Refractory Leukemia Research Articles

Impact of age, prior therapies, and subsequent transplant on long-term outcomes of adults with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) treated with brexucabtagene autoleucel (brexu-cel) in ZUMA-3.

7023 Background: Brexu-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the US for adults with R/R B-ALL and in the EU for adults ≥26 y with R/R B-ALL based on positive results of ZUMA-3. After 3-y follow-up in ZUMA-3, brexu-cel demonstrated an overall complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate of 71% and a median overall survival (OS) of 26.0 mo in all treated pts (N = 55) and 38.9 mo in pts with CR (n = 31; Shah et al. EU CAR T 2023. Abstract 34). Here we report 3-y outcomes by age, prior therapies, and subsequent allogeneic stem cell transplant (alloSCT). Methods: Pts (≥18 y) had R/R B-ALL and received 1 brexu-cel infusion (1×10⁶ CAR T cells/kg) following leukapheresis and conditioning chemotherapy. The primary endpoint was overall CR/CRi rate per independent review. Post hoc subgroup analyses were exploratory, with descriptive statistics reported. Results: As of July 23, 2022, the median follow-up in Phase 2 (N = 55) was 38.8 mo (range, 32.7-44.6). The CR/CRi rate (95% CI) was 67% (35-90) for pts < 26 y (n = 12) and 72% (56-85) for pts ≥26 y (n = 43). The median (95% CI) OS was 28.6 mo (0.6-not estimable [NE]) for pts < 26 y and 34.1 mo (15.9-NE) for pts ≥26 y. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 92% of pts < 26 y and in 88% of pts ≥26 y. For pts with 1 prior therapy (n = 10), the CR/CRi rate was 90% (95% CI, 55-100) and for pts with ≥2 prior therapies (n = 45), the CR/CRi rate was 67% (95% CI, 51-80); medians (95% CI) for OS were not reached (NR; 2.1-NE) and 25.6 mo (14.2-38.9), respectively. The incidence of Grade ≥3 TRAEs was 90% for pts with 1 prior therapy and 89% for pts with ≥2 prior therapies. The CR/CRi rates (95% CI) for pts with (n = 25) and without (n = 30) prior blinatumomab (blina) were 60% (39-79) and 80% (61-92). The median (95% CI) OS was 14.2 mo (3.2-26.0) for pts with prior blina and NR (18.6-NE) for pts without prior blina; Grade ≥3 TRAEs occurred in 80% and 97% of pts, respectively. For responders (CR/CRi) who did (n = 10) or did not (n = 29) proceed to subsequent alloSCT, the median (95% CI) OS was NR (7.6-NE) and 38.9 mo (18.6-NE), respectively. Similar efficacy results were observed in a pooled subgroup analysis of Phase 1 and 2 pts treated at the pivotal dose (N = 78), with a median follow-up of 41.6 mo (range, 32.7-70.3). Conclusions: Adults with R/R B-ALL benefitted from brexu-cel, regardless of age, number of prior therapies, prior blina exposure, or subsequent alloSCT status. Survival appeared longer in pts with fewer prior therapies and in blina-naïve pts; however, small pt numbers and unmatched baseline characteristics limit interpretation of these results. Additional studies are needed to determine the impact of prior therapies and/or subsequent alloSCT on outcomes of pts who receive brexu-cel. Clinical trial information: NCT02614066 .

Preliminary results of a phase 1, first-in-human study of INA03, an anti-CD71 antibody-drug conjugate, in patients with relapsed or refractory (R/R) acute leukemias.

7045 Background: R/R acute leukemias (AL) represent major therapeutic challenges. Several reports have highlighted the role of iron metabolism in various proliferative tumor models including AL including the over-expression of the transferrin receptor (TfR1/CD71). Our strategy is thus to harness CD71 overexpression to specifically target cytotoxic agents to leukemic cells. INA03 is an antibody drug conjugate (ADC) constituted of a humanized monoclonal IgG4 against CD71 and the microtubule disrupting agent monomethyl auristatin E (MMAE). We herein report the preliminary safety and efficacy data of INA03 from a phase 1/2 trial in patients (pts) with R/R AL (NCT03957915). Methods: INA03 is given as 30 minutes IV infusion on days 1 (Loading dose (LD)) followed by maintenance injections on D15 for cycle 1 and on D1 and D15 of cycle 2 and beyond. Eligibility criteria are: R/R AL after at least one line of treatment including high dose chemotherapy and/or Vidaza and Venetoclax, AlloSCT > 18y, with FEVG > 50%, Creatinine Clearance > 30ml/min, normal liver function, ECOG < 2. The study design is based on a continuous reassessment method and includes 2 parts: a LD Titration study (Part 1, completed), followed by a Dose Escalation Part 2. During Part 1, sequential cohorts of 2 pts were included to receive ascending LD of INA03 followed by subsequent fixed dose of INA03 to deal with a potential sink effect related to the high expression of CD71 in normal erythroblasts. During Part 2, sequential cohorts of 3 pts received escalating doses of INA03 Q2 weeks in 28-day cycles. The objectives were to establish the MTD for subsequent administration and both safety/tolerability and anti-leukemic activity. Results: With a cutoff date of January 18, 2023, 22 pts across 8 cohorts were included in the study. The median age was 73 (range: 39 – 83), 20 (91%) pts had AML and two (9%) had ALL. Three (13.6%) pts had a prior allo-SCT and 12 (54.5%) had prior VEN exposure. Pts received escalating doses of INA03 of 0.02 mg/kg to 2 mg/kg. MMAE pharmacokinetics (PK) appears dose-proportional with a small accumulation after repeated IV, while INA03 PK exhibits target-mediated drug disposition without accumulation. No DLT was observed among the 18 DLT-evaluable pts, up to the highest dose of 2 mg/kg. No grade 2-4 TEAEs were observed. One related grade 1 TEAE (hyperkalemia/phosphatemia) was reported. Transient decrease of reticulocyte count and erythroblasts percentage were observed at 0.5 mg/kg and above. Blasts reductions were seen in 3/18 evaluable pts at dose > 1 mg/kg including two partial responses. Conclusions: INA03 is well tolerated up to the dose of 2 mg/kg with some efficacy signals in R/R AL. The trial continues to accrue patients. Clinical trial information: NCT03957915 .

CO116 Real-World Treatment Patterns, Healthcare Resource Use and Hospital Provider Cost of Recently Approved Treatments for Adult Relapsed or Refractory Acute Lymphoblastic Leukemia in the US: Blinatumomab and/or Inotuzumab Ozogamicin

To describe treatment patterns, healthcare resource use (HRU), and hospital system cost associated with blinatumomab (blina)- and inotuzumab ozogamicin (ino)-containing regimens to treat adult R/R ALL in the US.

Real-world Experience of Approved Chimeric Antigen Receptor T-cell Therapies Compared to Clinical Trials Data.

Real-world Experience of Approved Chimeric Antigen Receptor T-cell Therapies Compared to Clinical Trials Data.

EE53 Cost-Minimization and Budget Impact Analysis of Venetoclax Versus Acalabrutinib for 1L and R/R Chronic Lymphocytic Leukemia in the Brazilian Public Healthcare System

To demonstrate the economic advantages of using venetoclax (plus obinutuzumab [VenO] or rituximab [VenR]) vs acalabrutinib monotherapy (Acala) in the first line (1L) and relapse or refractory (R/R) chronic lymphocytic leukemia (CLL) treatment under the Brazilian public healthcare system (SUS).

Health‐related quality of life in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma treated with liso‐cel in TRANSCEND CLL 004

Health‐related quality of life in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma treated with liso‐cel in TRANSCEND CLL 004

Exploratory study on the efficacy of bortezomib combining mitoxantrone or CD22-CAR T therapy targeting CD19-negative relapse after CD19-CAR T cell therapy with a simpler cell-line-based model.

Target-negative relapse after CD19 chimeric antigen receptor engineered (CAR) T cell therapy for patients with B lineage acute lymphoblastic leukemia (B-ALL) presents limited treatment options with dismal outcomes. Although CD22-CAR T cells mediate similarly potent antineoplastic effects in patients with CD19dim or even CD19-negative relapse following CD19-directed immunotherapy, a high rate of relapse associated with diminished CD22 cell surface expression has also been observed. Therefore, it is unclear whether any other therapeutic options are available. Mitoxantrone has shown significant antineoplastic activity in patients with relapsed or refractory leukemia over the past decades, and in some cases, the addition of bortezomib to conventional chemotherapeutic agents has demonstrated improved response rates. However, whether this mitoxantrone and bortezomib combination therapy is effective for those patients who have relapsed B-ALL after receiving CD19-CAR T cell therapy remains to be elucidated. In this study, we established a cellular model system using a CD19-positive B-ALL cell line Nalm-6 to investigate the treatment options for CD19-negative relapsed B-ALL after CD19-CAR T cell therapy. In addition to CD22-CAR T therapy, we observed that the combination of bortezomib and mitoxantrone exhibited effective anti-leukemia activity in the CD19-negative Nalm-6 cell line by downregulating p-AKT and p-mTOR. These results suggest that this combination therapy is a possible option for target-negative refractory leukemia cells after CAR-T cell treatment.

CAR-T Cells Immunotherapies for the Treatment of Acute Myeloid Leukemia-Recent Advances.

In order to increase the effectiveness of cancer therapies and extend the long-term survival of patients, more and more often, in addition to standard treatment, oncological patients receive also targeted therapy, i.e., CAR-T cells. These cells express a chimeric receptor (CAR) that specifically binds an antigen present on tumor cells, resulting in tumor cell lysis. The use of CAR-T cells in the therapy of relapsed and refractory B-type acute lymphoblastic leukemia (ALL) resulted in complete remission in many patients, which prompted researchers to conduct tests on the use of CAR-T cells in the treatment of other hematological malignancies, including acute myeloid leukemia (AML). AML is associated with a poorer prognosis compared to ALL due to a higher risk of relapse caused by the development of resistance to standard treatment. The 5-year relative survival rate in AML patients was estimated at 31.7%. The objective of the following review is to present the mechanism of action of CAR-T cells, and discuss the latest findings on the results of anti-CD33, -CD123, -FLT3 and -CLL-1 CAR-T cell therapy, the emerging challenges as well as the prospects for the future.

MRI findings of nelarabine-related rhabdomyolysis in a patient with refractory T-cell acute lymphoblastic leukemia.

MRI findings of nelarabine-related rhabdomyolysis in a patient with refractory T-cell acute lymphoblastic leukemia.

Real-world treatment patterns of novel drugs in relapsed or refractory acute lymphoblastic leukemia patients in Japan.

Aim: To evaluate treatment patterns of novel therapies (inotuzumab ozogamicin (inotuzumab), blinatumomab, and tisagenlecleucel) in patients with acute lymphoblastic leukemia (ALL) in a Japanese real-world setting. Patients & Methods: Patients with ALL diagnoses from a Japanese claims database were examined. Results: We included 194 patients (97 patients were prescribed inotuzumab; 97 patients were prescribed blinatumomab; and no patient was prescribed tisagenlecleucel); 81.4% in the inotuzumab group and 78.4% in the blinatumomab group were prescribed chemotherapy prior to the initiation of those drugs. Most patients were prescribed subsequent treatment (60.8 and 58.8%, respectively). A small number of patients were prescribed sequential treatment of inotuzumab-to-blinatumomab or blinatumomab-to-inotuzumab (20.3 and 10.5%, respectively). Conclusion: This study revealed inotuzumab and blinatumomab treatment features in Japan.

Sorafenib regulates c-CBL gene-mediated chemoresistance in acute myeloid leukemia cells

ABSTRACTChemotherapeutic regimens containing sorafenib are widely used in salvage treatment for patients with relapsed and refractory acute leukemia, especially those with FLT3-ITD mutations. However, the therapeutic effects in individuals are heterogeneous, and the effective maintenance period is relatively short. Our clinical analysis showed patients with high c-kit (CD117) expression in leukemia cells generally had a better response to sorafenib, but the reason for this finding was not clear. c-kit (CD117) is a receptor tyrosine kinase, and its signal inactivation and hydrolytic metabolism are regulated by the CBL protein, a Ring finger E3 ubiquitin ligase, encoded by the c-CBL gene. And we also found that the c-CBL gene expression in refractory and relapsed patients was significantly lower than that in healthy hematopoietic stem cell donors. Therefore, we assumed that there is a relationship among c-CBL gene function, high expression of c-kit (CD117) and a better clinical response to sorafenib. To confirm this hypothesis, we packaged interfering lentiviruses and overexpressed adenoviruses targeting the c-CBL gene respectively, and infected leukemia cell lines with these viruses to regulate the expression of the c-CBL gene, and observed the subsequent changes of these cells in various biological behaviors. Our results showed when the c-CBL gene was silenced, the cells proliferation was accelerated, drug sensitivity to cytarabine or sorafenib was decreased, and apoptosis ratio was decreased. And all these phenomena were reversed when the gene was overexpressed, which confirmed the expression of c-CBL gene was related to drug resistance in leukemia cells. At last, we explored the possible molecular mechanisms underlying these phenomena.

From bench to bedside: the history and progress of CAR T cell therapy.

Chimeric antigen receptor (CAR) T cell therapy represents a major breakthrough in cancer care since the approval of tisagenlecleucel by the Food and Drug Administration in 2017 for the treatment of pediatric and young adult patients with relapsed or refractory acute lymphocytic leukemia. As of April 2023, six CAR T cell therapies have been approved, demonstrating unprecedented efficacy in patients with B-cell malignancies and multiple myeloma. However, adverse events such as cytokine release syndrome and immune effector cell-associated neurotoxicity pose significant challenges to CAR T cell therapy. The severity of these adverse events correlates with the pretreatment tumor burden, where a higher tumor burden results in more severe consequences. This observation is supported by the application of CD19-targeted CAR T cell therapy in autoimmune diseases including systemic lupus erythematosus and antisynthetase syndrome. These results indicate that initiating CAR T cell therapy early at low tumor burden or using debulking strategy prior to CAR T cell infusion may reduce the severity of adverse events. In addition, CAR T cell therapy is expensive and has limited effectiveness against solid tumors. In this article, we review the critical steps that led to this groundbreaking therapy and explore ongoing efforts to overcome these challenges. With the promise of more effective and safer CAR T cell therapies in development, we are optimistic that a broader range of cancer patients will benefit from this revolutionary therapy in the foreseeable future.

Clinical applications of gene therapy for rare diseases: A review.

Rare diseases collectively exact a high toll on society due to their sheer number and overall prevalence. Their heterogeneity, diversity, and nature pose daunting clinical challenges for both management and treatment. In this review, we discuss recent advances in clinical applications of gene therapy for rare diseases, focusing on a variety of viral and non-viral strategies. The use of adeno-associated virus (AAV) vectors is discussed in the context of Luxturna, licenced for the treatment of RPE65 deficiency in the retinal epithelium. Imlygic, a herpes virus vector licenced for the treatment of refractory metastatic melanoma, will be an example of oncolytic vectors developed against rare cancers. Yescarta and Kymriah will showcase the use of retrovirus and lentivirus vectors in the autologous ex vivo production of chimeric antigen receptor T cells (CAR-T), licenced for the treatment of refractory leukaemias and lymphomas. Similar retroviral and lentiviral technology can be applied to autologous haematopoietic stem cells, exemplified by Strimvelis and Zynteglo, licenced treatments for adenosine deaminase-severe combined immunodeficiency (ADA-SCID) and β-thalassaemia respectively. Antisense oligonucleotide technologies will be highlighted through Onpattro and Tegsedi, RNA interference drugs licenced for familial transthyretin (TTR) amyloidosis, and Spinraza, a splice-switching treatment for spinal muscular atrophy (SMA). An initial comparison of the effectiveness of AAV and oligonucleotide therapies in SMA is possible with Zolgensma, an AAV serotype 9 vector, and Spinraza. Through these examples of marketed gene therapies and gene cell therapies, we will discuss the expanding applications of such novel technologies to previously intractable rare diseases.

Results of hematopoietic stem cell transplantation in children with acute leukemia: a single-center experience

Currently, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment option for relapsed / refractory (R / R) acute leukemia (AL) and high-risk AL. In this article, we present our own experience of allo-HSCT in children with R / R AL. The study was approved by the Independent Ethics Committee and the Scientific Council of the N. N. Blokhin National Medical Research Center of Oncology. Fifty-one patients with R / R AL were included in the study: 32 patients had acute lymphoblastic leukemia (ALL), 17 patients had acute myeloid leukemia (AML) and 2 patients had biphenotypic leukemia (BL). All patients underwent allo-HSCT from January 2021 to October 2022. The median age was 8.7 years (5 months – 17 years). At the time of allo-HSCT, 26 patients were in the second (and further) remission, the rest were in the first clinical and hematologic remission (high-risk AML and refractory ALL). Twenty-one (41.2 %) patients received allo-HSCT from a haploidentical donor, 19 (37.2 %) patients underwent allo-HSCT from an HLA-matched related donor and 11 (21.6 %) patients – from an HLA-matched unrelated donor. Pre-transplant conditioning in ALL: 27 patients received regimens based on total body irradiation at a dose of 12 Gy, 4 patients received busulfan-based conditioning regimens, and in 1 patient we used treosulfan. In AML and BL, we used conditioning regimens based on treosulfan/thiotepa (n = 10), treosulfan/melphalan (n = 8) or busulfan / melphalan (n = 1). Bone marrow (in 14 patients) and peripheral blood stem cells (in 37 patients) were used as a source of hematopoietic stem cells. In haploidentical allo-HSCTs in order to prevent graft-versus-host disease (GVHD) we performed TCRab/CD19 depletion followed by additional administration of abatacept / tocilizumab / rituximab on day –1 in 15 patients, 6 patients received post-transplant cyclophosphamide. In transplantations from HLA-matched related and unrelated donors, patients received combined immunosuppressive therapy with abatacept and rituximab on day –1, and calcineurin inhibitors were used as basic immunosuppressive therapy. All patients engrafted with a median time to engraftment of 13 (range, 9 to 24) days after allo-HSCT. Eight (15.7 %) patients developed a relapse of AL at different times after HSCT (five of them are alive). At the median follow-up of 9 (5–25) months, the overall and disease-free survival survival rates were 76.4 % and 68.8 %, respectively, for patients with AL. Acute GVHD was observed in 72.5 % of children, grade 3–4 GVHD was observed in 5.3 % of patients, and 13.7 % of children developed chronic GVHD. Most patients developed infectious complications in the early post-transplant period: febrile neutropenia (96.0 %), reactivation of viremia (47.3 %,) oropharyngeal mucositis (78.4 %), acute cystitis (12.3 %). The overall mortality rate was 17.6 %. Late mortality was associated with a relapse of AL.

Thrombotic Events Are Unusual Toxicities of Chimeric Antigen Receptor T-Cell Therapies.

Chimeric antigen receptor (CAR) T-cell therapy has greatly transformed the treatment and prognosis of B-cell hematological malignancies. As CAR T-cell therapy continues to be more readily adopted and indications increase, the field's recognition of emerging toxicities will continue to grow. Among the adverse events associated with CAR T-cell therapy, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are the most common toxicities, while thrombotic events represent an under-reported, life-endangering complication. To determine thrombosis incidence post CAR T-cell therapy, we performed a multi-center, retrospective study on CAR T-cell therapy adult patients (N = 140) from Indiana University Simon Cancer Center and the University of North Carolina Medical Center treated from 2017 to 2022 for relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL, N = 3), diffuse large B-cell lymphoma (DLBCL, N = 92), follicular lymphoma (FL, N = 9), mantle cell lymphoma (MCL, N = 2), and multiple myeloma (MM, N = 34). We report 10 (7.14%) thrombotic events related to CAR T-cell therapy (DLBCL: N = 8, FL: N = 1, MM: N = 1) including 9 primary venous events and 1 arterial event that occurred with median time of 23.5 days post CAR T-cell infusion. In search of parameters associated with such events, we performed multivariate analyses of coagulation parameters (i.e., PT, PTT, and D-Dimer), scoring for adverse events (Padua Score and ISTH DIC Score) and grading for CAR T-cell toxicity severity (CRS grade and ICANS grade) and found that D-Dimer peak elevation and ICANS grade were significantly associated with post-CAR T-cell infusion thrombosis. While the pathophysiology of CAR T-cell associated coagulopathy remains unknown, our study serves to develop awareness of these emerging and unusual complications.

Phase 2 study of combination chemotherapy with bortezomib in children with relapsed and refractory acute lymphoblastic leukemia.

Treatment outcomes for children with relapsed and refractory acute lymphoblastic leukemia (R/R-ALL) remain poor, and the optimal induction therapy has not been determined. Bortezomib is a proteasome inhibitor that acts synergistically and additively with standard chemotherapy for ALL. We evaluated the efficacy and safety of combination chemotherapy with bortezomib in children with R/R-ALL. This single-arm, multicenter, phase 2 study was conducted in Japan between 2016 and 2020. Eligible patients were divided into two cohorts: a high-risk first-relapse cohort of untreated patients with high-risk first-relapsed ALL and an expansion cohort of patients with refractory ALL, including multiple relapses, relapse after allogeneic hematopoietic cell transplantation, and induction failure. All patients received a single course of chemotherapy as induction therapy. Sixteen patients (10 in the high-risk first-relapse cohort, six in the expansion cohort) were evaluable. The overall remission rate after induction therapy was 60% in the high-risk first-relapse cohort and 16.7% in the expansion cohort. All patients had minimal residual disease. Adverse events were acceptable except for interstitial lung disease and hypoxia in a patient in the expansion cohort, but addition of bortezomib to conventional chemotherapy did not produce obvious improvement in children with R/R-ALL.

Palbociclib in Acute Leukemias With KMT2A-rearrangement: Results of AMLSG 23-14 Trial.

Palbociclib in Acute Leukemias With KMT2A-rearrangement: Results of AMLSG 23-14 Trial.

Abstract #1393925: An Interesting Case of Bisphosphonate Resistant Hypercalcemia in Acute Myelogenous Leukemia (AML)

Hypercalcemia of malignancy (HCM), a PTH-independent process, usually occurs in solid tumors, multiple myeloma, and occasionally lymphomas. It generally results from excess secretion of parathyroid hormone related protein (PTHrP) by the tumor, osteolytic metastases, or rarely, tumor production of 1,25-(OH)2 vitamin D. We present an unusual case of HCM in a patient with refractory acute myelogenous leukemia (AML) without a defined mechanism that was resistant to bisphosphonate therapy. A 49-year-old woman with refractory AML presented acutely with altered mental status, decreased appetite, nausea, and fatigue. She was found to have HCM with a low intact parathyroid hormone (PTH) level. Her PTHrP and 25-(OH) vitamin D levels were normal, and her 1,25-(OH)2 vitamin D level was suppressed. Other labs were unrevealing, and imaging showed no new osseous lesions. Her hypercalcemia was treated with normal saline, intravenous furosemide, calcitonin, and two doses of pamidronate. Her calcium level normalized but then rebounded and remained elevated despite pamidronate therapy. Denosumab was considered, but due to rapid clinical deterioration, the patient’s family pursued comfort care. AML is an extremely rare cause of HCM. This is the eighth reported case of AML-related HCM since 2000 and the first known case with bisphosphonate resistance. Our patient’s HCM was not explained by typical mechanisms. Based on similar cases, one plausible mechanism for our patient's hypercalcemia was upregulation of receptor activator of nuclear factor κB ligand (RANKL) on osteoblasts due to elevated proinflammatory cytokines. RANKL binds to receptor activator of nuclear factor κB (RANK) on osteoclasts to promote their maturation and thus bone resorption. Regarding treatment, several case reports have demonstrated that denosumab can successfully treat bisphosphonate resistant HCM and is a potential therapeutic option.

Principle and Application of CAR-T Cell Therapy for Cancer

CAR-T therapy is a High-profile technology in cancer immunotherapy, which has developed rapidly and has made great achievements in the treatment of hematologic tumors. Its therapeutic principle makes CAR-T cell therapy a great advantage in the treatment of relapsed refractory chronic lymphocytic leukemia. However, CAR-T cell therapy still faces many problems, such as side effects, off-target effects, and the lack of specific antigen deficiency on the surface of solid tumors and so on. At present, it is an important research direction to reduce the impact of side effects on patients and its application in solid tumors. This paper focused on the principles and application of involved in CAR-T cell therapy, and the side effects brought by CAR-T therapy were sorted out. Finally, the further development of CAR-T therapy has prospected

Total marrow irradiation in hematopoietic stem cell transplantation for hematologic malignancies.

Total body irradiation (TBI) has been an essential component of the conditioning regimen in hematopoietic cell transplantation for many years. However, higher doses of TBI reduce disease relapse at the expense of more significant toxicities. Therefore, total marrow irradiation and total marrow and lymphoid irradiation have been developed to deliver organ-sparing targeted radiotherapy. Data from different studies show that TMI and TMLI can be safely administered in escalating doses in association with different chemotherapy conditioning regimen protocols, in situations with unmet needs, such as multiple myeloma, high-risk hematologic malignancies, relapsed or refractory leukemias, and elderly or frail patients, with low rates of transplant-related mortality. We reviewed the literature on applying TMI and TMLI techniques in autologous and allogeneic hematopoietic stem cell transplantation in different clinical situations.