the risk of infertility with myeloablative conditioning. Advise patients of the option to cryopreserve semen before treatment if appropriate. Please see full Prescribing Information for SKYSONA. SOURCE Orsini 21% more press release views with Request a Demo

临床试验和真实世界证据已经确立了嵌合抗原受体（CAR）T细胞疗法在降低血液系统恶性肿瘤进展方面的益处，并且在某些情况下，能提高总生存率。然而，最近的研究强调，处于长期缓解期的患者仍然存在发病和非复发死亡的风险，这主要是由于感染和后续的髓系恶性肿瘤。此外，这些患者可能也是化疗、放疗和/或干细胞移植的幸存者，具有广泛的生存期管理需求。在此，我们为CAR-T细胞治疗后处于长期缓解期的患者的护理提供一份路线图，并讨论未来研究的方向。 生存期护理路线图 嵌合抗原受体（CAR）T细胞疗法已经改变了复发/难治性血液系统恶性肿瘤患者的治疗格局。许多关注点集中在CAR-T细胞疗法的早期不良效应上，如细胞因子释放综合征（CRS）和神经毒性，这是合理的，因为它们影响发病率、死亡率和医疗资源利用。然而，值得注意的是，CAR-T细胞疗法的许多问题远在这个最初的急性期之后出现。首先，CAR-T细胞治疗后最常见的死亡原因是原始恶性肿瘤的复发，因此，提高CAR-T细胞的长期抗肿瘤疗效至关重要。其次，处于缓解期的长期幸存者仍面临持续的非复发死亡（NRM）风险。美国淋巴瘤联盟最近的一份报告描述了5年NRM率为16%，其中超过一半的NRM事件发生在2年之后。相反，晚期复发是罕见的。荟萃分析、回顾性研究和大型登记处的数据惊人地一致：CAR-T细胞幸存者中的NRM主要归因于感染，并且由于继发性恶性肿瘤（包括髓系恶性肿瘤和实体瘤），存在显著的晚期NRM（占患者的5%-10%）。 表 1. CD19和BCMA导向CAR-T细胞的部分晚期毒性 除了死亡事件，长期发病率和患者报告的不良结局也很常见。总体而言，针对CAR-T细胞受者的筛查、预防和管理的循证指南还很匮乏。虽然CAR-T细胞治疗后的生存期考虑因素与造血干细胞移植（HCT）后观察到的一些主题相似——例如免疫功能障碍、血细胞减少和感染风险——但CAR-T细胞疗法在生物学和临床上都是不同的。鉴于这些差异，并承认当前CAR特异性数据的空白，我们概述了一个实用的生存期护理路线图（图1 ，表1 ）。 图 1. CAR-T细胞受者的生存护理路线图。该图概述了针对CD19或BCMA导向的CAR-T细胞疗法后的生存管理和晚期效应监测的多学科方法。干预措施按系统领域和随访年份进行组织，反映了不同的风险时间模式。根据护理模式及患者偏好，这些活动有些可能在CAR-T治疗中心完成，有些可能在转诊的社区诊所完成，还有些可能涉及初级保健提供者。BCMA, B细胞成熟抗原；BMBX, 骨髓活检；CAR-T,嵌合抗原受体T细胞疗法；CHIP, 潜能未定的克隆性造血；LVEF, 左心室射血分数；NGS, 二代测序。 感染 感染是CAR-T细胞疗法的主要并发症，发生在20%-60%的CAR-T受者中。虽然大多数患者能够康复，但感染是NRM最重要的原因，占所有事件的一半。我们发现，17%的淋巴瘤患者在CAR-T细胞治疗后6至12个月之间需要住院或静脉注射抗生素，10%的患者在输注后1至2年之间需要。接受CAR-T细胞疗法治疗的患者由于与活动性癌症相关的炎症和免疫抑制以及先前治疗的影响，存在潜在的免疫失调。淋巴细胞清除化疗、使用抑制细胞因子炎症的治疗以及CAR-T细胞的靶向效应进一步破坏了免疫力，导致B细胞发育不全。从长远来看，许多患者随后会出现持续的血细胞减少以及B细胞和T淋巴细胞的免疫重建不良。 细菌感染 细菌感染占CAR-T术后早期感染的大多数；然而，关于晚期感染的数据有限。应特别关注鼻窦和肺部感染，在症状出现时或对于综合征无法缓解的患者，应降低抗生素覆盖的门槛。对于经历复发性或无法缓解的感染的患者，建议补充免疫球蛋白。对于接受浆细胞导向治疗（即针对多发性骨髓瘤的BCMA靶向CAR-T细胞）的患者，建议预防性补充免疫球蛋白。总体而言，应保持高度临床警惕性，及时进行诊断性评估并尽早开始经验性抗微生物治疗。 病毒感染 呼吸道病毒感染是晚期感染的主要原因，部分原因是B细胞和T细胞免疫重建延迟。在一项针对BCMA CAR-T受者的研究中，1年累积呼吸道感染发生率为22%，大多数病例被描述为轻度/中度。虽然大多数患者能康复，但一部分患者可能会出现严重并发症，包括呼吸衰竭、继发性细菌和/或真菌感染，甚至死亡。 SARS-CoV-2感染 在COVID-19大流行期间，由于严重的B细胞发育不全和体液免疫受损，CAR-T受者的重症SARS-CoV-2感染率异常高。在一项关于细胞治疗后SARS-CoV-2疫苗接种安全性和免疫原性的多中心前瞻性观察研究中，疫苗相关不良事件并不常见。然而，由于在持续性B细胞发育不全的CAR-T患者中，结合抗体和中和抗体在疫苗接种后并未增加，因此疗效被削弱。有意义的是，在第二剂疫苗后观察到了疫苗特异性T细胞反应。因此，美国传染病学会（IDSA）指南建议在CAR-T治疗后≥3个月开始接种COVID-19疫苗。 尽管随着时间的推移，SARS-CoV-2感染的严重程度有所减轻，但细胞治疗受者仍然面临不良结局的风险。对于出现症状性SARS-CoV-2感染的CAR-T细胞幸存者，我们降低抗病毒治疗和免疫球蛋白替代的门槛。 非呼吸道病毒再激活 在CD19和BCMA导向的CAR-T细胞治疗受者中，病毒再激活的报道很少。根据HCT文献推断，美国移植与细胞治疗学会（ASTCT）指南建议将HIV、乙型和丙型肝炎等传染病标志物的检测作为初始CAR-T工作的一部分。在慢性乙型肝炎携带者中已有致命性再激活的病例描述，这些患者需要在CAR-T输注后至少进行一年的预防治疗，并在停止预防治疗后进行密切监测（假设B细胞恢复）。先前已根除丙型肝炎的患者不需要特殊监测。HIV再激活很罕见，在解释使用在CAR转基因中包含HIV序列的产品治疗后的病毒检测结果时需要谨慎。 巨细胞病毒（CMV）再激活在CMV血清反应阳性的患者中观察到20%-60%，大多数感染发生在CAR-T治疗后2-6周内。风险因素包括BCMA靶向治疗和接受≥3天的皮质类固醇和/或阿那白滞素治疗。在这种情况下，CMV病毒血症的临床意义尚不明确，仅有罕见的CMV终末器官疾病报道。ASTCT指南建议在最初2-6周内对高危患者进行每周CMV监测，包括接受BCMA导向疗法治疗的CMV血清反应阳性患者以及需要≥3天皮质类固醇治疗的患者。治疗根据具体情况进行决策。目前没有支持CMV预防（即替莫韦）的数据，但这值得进一步评估。 抗微生物药物预防 抗微生物药物预防的建议主要依赖于回顾性经验和移植文献的推断。应考虑评估CAR-T治疗前的风险因素，如既往异基因HCT和持续的血细胞减少，以便个性化监测和干预。我们建议对持续性重度中性粒细胞减少症患者使用氟喹诺酮类药物进行抗菌预防。对于单纯疱疹病毒和水痘-带状疱疹病毒（VZV）的预防，我们使用阿昔洛韦或伐昔洛韦至少6个月，并且对于持续性B细胞发育不全、无法对带状疱疹疫苗产生体液反应的患者，通常使用更长时间。为预防耶氏肺孢子菌，我们建议使用甲氧苄啶/磺胺甲恶唑（TMP/SMX）或阿托伐醌，直至至少6个月且CD4计数>200个细胞/mm³。虽然侵袭性真菌感染很少见，但它们可能危及生命，建议对有风险因素（如持续性血细胞减少、长期使用类固醇或有侵袭性真菌感染史）的患者使用抗霉菌唑类药物。 B细胞发育不全、低丙种球蛋白血症和疫苗接种 低丙种球蛋白血症和对疫苗接种的免疫反应可能取决于CAR-T细胞靶点、CAR-T细胞持久性以及B细胞和T细胞的免疫重建。例如，CD19在正常B细胞上表达，但通常不在长寿命浆细胞上表达，而长寿命浆细胞表达BCMA。因此，接受CD19 CAR-T细胞治疗的患者在B细胞发育不全期间不会对疫苗接种产生新的体液反应，但其长寿命浆细胞中确实保留了一些预先存在的抗体介导的免疫力。在淋巴瘤患者中，通常在治疗后1年内50%-70%的患者恢复正常B细胞，3年后恢复的比例更高。相比之下，BCMA靶向的CAR-T会消耗浆细胞，而浆细胞对于维持现有体液免疫至关重要。这可能是该患者群体晚期感染增加的原因；然而，对新疫苗接种的反应仍然可能发生。与CD19 CAR-T受者相比，BCMA CAR-T受者观察到对流感和SARS-CoV-2疫苗的血清转化率更高。 迄今为止的经验表明，CAR-T细胞幸存者接种疫苗是安全的；关于它们预防感染的有效性数据尚不明确，因此，强制推行CAR-T术后通用疫苗接种计划仍为时过早。考虑到这一点，在输注后3-6个月开始考虑使用非活疫苗是合理的，并且对于表现出B细胞和T细胞重建的患者更可能有效。由于CAR-T细胞治疗后大多数具有临床意义的感染涉及呼吸道病原体，初始疫苗接种工作的重点包括流感、SARS-CoV-2感染和肺炎链球菌，以及VZV（因为在免疫功能低下时存在带状疱疹风险）。RSV疫苗最近获得批准，作为一种呼吸道病原体备受关注，但目前缺乏CAR-T人群中的数据。通常在HCT术后人群中进行的其他疫苗（例如破伤风或乙型肝炎）在指南中有推荐，但其益处不太明确，一些中心采用个体化策略，如滴度指导的再接种或其他风险分层。虽然尚未具体描述CAR-T患者的危害，但通常避免在细胞输注后至少1年内使用活疫苗，适用于那些已证明免疫重建且在过去8个月内未使用静脉注射免疫球蛋白（IVIG）的患者。 呼吸道感染的一个关键风险因素是低丙种球蛋白血症。对于浆细胞导向的CAR-T细胞（即BCMA），专家共识是在第一年内提供普遍预防，直到IgG水平恢复至400 mg/dL以上。对于CD19 CAR-T细胞治疗幸存者，建议对IgG水平≤400 mg/dL且反复感染的患者进行替代治疗。总的来说，现有数据未能明确哪些患者应在无感染情况下接受免疫球蛋白预防，以及哪些患者仅在出现复发性或无法缓解的感染时才需要免疫球蛋白替代。此外，关于IVIG治疗的持续时间，实践各异，因为有些患者在CAR-T细胞治疗后多年甚至无法恢复B细胞生成，且无限期每月IVIG可能不切实际或成本高昂。对于持续性低丙种球蛋白血症的长期幸存者，可考虑提供IVIG治疗3个月，然后恢复观察，如果症状未缓解或感染严重或复发，则继续更长时间的替代治疗。目前正在进行前瞻性研究，以确定哪些患者最有可能从CAR-T细胞治疗后的IVIG中获益。 血细胞减少 血细胞减少在CAR-T细胞治疗后很常见，欧洲合作小组已经开发了免疫效应细胞相关血液毒性（ICAHT）分级系统，包括中性粒细胞减少症（N-ICAHT）和血小板减少症（T-ICAHT）的具体标准。该系统结合了血细胞减少的深度和持续时间，并区分早期（0-30天）和晚期（>30天）血液毒性。严重的N-ICAHT与持续中性粒细胞减少、多系血细胞减少、输血依赖、更高的感染率、增加的NRM和更差的总生存期（OS）相关，而T-ICAHT同样与输血负荷、出血风险和较差的生存结局相关。 早期血细胞减少（第1-30天） 大多数患者已经接受了多线化疗，并且通常在基线时就存在血细胞减少。随后，淋巴细胞清除方案——通常是氟达拉滨和环磷酰胺——具有高度骨髓抑制性，导致超过一半的患者出现4级血细胞减少。 晚期血细胞减少（第30天后） 持续性和复发性血细胞减少越来越被认为是CAR-T细胞疗法的显著并发症。严重血细胞减少影响50%-80%的患者，大约5%-10%的患者在治疗后两年内仍有显著的血细胞减少。持续性重度中性粒细胞减少症，特别是再生障碍性表型，与严重或致命感染的风险相关。新兴数据表明，CAR-T细胞是血细胞减少的病因，其机制包括细胞因子诱导的髓系祖细胞损伤和成熟中性粒细胞的早期凋亡。 晚期血细胞减少可能反映了多因素的病理生理学。骨髓疾病负荷是一个关键预测因素，由于广泛的骨髓受累，ALL患者的血细胞减少比淋巴瘤患者更严重、更持久。此外，CAR-T术后特异性机制——如细胞因子介导的骨髓损伤、抑制性克隆性T细胞群的出现和突变髓系克隆的扩增——进一步损害了造血恢复。 在这些机制中，潜能未定的克隆性造血是一个新出现的因素。CHIP指的是在无明显髓系恶性肿瘤的个体中，髓系基因突变且变异等位基因频率≥2%。在接受淋巴细胞清除前，30%-50%的受者中可发现CHIP，CAR-T输注后高达80%。某些突变——特别是DNMT3A、TET2和ASXL1——与早期免疫毒性发生率增加有关。在某些情况下，特别是结合临床变量如炎症和既往血细胞减少时，CHIP与血液学毒性相关，而在其他研究中，这种关联更为有限。结合CHIP负荷、突变类型和炎症标志物的精细化风险分层模型，可能更好地识别CAR-T细胞治疗后处于血液学脆弱风险的患者。正如后续章节将讨论的，CHIP也可能使患者面临继发性髓系恶性肿瘤的风险。 血液毒性预测模型 CAR-HT评分使用基线实验室检查值和炎症标志物对CAR-T术后血液学毒性风险进行分层。高分可预测持续性血细胞减少、感染、NRM和较差的无进展生存期/总生存期。其效用已在淋巴瘤和骨髓瘤队列中得到验证，并有一个在线计算器可供临床使用。在B-ALL中，由于骨髓浸润几乎是普遍的，CAR-HT显示出有限的预测价值。ALL-HT评分用骨髓疾病负荷替代铁蛋白，能更好地区分风险。 CAR-T术后血细胞减少的检查 确定CAR-T细胞治疗后血细胞减少的原因通常很复杂。初步评估应审查骨髓抑制药物、营养状况、感染风险和疾病状况。例如，使用TMP/SMX的患者可能受益于替代预防药物。铁蛋白快速升高可能提示免疫效应细胞相关噬血细胞综合征。同时存在循环LGL可能值得尝试使用皮质类固醇。病毒检测——根据临床背景进行针对性检测——可能包括CMV、EBV、细小病毒B19和腺病毒。进一步的检查可能包括骨髓评估和分期研究以确定癌症缓解状态。大多数持续性血细胞减少可归因于ICAHT，通常表现为骨髓增生低下而无其他可识别原因，并随时间推移而缓解。 血细胞减少的管理 管理核心在于密切监测和支持性护理，包括输血、抗微生物药物和生长因子（图2）。尽管有这些方法，大多数可用治疗仍是经验性的，且常常无效。 图 2. CAR-T治疗后血细胞减少的推荐检查与管理流程（虚线表示疗效有限）。BMBX，骨髓活检；CAR-T，嵌合抗原受体T细胞疗法；ESA，红系生成刺激剂；GCSF，粒细胞集落刺激因子；HLH，噬血细胞性淋巴组织细胞增多症；HSB，造血干细胞增强；ICAHT，免疫效应细胞相关血液毒性；IEC-HS，免疫效应细胞相关噬血细胞综合征；IVIG，静脉注射免疫球蛋白；LGL，大颗粒淋巴细胞；MDS，骨髓增生异常综合征；TPO RA，血小板生成素受体激动剂。 粒细胞集落刺激因子的使用 G-CSF是治疗晚期中性粒细胞减少症的主要支持手段。然而，许多严重的ICAHT病例对G-CSF无效，限制了其益处。应避免使用粒细胞-巨噬细胞集落刺激因子，因为它可能加重炎症并发症。 免疫抑制治疗 对于严重的血细胞减少病例，如果流式细胞术显示寡克隆T细胞或LGL扩增，可考虑尝试低剂量类固醇以抑制可能的细胞因子介导的血细胞减少。 造血干细胞增强 自体CD34+ HSC增强似乎是少数对CAR-T细胞治疗后持续性血细胞减少患者恢复造血有效的干预措施之一。然而，储存的干细胞通常有限，尤其是随着CAR-T疗法在治疗算法中应用更早。欧洲血液学协会/欧洲血液与骨髓移植学会小组建议，对于重度ICAHT患者，如果有可用产品且患者对G-CSF无效，可在不进行预处理的情况下进行HSC输注。有报告称干细胞增强可能加剧炎症，因此，如果对于既往有IEC-HS的患者绝对必要进行增强，建议谨慎使用低初始干细胞剂量。 血小板生成素受体激动剂和红系刺激剂 支持治疗仍然是CAR-T术后血小板减少和贫血的主要手段。关于血小板生成素受体激动剂的数据有限，其最佳剂量和总体效用仍不确定。 异基因HCT 在此情况下使用的理由是从再生障碍性贫血中推断出来的，其中移植可以是治愈性的。重要的是，大多数ICAHT病例会随时间自发恢复，而移植相关的显著发病和死亡风险通常超过不确定的益处。 长期数据显示，CAR-T细胞治疗后继发性恶性肿瘤的发生率为4%-16%。虽然这些比率与血液系统恶性肿瘤常规治疗所见比率相当，但其潜在机制尚不完全清楚。促成因素可能包括既往的基因毒性治疗、CAR-T诱导的炎症、持续性B细胞发育不全、免疫抑制和既往存在的CHIP。 继发性实体瘤 一项大型上市后研究观察到5年累积发生率为15.2%，中位发病时间为26.4个月。这些比率似乎与基于年龄和既往治疗的预期一致，目前尚不清楚CAR-T细胞疗法是否独立增加实体瘤风险。 治疗相关髓系肿瘤 在继发性恶性肿瘤中，治疗相关髓系肿瘤尤为令人担忧。一项研究报告t-MN发生率为9%，其中5%进展为需要治疗的高级别MDS或AML。另一项研究观察到BCMA CAR-T术后MDS/AML的总体发生率较低。CHIP也与升高的t-MN风险相关：一项研究报告CHIP阳性患者的24个月累积发生率为19%，而CHIP阴性患者为4.2%，在某些病例中，基线CH和后续t-MN之间存在共享突变。然而，其他研究发现t-MN很罕见，强调了不同疾病背景和队列间的异质性。关键的是，TP53突变的CHIP克隆已显示出强烈的白血病发生潜力，通常在CAR-T术后表现出显著的扩增，并预示着不良结局。相比之下，其他CHIP突变并未表现出类似行为。这些发现强调了TP53突变CHIP的高白血病潜力，表明CAR-T细胞疗法可能创造有利于高风险克隆扩增的选择压力。一个挑战是缺乏有效疗法来阻止CHIP进展为t-MN，并且哪些CAR-T患者群体将从筛查、监测或其他干预中受益尚待确定。 T细胞淋巴瘤 CAR-T细胞治疗后，罕见继发性TCL病例被报道，在美国食品药品管理局不良事件报告系统中约8000名患者中识别出22例。提出的机制包括既往存在的淋巴样突变，以及在罕见情况下，来自CAR构建体的载体整合。然而，并非所有CAR-T术后TCL都携带CAR转基因，并且载体整合仍是一种研究工具，临床应用有限。目前，这些病例使用与新发TCL相同的标准方案进行管理，尽管详细的分子特征研究可能支持对个别患者采用靶向治疗方法。 继发性恶性肿瘤的生存管理考量 关于继发性恶性肿瘤的新兴数据——包括实体瘤和血液系统肿瘤——强调了采取主动生存管理策略的必要性。根据国家指南，坚持适合年龄的癌症筛查，包括皮肤科筛查，应成为长期护理的核心组成部分。对于持续性血细胞减少、免疫重建不良或已知CHIP的个体，可能需要进行更频繁和个体化的监测。随着我们对CAR-T细胞疗法、CHIP和长期免疫功能障碍之间相互作用的理解不断深入，个体化监测框架对于减轻晚期毒性和优化CAR-T细胞受者的结局至关重要。 器官功能障碍 虽然在CAR-T治疗后，CRS背景下的多器官功能障碍已有充分描述，但迟发性器官功能障碍并不常见，且通常发生在感染和/或先前治疗的后遗症背景下。在此，我们描述CAR-T治疗后更常见观察到的器官毒性，并提出监测指南。 心脏毒性 回顾性研究报告，约10%-20%的CAR-T受者在CRS期间发生早期心肺不良事件，主要由肌钙蛋白升高和心律失常驱动。关于长期心脏结局知之甚少。根据HCT文献推断，我们建议从CAR-T治疗后6个月开始，每年评估和管理心脏风险。此外，CHIP是自体HCT受者心血管疾病的已知预测因子，与更高的心力衰竭、冠心病、中风和NRM发生率相关，并且由于CAR-T细胞疗法长期幸存者基线CHIP负荷高和CAR-T术后克隆扩增，需要进一步研究。 神经毒性 ICANS在CAR-T细胞治疗后很常见；然而，它几乎总是在输注后前两周内开始。大多数脊髓病病例也在CAR-T治疗后两周内报告，但也可能较晚发生，表现为亚急性下肢无力、步态障碍和排尿功能障碍，并且通常与脊髓MRI异常和脑脊液细胞增多相关。BCMA导向的CAR-T细胞疗法特有的一种非ICANS神经毒性，表现为帕金森综合征或颅神经麻痹。接受cilta-cel治疗的患者中，运动功能减退障碍的发生率为1%-5%，发病时间范围为11至108天。颅神经麻痹发生更频繁，发病时间相似。最佳管理方法尚不清楚，但皮质类固醇、静脉注射免疫球蛋白、鞘内化疗和/或环磷酰胺均有使用。晚期发病的可能性描述不足，但已有病例报告发生在CAR-T治疗后长达2.5年，强调了长期随访的重要性。我们建议在常规随访中除了进行患者咨询外，还应进行全面的神经系统检查。 胃肠道毒性 免疫效应细胞相关小肠结肠炎，其特征是在CAR-T治疗后中位3个月开始出现大量腹泻，是BCMA导向CAR-T疗法新出现的关键毒性。该病症的特点是CAR-T细胞浸润到胃肠道，并与肠道穿孔和败血症相关。最佳管理尚不清楚，一些病例通过皮质类固醇或抗TNF或JAK抑制剂解决，而其他病例则需要环磷酰胺或其他尝试清除CAR-T细胞的方法。在BCMA CAR-T治疗后数月内出现的新发腹泻应进行彻底检查，并考虑诊断为IEC-EC。 心理社会影响和患者报告结局 患者报告结局是理解患者生活经历的关键。在我们机构接受CAR-T治疗的120名患者中，生活质量评分在治疗的第一年内有所改善或保持相似。随机试验也报告了类似的发现。在单一机构的经验中，既往存在的心理健康障碍与CAR-T治疗后毒性风险增加相关，但不影响疗效。仍存在一些知识空白，包括对生育能力的影响、CAR-T术后重返工作岗位的能力及其财务影响，以及治疗后最初几个月之后的PRO轨迹。我们支持TCT的立场，即在临床实践和临床试验中纳入患者报告结局测量信息系统工具。 在我们机构接受CAR-T治疗的弥漫性大B细胞淋巴瘤患者中，生活质量评分在治疗的第一年内有所改善或保持相似。随机试验也报告了类似的发现。在单一机构的经验中，既往存在的心理健康障碍与CAR-T治疗后毒性风险增加相关，但不影响疗效。仍存在一些知识空白，包括对生育能力的影响、CAR-T术后重返工作岗位的能力及其财务影响，以及治疗后最初几个月之后的PRO轨迹。我们支持TCT的立场，即在临床实践和临床试验中纳入患者报告结局测量信息系统工具。 特殊人群的考量 老年人 淋巴瘤和多发性骨髓瘤主要影响老年人。真实世界数据表明，接受CAR-T治疗的老年患者与年轻患者具有相似的反应率。然而，在淋巴瘤CAR-T细胞治疗受者中，年龄大于60岁的患者OS相似，但NRM率更高，强调了老年人生存护理的特别重要性。越来越多的证据支持虚弱是比年龄更好的结局决定因素。需要进一步研究以优化基线风险分层。此外，在基线、6个月和1年时进行系列老年综合评估可能有助于优化老年人的结局。 青少年和年轻成人 生存管理对年龄在15-39岁患有血液系统恶性肿瘤的青少年和年轻成人来说是一个重要问题。在这一独特的患者群体中，性健康和生育能力下降是关键问题。在一项纵向研究中，超过一半的AYA癌症幸存者在每个评估时间点都报告有问题的性功能，且性功能障碍随时间恶化。虽然对CAR-T术后生育能力知之甚少，但已有健康婴儿活产的病例报告。为了解决当前的知识空白，一项正在进行的研究正在招募幸存者，以收集详细的患者报告的生殖史，包括生育力保留决策、妊娠结局和心理社会影响。我们建议在初次咨询时，就对有生育力保留兴趣的患者早期转诊至生殖内分泌科，并建立系统性的AYA策略。 儿科 儿科幸存者有独特的需求，许多幸存者既有CAR-T细胞治疗史，也有allo-HCT史。对于在年轻时接受这些治疗并可能成为真正长期幸存者的患者来说，针对CAR-T细胞相关突变发生、继发性恶性肿瘤、复发、生育能力、生长和发育的计划性长期监测尤其关键。 研究和未来方向 HCT术后的结构化生存管理计划可改善长期结局，但CAR-T幸存者缺乏类似数据。为了概述未来的挑战，表2重点列出了一些关键的未解问题，涵盖护理交付模式、降低NRM的策略、心脏代谢风险以及治疗相关毒性的长期负担。值得注意的是，前瞻性CAR-T细胞试验中NRM和晚期不良事件的标准化和透明报告仍然不一致，限制了我们准确量化和减轻生存风险的能力。为了加速进展，需要协调一致的多机构努力、国家登记处和前瞻性生存试验。需要努力构建一个整合了临床特征、基因组图谱、炎症标志物和PRO的精准生存管理框架，以支持个体化护理并改善生存结局。 表 2. CAR-T术后生存管理的关键问题和拟议方法 参考文献：Faramand RG, Xie Z, Jain MD. Long-Term Survivorship After Chimeric Antigen Receptor T-Cell Therapy for Hematologic Malignancies. J Clin Oncol. Published online February 11, 2026. doi:10.1200/JCO-25-02087 版权声明：本文系Leuk独立撰稿，享有原创版权，欢迎个人转发分享，其他任何媒体、网站如需转载或引用本网页版权所有内容，须获得授权。本文仅供医学专业人士参考，不作为诊疗依据，未经著作人许可，不可出版发行。 （欢迎分享，点赞+关注！）