FDA Approval Summary: Axicabtagene Ciloleucel for Relapsed or Refractory Follicular Lymphoma

In March 2021, the U.S. Food and Drug Administration granted accelerated approval to axicabtagene ciloleucel, a CD19-directed chimeric antigen receptor T-cell therapy, for the treatment of adult patients with relapsed or refractory follicular lymphoma (r/r FL) after at least 2 lines of systemic therapy. Approval was based on ZUMA-5, a single-arm, open-label, multicenter trial that evaluated a single infusion of axicabtagene ciloleucel, preceded by lymphodepleting chemotherapy with cyclophosphamide and fludarabine, in this population. Efficacy was based on objective response rate (ORR) and duration of response (DOR) as determined by an independent review committee. Among 81 patients in the primary efficacy analysis, having a median of 3 (range 2-9) prior lines of systemic therapy, the ORR was 91% (95% confidence interval [CI]: 83-96) with a complete remission (CR) rate of 60% and a median time-to-response of 1 month. The median DOR was not reached, and the 1-year rate of continued remission was 76% (95% CI: 64-85). For all leukapheresed patients with FL in this trial (n = 123), the ORR was 89% (95% CI: 83-94) with a CR rate of 62%. Among 146 patients with indolent lymphoma evaluated for safety, cytokine release syndrome occurred in 84% (Grade ≥3, 8%) and neurological toxicities occurred in 77% (Grade ≥3, 21%), leading to implementation of a risk evaluation and mitigation strategy. Serious adverse reactions occurred in 48%. Post-marketing studies will further evaluate clinical benefit in patients with r/r FL and long-term safety.     

Safety of Axicabtagene Ciloleucel for the Treatment of Relapsed or Refractory Large B-Cell Lymphoma

BackgroundDiffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma. Recent advances in immunotherapy have resulted in the development of chimeric antigen receptor–modified T-cell (CAR-T) therapy, such as axicabtagene ciloleucel (axi-cel). However, axi-cel administration is not without risks of toxicity.Patients and MethodsThis retrospective study of 37 patients with relapsed or refractory diffuse large B-cell lymphoma evaluated the incidence and severity of common and severe safety events after axi-cel treatment in a real-world setting. Ninety percent of patients had received 3 or more prior lines of therapy (median prior therapies 3, range 2-7) before receiving CAR-T therapy, and 32.4% had relapsed after prior stem-cell transplantation.ResultsAll but one patient experienced cytokine release syndrome (CRS) of any grade (97.3%). Of those 36 patients, 83.3% experienced maximum CRS grade of 1 or 2, occurring after a median of 27 hours and persisting for a median of 6 days. Twenty-seven patients (73.0%) experienced neurotoxicity of any grade. Of those 27 patients, 96.3% experienced maximum neurotoxicity grade of 2 or higher, occurring after a median of 145 hours (6 days) and persisting for a median of 7 days. All 10 patients aged 65 or older had neurotoxicity of grade 2 or higher, compared to 59.3% (11/27) under age 65 (P = .02). Patients with baseline Eastern Cooperative Oncology Group performance status score of 2 were significantly more likely to have shorter time to neurotoxicity compared to patients with performance status of 0 (P = .01).ConclusionWith more real-life experience and data, we will be able to define and refine management of toxicities unique to CAR-T therapy.     

IVAC With or Without Rituximab for Relapsed or Refractory B-Cell Non-Hodgkin Lymphomas: Real-World Experience in the Modern Era

IntroductionPart B of the modified Magrath regimen (IVAC) +/- rituximab (R) is recommended as standalone therapy by national guidelines for management of relapsed/refractory Burkitt lymphoma, and is used in other non-Hodgkin lymphomas (NHL). Activity of IVAC in B-cell NHL, particularly with R, and its toxicity remain incompletely described.Patients and MethodsWe reviewed patients with relapsed/refractory B-cell NHL treated with IVAC +/- R between 2004 and 2019 at Memorial Sloan Kettering Cancer Center to assess efficacy and toxicity.ResultsAmong 54 eligible patients (median 2 prior lines of therapy), 76% had diffuse large B-cell lymphoma; 30% had central nervous system involvement at IVAC initiation. Objective response rate was 48%. At median 22-month follow-up, median progression-free and overall survival were 3.1 months and 4.9 months, respectively. Grade ≥ 3 anemia (93%), neutropenia (94%), and thrombocytopenia (100%; all grade 4) were common. Febrile neutropenia occurred in 65% and did not appear to be influenced by use of antimicrobial or granulocyte colony stimulating factor prophylaxis. Mortality was attributed to treatment in 19% of evaluable patients.ConclusionThe clinical efficacy and utility of IVAC +/- R remain unclear. However, its profound hematologic toxicity and life-threatening complications despite prophylactic measures warrant careful consideration of alternatives.     

Polatuzumab Vedotin for Relapsed/Refractory Aggressive B-cell Lymphoma: A Multicenter Post-marketing Analysis

IntroductionPolatuzumab vedotin is approved therapy in the United States for relapsed/refractory diffuse large B-cell lymphoma in combination with bendamustine and rituximab (Pola+BR). However, the safety and efficacy of Pola+BR outside of a clinical trial setting is unknown.Patients and MethodsWe analyzed use of pola-based therapy at 5 centers in the United States, including dose, response rates, progression-free survival (PFS), survival, and toxicity.ResultsSixty-nine patients with aggressive B-cell lymphoma, including 66 with diffuse large B-cell lymphoma/high-grade B-cell lymphoma and 84% refractory to prior therapy, were treated. Responses occurred in of 50%, including 24% complete response. Median duration of response was 5.1 months, PFS was 2.0 months, and survival was 5.3 months, at 4 months median follow-up. Inferior PFS was associated with prior refractory disease (median, 57 days vs. not reached; P = .003) and lack of response to Pola+BR (PFS, 27 days vs. 152 days; P < .001). Discontinuation owing to planned cellular therapy was seen in 36% and owing to toxicity occurred in 12%; unplanned hospitalizations occurred in 36%.ConclusionsWe conclude that commercial Pola is applied to highly refractory lymphomas at our centers, often with intent to bridge to subsequent therapy. Although some clinical benefit was observed, efficacy was inferior to clinical trial data, especially among those with refractory disease.     

Outcomes After Salvage Autologous Hematopoietic Cell Transplant for Patients With Relapsed/Refractory Multiple Myeloma: A Single-Institution Experience

BackgroundThe role of salvage autologous hematopoietic cell transplantation (sAHCT2) for patients with relapsed/refractory multiple myeloma (RRMM) in the era of modern therapeutics is unclear. As prospective data is limited, we conducted a retrospective analysis to determine the outcomes of sAHCT2.Patients and methodsWe conducted a single-institution, retrospective analysis of patients who received sAHCT2 at The Ohio State University from 2000 to 2018. Patients who received a second transplant as part of a planned tandem or autologous-allogeneic transplant were excluded.ResultsFifty-seven patients were treated with sAHCT2. Patients had a median of 2 lines of therapy after AHCT1 prior to their sAHCT2; 70% had prior immunomodulatory imide drugs, 82% had prior proteasome inhibitor, and 20% had prior anti-CD38 monoclonal antibodies as part of re-induction therapy. Forty-two percent of patients attained ≥VGPR prior to sAHCT2. Seventy-four were treated with melphalan 200 mg/m² as conditioning regimen before infusion of a median of 3.8 × 10⁶ CD34+ cells/kg. Fifty-eight percent patients had maintenance therapy and 81% patients attained CR/VGPR as the best response after sAHCT2. The median PFS and OS after sAHCT2 were 1.6 and 3.6 years, respectively. On multivariable analysis, high-risk cytogenetics, not having attained CR/VGPR, and having more than 2 lines of therapy post-AHCT1 were associated with inferior PFS. Melphalan 140 mg/m² compared to melphalan 200 mg/m² and no maintenance therapy compared to maintenance therapy were not associated with inferior PFS. There was no transplant-related mortality in this patient cohort.ConclusionsFor MM patients deriving durable remission after their AHCT1, sAHCT2 was safe and resulted in deep and durable remissions.     

Relapsed,Refractory, or Advanced Hodgkin Lymphoma: A Single-Center Experience

PurposeTo assess the treatment and outcomes of patients with relapsed, refractory, or advanced Hodgkin lymphoma treated with consolidation or salvage radiotherapy.Patients and MethodsWe studied all patients diagnosed with this profile treated by radiotherapy in our center between 2006 and 2019.ResultsA total of 33 patients who received external-beam radiotherapy for advanced (21%), relapsed (52%), or refractory (24%) Hodgkin lymphoma were studied. Median [interquartile range] age was 25 [22-38] years, with 11 women (33%). The follow-up after first-line treatment was 28 [10-53] months. Number of chemotherapy lines received before radiotherapy was 3 [1-4]. Fourteen patients (42%) had undergone autologous stem-cell transplantation before radiotherapy, and 2 patients were treated by radiotherapy alone. Nine patients (27%) were treated by involved-field radiotherapy, 17 (52%) by involved-site radiotherapy, 5 (17%) by involved-node radiotherapy, and 2 by other volumes. The acute toxicity profile was favorable, with grade 1 radiodermatitis (33%) or dysphagia (30%). Overall, 21 patients (64%) experienced prolonged complete response and 12 experienced relapse (36%) after radiotherapy. Median disease-free survival was 68.8 months.ConclusionsExternal-beam radiotherapy should be considered an effective treatment modality for advanced, relapsed, or refractory Hodgkin lymphoma as part of a multimodal approach.     

GDP方案治疗侵袭性复发性或难治性非霍奇金淋巴瘤

目的:探讨吉西他滨联合顺铂、地塞米松(GDP方案)治疗侵袭性复发性或难治性NHL的疗效和毒副作用。方法:从2003年5月到2008年5月,共治疗53例侵袭性复发难治的NHL患者,其中复发和难治者分别为35例和18例。B细胞和T细胞来源分别为30例和23例。中度和高度侵袭性NHL分别为44例和9例,分别接受过CHOP方案或CHOP类方案和HyperCVAD方案治疗至少2个周期,既往接受过局部放疗22例。所有患者采用GDD方案挽救化疗,3~4周为一个周期,共2~6个周期。结果:53例患者接受平均4.4个周期化疗(共231个周期),所有患者可评价疗效和不良反应。完全缓解(CR)率24.5%(13/53),总有效率(RR)为52.8%(28/53)。其中难治者CR率5.6%(1/18),RR率为33.3%(6/18),复发者CR率为34.3%(12/35),RR率为62.9%(22/35),两者差别具有统计学意义(P<0.05)。此外,高度侵袭性患者和血清LDH高的患者,具有较低的CR率和RR率(P<0.05)。全组中位随访时间36个月(5个月~51个月),中位复发时间为7个月(3个月~34个月),中位生存时间11个月(3个月~51个月),1年和2年总生存率分别35.0%和11.4%。复发NHL和难治NHL没有显示生存差别(P=0.261)。主要不良反应是骨髓抑制,出现Ⅲ度~Ⅳ度的粒细胞和血小板减少的发生率分别为39.6%和26.4%。结论:GDP方案是中度侵袭性复发性或难治性非霍奇金淋巴瘤安全有效的化疗方案,对高度侵袭性NHL,该方案疗效值得进一步验证。LDH升高、高度侵袭性患者和难治者具有较差反应率。     

改良ProMACE-CytaBOM方案治疗复发、难治侵袭性NHL的疗效评价

目的评价改良ProMACE-CytaBOM方案治疗复发、难治侵袭性NHL的疗效及安全性。方法回顾性分析2005年5月至2010年9月期间,我院收治的27例复发、难治性侵袭性淋巴瘤患者,其中男19例,女8例,中位年龄47（15～74）岁;均采用改良ProMACE-CytaBOM方案;21天为1周期。结果27例患者均可评价疗效,总有效率51.8%（完全缓解率22.2%）。中位无进展生存期为7月,中位总生存期为19月。B细胞、LDH正常NHL患者中位无进展生存期长于T细胞、LDH高者,差异均有统计学意义（P＜0.05）。B细胞、IPI≤2、LDH正常的NHL患者中位总生存期长于T细胞、IPI＞2、LDH高者,差异均有统计学意义（P＜0.05）。不良反应主要有Ⅱ～Ⅲ度血液学毒性及Ⅰ～Ⅱ度非血液学毒性,6例并发轻度感染,经一般抗生素治疗可控制。结论ProMACE-CytaBOM改良方案治疗复发、难治侵袭性NHL疗效肯定,不良反应可耐受,值得进一步研究。     

High-Dose Chemotherapy in Relapsed or Refractory Metastatic Germ-Cell Cancer: The Scotland Experience

Purpose

To report outcomes from high-dose chemotherapy (HDCT) and autologous stem-cell transplantation (ASCT) for metastatic germ-cell cancer in Scotland.

Pomalidomide,Cyclophosphamide, and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma: Real-World Analysis of the Pethema-GEM Experience

IntroductionTreatment of relapsed/refractory multiple myeloma (RRMM) is highly challenging, especially for patients with disease refractory to initial therapy, and in particular for disease developing refractoriness to lenalidomide. Indeed, with currently approved treatments, median progression-free survival (PFS) in the lenalidomide-refractory setting is less than 10 months, reflecting the difficulty in treating this patient population. Pomalidomide is a second-generation immunomodulatory drug that has shown activity in lenalidomide-refractory disease in the setting of different combinations.Patients and MethodsA real-world study was conducted by the Spanish Myeloma group in a cohort of patients with RRMM treated with pomalidomide, cyclophosphamide, and dexamethasone (PomCiDex). One hundred patients were treated with a median of 3 prior lines of therapy.ResultsOverall response rate was 39%, with a clinical benefit rate of 93%. Median PFS was 7.6 months; median overall survival (OS) was 12.6 months. Median PFS and OS survival were consistent across the different subgroups analyzed. Prolonged PFS and OS were found in patients with responsive disease.ConclusionOur results compared favorably with those obtained with different pomalidomide-based combinations in a similar patient population. PomCiDex remains a manageable, cost-effective, and all-oral triplet combination for RRMM patients.     

Consolidative Radiotherapy After Autologous Stem Cell Transplantation for Relapsed or Refractory Diffuse Large B-cell Lymphoma

Introduction

We evaluated the role of consolidative radiotherapy (RT) for patients undergoing high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) for relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

Treatment of Relapsed or Refractory Aggressive Non-Hodgkin Lymphoma with Two Ifosfamide-Based Regimens,IMVP and ICE

Abstract

We report the outcomes of 45 patients with relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL) treated with a combination of ifosfamide, carboplatinum and etoposide (ICE) and 28 patients treated with a combination of ifosfamide, methotrexate and etoposide (IMVP) during two 5-year periods. The response rate (RR) to ICE was 47%, 2-year overall survival (OS) 31% and 2-year event-free survival (EFS) 22%. These results were similar to those obtained with IMVP (RR 39%, 2-year OS 23%, 2-year EFS 13%; p=0.355 for RR, 0.275 for OS, 0.668 for EFS). Higher IPI scores and refractoriness to treatment were negative prognostic factors, immunophenotype (B vs. T) had no influence on prognosis. Changing from IMVP to ICE does not substantially improve the outcome of patients with relapsed or refractory aggressive NHL. Patients with relapsed/refractory aggressive B-NHL do not have a superior out-come in comparison to those with T-NHL if treated with chemotherapy alone.     

Panobinostat: A Review in Relapsed or Refractory Multiple Myeloma

Oral panobinostat (Farydak®), a potent nonselective histone deacetylase inhibitor, is approved in several countries for use in combination with bortezomib and dexamethasone in patients with multiple myeloma (MM) [USA] or relapsed and/or refractory MM (EU) who have received at least two prior treatment regimens, including bortezomib and an immunomodulatory drug (IMiD). In a pivotal phase III trial (PANORAMA 1) in patients with relapsed or relapsed and refractory MM who had received one to three previous lines of therapy, progression-free survival (PFS) was significantly prolonged with panobinostat plus bortezomib and dexamethasone compared with placebo plus bortezomib and dexamethasone. The significantly favourable effect of panobinostat- versus placebo-based treatment on PFS was also observed in a subgroup analysis of patients who had previously received an IMiD, bortezomib plus an IMiD, or at least two lines of treatment including bortezomib and an IMiD. Panobinostat plus bortezomib and dexamethasone had a generally manageable tolerability profile, with the most frequent grade 3–4 adverse events being myelosuppression, diarrhoea, asthenia or fatigue, peripheral neuropathy and pneumonia. Thus, panobinostat, in combination with bortezomib and dexamethasone, is a useful addition to the available treatment options for patients with relapsed or refractory MM.     

Ixazomib: A Review in Relapsed and/or Refractory Multiple Myeloma

The oral proteasome inhibitor ixazomib (Ninlaro^®) is approved in the USA, EU and Japan in combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. In adults with relapsed and/or refractory MM who had received one to three prior therapies, progression-free survival (PFS) was significantly prolonged in patients who received the ixazomib- versus placebo-based triple therapy in the pivotal, global TOURMALINE-MM1 trial and its regional expansion (China continuation study). A significantly longer time to progression and favourable hazard ratios for PFS were observed across all prespecified subgroups, including patients with high cytogenetic risk. Overall response was achieved in a significantly higher proportion of patients receiving ixazomib- than placebo-based treatment. Ixazomib had a manageable tolerability profile in patients with MM. Ixazomib is the first orally-administered proteasome inhibitor approved for patients with MM, and in combination with lenalidomide and dexamethasone represents an important new option for use in patients with relapsed and/or refractory MM who have previously received at least one prior therapy.

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Clinical Experience With Venetoclax Combined With Chemotherapy for Relapsed or Refractory T-Cell Acute Lymphoblastic Leukemia

BackgroundPatients with relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) have dismal outcomes. Preclinical studies have suggested that T-ALL cells are sensitive to BCL2 inhibition. The clinical activity of venetoclax, a selective BCL2 inhibitor, in T-ALL is unknown.Patient and MethodsWe retrospectively reviewed the efficacy and safety of venetoclax combined with chemotherapy for patients with R/R T-ALL treated at our institution.ResultsThirteen patients with R/R T-ALL with a median age of 46 years (range, 20-75 years) were treated with venetoclax plus chemotherapy. Five patients (38%) had early T-cell precursor ALL. The patients had received a median of 2 previous lines of therapy (range, 1-11). Venetoclax at a median dose of 200 mg/d for 21 days, generally with a concomitant azole antifungal, was combined with various agents, including hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone), asparaginase, nelarabine, decitabine, or other intensive chemotherapy. Of the 10 patients evaluable for bone marrow response, 6 (60%) achieved a remission with bone marrow blasts < 5%, including 3 with complete hematologic recovery. The median overall survival and relapse-free survival were 7.7 and 4.0 months, respectively. No early death or clinically significant tumor lysis syndrome were reported. The median interval to neutrophil recovery and platelet recovery were 15 days and 44 days, respectively, with prolonged cytopenias observed with venetoclax 400 mg/d or when given for > 14 days per cycle.ConclusionCombination therapy with venetoclax showed promising clinical efficacy in R/R T-ALL. Further studies are warranted to evaluate the clinical benefit of BCL2 inhibitors in T-ALL.     

Impact of Radiation Therapy After High Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation in Patients With Relapsed/Refractory Lymphomas: A Single Center Experience

IntroductionAfter high dose chemotherapy (HDC) and autologous stem cell transplantation (auto-SCT), in patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL) and Hodgkin lymphoma (HL), involved field radiation therapy (RT) for consolidation and residual/progressive disease (PD) eradication is a common practice.Materials and methodsRetrospective single-institution cohort analysis to evaluate the impact of early RT after HDC auto-SCT.ResultsBetween 1996 and October 2019, 153 patients (43 DLBCL, 110 HL) underwent RT after HDC auto-SCT. Males 95 (62%), females 58 (38%), median age 24 years. Indications for RT was consolidation 65%: residual disease eradication 16%: and PD eradication 19%. For DLBCL, the median overall survival (OS) for the above indications was not reached (NR):NR:2 months and the KM 5-year OS was 72.6%:64.3%:12.5% respectively (P ≤ .000). Pair-wise analysis showed that consolidation versus residual disease eradication had no difference (P = .88) but both were superior to PD disease eradication (P ≤ 000 and P = .005 respectively). For HL, indication for RT was, 54%:23%:24% respectively. The median OS was NR:NR:28.8 months and KM 5-year OS was 82.3%:78%:30% respectively (P ≤ .000). Pair-wise analysis showed that consolidation versus residual disease eradication had no difference (P = .98) but both were superior to the PD eradication group (P ≤ 000). RT was well tolerated with no significant long-term toxicity.ConclusionPost HDC auto-SCT RT was well tolerated. DLBCL and HL patients with residual disease treated with the RT had similar long-term survival as those who received RT for consolidation. RT failed to improve the poor survival in patients with post-HDC auto-SCT PD.     

Allogeneic Hematopoietic Stem Cell Transplantation for Relapsed/Refractory Acute Myeloid Leukemia: A Single-Centre Experience

IntroductionPatients with relapsed/refractory acute myeloid leukemia (r/r AML) are characterized as having a poor prognosis. The only viable option of treatment for these patients is allogenic stem cell transplantation (allo-HSCT). Therefore, we have attempted to analyse factors related to both the disease itself and the transplantation procedure that could have an influence on the improvement of outcomes in this group of patients.Patients and methodsSixty-four patients with r/r AML underwent allo-HSCT at our center in 2012 to 2021. Fifty-two had active disease at the beginning of theallo-HSCT procedure, with amedian number of blasts in bone marrow (BM) of 18, and 12 had therapeutic aplasia after the last reinduction (blasts < 5% in BM).ResultsThe probability of overall survival (OS) at 2 years was 25%. The median follow-up for survivors was 21.5 months. Progression-free survival (PFS) estimates were above 46%. The main cause of death was disease progression (49%). A statistically significant effect on premature death was reported for the diagnosis of secondary AML (sAML) and cytomelovirus (CMV) reactivation post allo-HSCT. On the other hand, chronic graft versus host disease (cGVHD) decreased the risk of disease progression. sAML and CMV reactivation were found to have opposite effects.     

VID方案治疗复发性及难治性恶性淋巴瘤

[目的]探讨用异环磷酰胺（IFO）、威猛（VM26）、地塞米松（DXM,VID方案）治疗复发性难治性恶性淋巴瘤疗效。［方法］以VID方案治疗复发性难治性恶性淋巴瘤20例。〔结果〕完全缓解4例（20％）,部分缓解13％（65％）,无效3例（15％）,总有效率85％。［结论］认为VID方案对复发性及难治性淋巴瘤有一定疗效。