Salvage Chemotherapy Regimens Research Articles

Impact of salvage chemotherapy after immune checkpoint inhibitor for recurrent or metastatic head and neck cancer.

It is unclear witch regimen is optimal as salvage chemotherapy (SCT) after immune checkpoint inhibitor (ICI) monotherapy for recurrent or metastatic head and neck cancer (RM-HNC). This study enrolled 109 patients. Overall survival (OS) and progression-free survival 2 (PFS2) were compared between patients stratified by SCT regimen. Of the 109 patients, 55 underwent SCT after the failure of ICI monotherapy. The OS of these 55 patients was longer than that of patients who did not undergo SCT. The OS and PFS2 were similar between patients treated with paclitaxel (PTX) and cetuximab (Cmab) combination and those treated with PTX monotherapy. The occurrence of irAEs did not impact PFS2 nor OS. SCT can improve the survival outcomes of patients with RM-HNC. In addition to PTX and Cmab, PTX monotherapy is also considered an effective SCT regimen. SCT is effective regardless of the presence or absence of irAEs.

Role of Pegylated Liposomal Doxorubicin in Heavily Pretreated Relapsed Refractory Hodgkin Lymphoma Eligible for Autologous or Allogeneic Transplantation

In the context of relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL), various conventional single agents and salvage chemotherapy regimens have been explored, including bendamustine, brentuximab vedotin, nivolumab, and pembrolizumab. However, there is another drug, pegylated liposomal doxorubicin (PLD), which has shown interesting results but is comparatively less recognized and mostly used in combination. For heavily pretreated R/R cHL patients this drug, presenting a reduced cardiac toxicity compared to non-liposomal doxorubicin, may be considered as bridging therapy (BT) to transplantation (both autologous [ASCT] and allogeneic [alloSCT]). The present retrospective study aims to determine the role of PLD monotherapy in terms of safety and effectiveness in heavily pretreated R/R cHL patients as BT to ASCT or alloSCT. Our case series comprises 22 R/R cHL patients who were potentially eligible for transplantation and underwent PLD treatment successfully. These patients had a median of five previous treatments (range, 3-9), including ASCT in 50% of the cases and radiotherapy in 7 out of 22 cases. Of the total, 77% were primary refractory, and 63.6% remained refractory to the last previous therapy before PLD. Additionally, eight patients had advanced stage disease at the time of PLD treatment. PLD was administered at a fixed dose of 60 mg every 21 days with a median of 4 cycles (range, 1-8). No dose reduction was needed. Few toxicities occurred. In detail, four hematological adverse events (AE) were reported in 3 patients (all grade ≥3, drug related but rapidly resolved without sequalae). Only one grade 3 extra-hematological occurred (deep vein thrombosis). Final overall response rate (ORR) was 31.8%, with 4 complete and 3 partial responses (CR, PR). Best ORR of 54.5% was reached at the third cycle (5 CR and 7 PR). Five patients subsequently proceeded to ASCT and 2 to alloSCT with 5 final CR (two patients converted from a PR and 1 from a stable disease). At a median follow-up of 6 years, median overall survival was reached at 4 years. The findings from this retrospective analysis suggest that PLD monotherapy may be effective in treating a subset of patients with multi-relapsed or refractory cHL. PLD could be considered as a strategic and relatively low-toxicity bridging therapy option for patients undergoing transplantation.

A Phase 2 Study of Lenalidomide in Combination with Mitoxantrone, Etoposide, and Cytarabine (Len plus MEC) in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Background: Outcomes for patients with relapsed or refractory acute myeloid leukemia (R/R AML) remain extremely poor. Response rates with salvage chemotherapy regimens, such as mitoxantrone, etoposide, and Cytarabine (MEC), have been associated with a complete remission rate of around 20-30%. We previously reported a phase I study combining Lenalidomide (Len) with MEC salvage chemotherapy, with encouraging response rates in R/R AML compared to other historical standards (DeAngelo et al. AJH 2018). This led to the current phase 2 study (NCT03118466) of Len combined with MEC in R/R AML to evaluate for the efficacy of this combination. Methods: We conducted a phase 2 study of Len plus MEC in adult patients (≥ 18 yrs) with R/R AML after 1 or more cycles of induction chemotherapy. Patients received Len dosed at 50mg/day on days 1-10, and Mitoxantrone 8mg/m2/d, Etoposide 100mg/m2/d and Cytarabine 1000mg/m2/d on days 4 through 8 of induction (Kohrt et al AJH 2010). Patients who achieved a complete remission (CR), complete remission with incomplete blood count recovery (CRi) or incomplete platelet recovery (CRp) could proceed with consolidation chemotherapy or hematopoietic stem cell transplantation at the discretion of the treating physician. The study followed a Simon two-stage design powered to detect improvement to a 45% response rate. The primary objective was to determine the response rate. Secondary objectives included time to neutrophil and platelet count recovery, treatment related mortality, rates of relapse, and overall survival. Results: A total of 40 patients were enrolled and received study treatment. The median age was 56 years (range, 19-70); 58% of the patients were male. 73% of patients had relapsed after initial therapy (29/40) while 27% had primary refractory AML (11/40) after their initial induction chemotherapy. The median number of prior therapies was 2 (range, 1-4). The majority of patients had adverse ELN 2023 risk (n=22; 55%). Recurrent gene mutations in 5 or more patients included DNMT3A (n=8), TET2 (n=7), NRAS (n=6), IDH2 (n=5), and ASXL1 (n=5); 2 patients harbored TP53 mutations. The most frequent grade 3-4 treatment-related toxicities were febrile neutropenia (n = 30; 75%), platelet count decrease (n = 40; 100%), anemia (n = 18; 45%), neutrophil count decrease (n = 14; 34%), blood bilirubin increase (n=6, 14%), and anorexia (n = 5; 12%). Three patients (8%) died during the study treatment period, all secondary to hepatic failure; no other early deaths occurred. Two of these patients had baseline grade 1 bilirubin elevation (no other patients in the study reported baseline bilirubin elevations). Median follow-up was 21 months. The overall response rate was 50% (20/40) where 19 achieved CR while 1 achieved CRi. Of 20 responders, the median time to neutrophil count recovery was 28 days and to platelet recovery was 34 days. The median time to relapse was 22.6 months. The median overall survival (OS) of the entire cohort was 16 months (Figure 1). Conclusions: Len plus MEC was associated with a high response rate and improved OS in patients with R/R AML as compared to historical controls. The overall safety profile was similar to prior MEC chemotherapy trials but several patients did experience early hepatic toxicity. Overall these data support evaluating high-dose Len combined with MEC for patients with R/R AML in a randomized study.

Comparable Outcomes of Relapsed Acute Lymphoblastic Leukemia in Adolescents and Young Adults (AYA) Patients Treated with Pediatric-Inspired Chemotherapy (R3 protocol) Versus Adult-Based Salvage (FA) Protocol

Background Although the survival rate of adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) has improved by using pediatric-based treatment protocols, those who experience a relapse still have poor outcomes when treated with adult chemotherapy salvage-regimens, which have traditionally included high doses of Ara-C. The long-term survival rate for patients treated with these salvage-regimens is less than 10%. Salvage treatment with blinatumomab for adults with relapsed B-cell ALL results in a complete remission (CR) rate of 34%, a median survival of 7.7 months, and an overall survival (OS) of less than 30% at 18 months. In contrast, the ALLR3 protocol for relapsed ALL in patients up to the age of 18 years achieved a CR rate of 97% and an overall survival rate of 72%. Therefore, this study aims to compare the outcomes of AYA patients treated with pediatric-inspired regimen (R3 regimen) to those treated with adult-based regimen (FA (Fludarabine/Cytarabine) protocol). Methods The R3 protocol treated 17 AYA patients with relapsed Philadelphia-negative ALL, aged between 14 to 40 years old, who had received first-line therapy. Patients who achieved CR underwent allogenic transplant. The protocol included vincristine, mitoxantrone, asparaginase, dexamethasone, and intrathecal methotrexate. In comparison, 60 patients were treated with FA protocol, with patients achieved CR proceeded to allogeneic stem cell transplantation. Relapses were classified as very early (< 18 months from diagnosis), early (>18 months from diagnosis and <6 months from the end of therapy), and late (>6 months from the end of therapy). Patients' characteristics, response rate (RR) and overall survival (OS) were analyzed. Results The two arms had comparable characteristics. The median age in the R3 arm was 16 years (range: 14-40 years) compared to 22 years (range: 18-32 years) in the FA protocol arm. In the R3 arm, 88.2% of patients had B-cell ALL, while in the FA protocol arm, 92.2% had B-cell ALL. CNS involvement was seen in 28.8% and 17.6% of cases in the R3 and FA protocol arms, respectively. Relapses were classified as very early, early, or late in 2 (12%), 5 (29%), and 7 (41%) of cases in the R3 arm and were mostly late (25.2%) in the FA protocol arm. Relapses in the R3 arm were isolated bone marrow (BM), isolated extramedullary (EMD), or combined BM and EMD in 14 (82%), 1 (6%), and 2 (12%) cases, respectively, while EMD was around three times higher (16.9%) in the FA arm. The overall CR rate was 60% at the end of R3 induction, with negative MRD (<10 −4 cells) in 47.1% of patients. The overall CR rate was higher in the FA arm (76.3%), but the difference with the R3 arm was not statistically significant (p-value 0.1). The disease was refractory to subsequent salvage therapy in 42% of cases in both arms. About half of the patients who responded to R3 proceeded to allogeneic stem cell transplant (52.3%), while 78% of the patients post-FA underwent transplantation. Eight patients died (47%) in R3 arm, but only one patient died due to treatment-related sepsis, while the other seven patients died due to disease-related causes. At a median follow-up of 4 years, OS was 53% in the R3 arm compared to 30.8% in the FA arm, but the difference was not significant (p-value=0.8). The post-FA mortality was mainly due to infections (15.3% in FA vs. 5.9% in R3). Conclusion Pediatric-inspired protocols that have shown significant benefits in the front-line setting for ALL in the AYA population did not demonstrate a significant difference when compared to traditional adult-based salvage chemotherapy regimens in relapsed disease.

Q-HAM: a multicenter upfront randomized phase II trial of quizartinib and high-dose Ara-C plus mitoxantrone in relapsed/refractory AML with FLT3-ITD

BackgroundAbout 50% of older patients with acute myeloid leukemia (AML) fail to attain complete remission (CR) following cytarabine plus anthracycline-based induction therapy. Salvage chemotherapy regimens are based on high-dose cytarabine (HiDAC), which is frequently combined with mitoxantrone (HAM regimen). However, CR rates remain low, with less than one-third of the patients achieving a CR. FLT3-ITD has consistently been identified as an unfavorable molecular marker in both relapsed and refractory (r/r)-AML. One-quarter of patients who received midostaurin are refractory to induction therapy and relapse rate at 2 years exceeds 40%. The oral second-generation bis-aryl urea tyrosine kinase inhibitor quizartinib is a very selective FLT3 inhibitor, has a high capacity for sustained FLT3 inhibition, and has an acceptable toxicity profile.MethodsIn this multicenter, upfront randomized phase II trial, all patients receive quizartinib combined with HAM (cytarabine 3g/m2 bidaily day one to day three, mitoxantrone 10mg/m2 days two and three) during salvage therapy. Efficacy is assessed by comparison to historical controls based on the matched threshold crossing approach with achievement of CR, complete remission with incomplete hematologic recovery (CRi), or complete remission with partial recovery of peripheral blood counts (CRh) as primary endpoint. During consolidation therapy (chemotherapy and allogeneic hematopoietic cell transplantation), patients receive either prophylactic quizartinib therapy or measurable residual disease (MRD)-triggered preemptive continuation therapy with quizartinib according to up-front randomization.The matched threshold crossing approach is a novel study-design to enhance the classic single-arm trial design by including matched historical controls from previous clinical studies. It overcomes common disadvantages of single-armed and small randomized studies, since the expected outcome of the observed study population can be adjusted based on the matched controls with a comparable distribution of known prognostic and predictive factors. Furthermore, balanced treatment groups lead to stable statistical models. However, one of the limitations of our study is the inability to adjust for unobserved or unknown confounders.Addressing the primary endpoint, CR/CRi/CRh after salvage therapy, the maximal sample size of 80 patients is assessed generating a desirable power of the used adaptive design, assuming a logistic regression is performed at a one-sided significance level α=0.05, the aspired power is 0.8, and the number of matching partners per intervention patient is at least 1. After enrolling 20 patients, the trial sample size will be recalculated in an interim analysis based on a conditional power argument.ConclusionCurrently, there is no commonly accepted standard for salvage chemotherapy treatment. The objective of the salvage therapy is to reduce leukemic burden, achieve the best possible remission, and perform a hemopoietic stem-cell transplantation. Thus, in patients with FLT3-ITD mutation, the comparison of quizartinib with intensive salvage therapy versus chemotherapy alone appears as a logical consequence in terms of efficacy and safety.Ethics and disseminationEthical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings.Trial registrationClinicalTrials.gov NCT03989713; EudraCT Number: 2018-002675-17.

Response to ifosfamide, carboplatin, etoposide (ICE) vs. dexamethasone, cytarabine cisplatin (DHAP) as salvage chemotherapy in patients with relapsed/refractory lymphoma.

Non-Hodgkin's lymphomas are the eighth-most prevalent malignancy in females and the eleventh in males. No research has been conducted comparing dexamethasone, cytarabine cisplatin (DHAP) vs. ifosfamide, carboplatin, etoposide (ICE) as salvage chemotherapy regimens for relapsed or refractory lymphomas in Pakistan. This study aims to compare the response of ICE vs. DHAP as salvage chemotherapy in patients with relapsed/refractory lymphomas. A prospective follow-up study was conducted at the tertiary care hospital in Karachi, Pakistan, from 2019 to 2020. A total of 58 lymphoma patients after first-line chemotherapy were included in the study. The treatment response was evaluated after two cycles of salvage chemotherapy using WHO assessment criteria, and Cox regression was used to determine the hazard ratios considering the P value ≤0.05 significant. Of 58 patients, 19 (32.8%) patients achieved complete response (CR), and 8 (13.8%) patients achieved partial response (PR), with an overall response rate of overall response rate of 46.6%. In the ICE group, the response was assessed in 19 patients. Overall response was 42.1%, CR was 31.6% and PR was 10.5%. In the DHAP group, response was evaluated in 39 patients, the overall response rate was 48.7%, CR was 33.3% and PR was 15.4%. The hazard ratio for survival in patients with relapsed/refractory lymphomas who received DHAP was 1.40 times (95% CI: 1.27-3.63, P=0.001) compared to patients who received ICE as salvage chemotherapy. DHAP seems to have a marginally better overall response rate than the ICE regimen in patients with refractory or relapsed lymphoma. However, the toxicity profile of patients in both groups was similar.

Comparative effectiveness of salvage chemotherapy regimens and chimeric antigen T-cell receptor therapies in relapsed and refractory diffuse large B cell lymphoma: a network meta-analysis of clinical trials

The optimal salvage chemotherapy regimen (SC) for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) prior to autologous stem cell transplant remains unclear. Moreover, although chimeric antigen receptor T cell (CAR-T) therapies were recently approved for primary refractory DLBCL, head-to-head comparisons are lacking. We searched MEDLINE, EMBASE and CENTRAL to July 2022, for randomized trials that enrolled adult patients with R/R DLBCL and performed network meta-analyses (NMA) to assess the efficacy of SC and CAR-T therapies. NMA of SC (6 trials, 7 regimens, n = 1831) indicated that rituximab with gemcitabine, dexamethasone, cisplatin (R-GDP) improved OS and PFS over compared regimens. NMA of 3 CAR-T trials (n = 865) indicated that both axi-cel and liso-cel improved PFS over standard of care, with no difference in OS. Our results indicate that R-GDP may be preferred for R/R DLBCL over other SC compared. Longer follow-up is required for ongoing comparative survival analysis as data from CAR-T trials matures.

COMPARATIVE EFFECTIVENESS OF SALVAGE CHEMOTHERAPY AND CHIMERIC ANTIGEN T‐CELL RECEPTOR THERAPIES IN R/R DLBCL: A SYSTEMATIC REVIEW AND NETWORK META‐ANALYSIS

David Hodgson and John Kuruvilla are co-senior investigators Introduction: The optimal salvage chemotherapy (SC) regimen for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) prior to autologous stem cell transplant (ASCT) remains unclear. Head-to-head comparison of chimeric antigen receptor T cell (CAR-T) therapies for second line use in primary refractory DLBCL is lacking. Given these limitations, we conducted a systematic review and network meta-analysis (NMA) of randomized clinical trials (RCTs) to assess the efficacy and safety of SC and CAR-T therapies for R/R DLBCL. Methods: We searched MEDLINE, EMBASE and CENTRAL from Jan 1 2006 to July 7 2022 for RCTs enrolling patients diagnosed with R/R DLBCL following treatment (trt) with at least 1 prior regimen. The primary outcome was overall survival (OS), and secondary outcomes were progression free survival (PFS) and grade ≥ 3 adverse events (AEs). NMA was conducted using a fixed-effect model to synthesize evidence. Surface under the cumulative ranking curve was used to rank the relative effect of compared trt. Results: A total of 22 RCTs (n=4505) met eligibility criteria, 13 included for qualitative synthesis only. NMA of SC (6 RCTs, n=1831) compared 7 trt: GDP (gemcitabine, dexamethasone, cisplatin), rituximab (R)-GDP, ICE (ifosfamide, mesna, carboplatin, etoposide), R-ICE, DHAP (dexamethasone, cytarabine, cisplatin), R-DHAP, ofatumumab (O)-DHAP, ESHAP (etoposide, cytarabine, cisplatin, methylprednisolone). Results indicated that R-GDP had improved OS and PFS over other regimens (Table), and ranked highest for OS and PFS. NMA of AEs showed no differences for infection. NMA of 3 CAR-T RCTs (axi-cel, liso-cel, tisa-cel; n=733) showed that axi-cel and liso-cel had improved PFS over SC and ASCT, while no OS difference was observed. Comparing between CAR-T products, both axi-cel and liso-cel had improved OS and PFS over tisa-cel. Liso-cel ranked highest for PFS. NMA of AEs showed that tisa-cel and axi-cel had higher risk of cytokine release syndrome over SC, while axi-cel had higher risk of neurologic toxicity over SC. Conclusions: Our results suggest that R-GDP may be the optimal regimen for R/R DLBCL prior to ASCT. Both axi-cel and liso-cel had improved PFS over SC and ASCT, while tisa-cel did not. Although liso-cel ranked highest for PFS, longer follow-up is required for comparative survival analysis as data matures. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Therapeutics and Clinical Trials in Lymphoma - Other No conflicts of interests pertinent to the abstract.

A Review of CAR-T Therapy in Pediatric and Young Adult B-Lineage Acute Leukemia: Clinical Perspectives in Singapore.

Approximately 10-15% of pediatric B-cell acute lymphoblastic leukemia (B-ALL) are high risk at diagnosis or relapsed/ refractory. Prior to the availability of chimeric antigen receptor T-cell (CAR-T) in Singapore and the region, the treatment options for these paediatric and young adults are conventional salvage chemotherapy or chemo-immunotherapy regimens as a bridge to allogeneic total body irradiation-based hematopoietic stem cell transplantation (allo-HSCT). This results in significant acute and long-term toxicities, with suboptimal survival outcomes. Finding a curative salvage therapy with fewer long-term toxicities would translate to improved quality-adjusted life years in these children and young adults. In this review, we focus on the burden of relapsed/refractory pediatric B-ALL, the limitations of current strategies, the emerging paradigms for the role of CAR-T in r/r B-ALL, our local perspectives on the health economics and future direction of CAR-T therapies in pediatric patients.

Outcomes of relapsed/refractory extracranial germ cell tumors treated on conventional salvage chemotherapy without stem cell rescue: Experience from a tertiary cancer center.

Data on the outcome and prognostic indicators in extracranial relapsed/refractory germ cell tumors (rel/ref-GCTs) in children are limited to a few studies. This study looks at remission rates and outcomes of rel/ref-GCTs treated with conventional salvage chemotherapy (SC) regimens without stem cell rescue at a single center in the developing world. Patients treated at our center from January 2009 to December 2018 were included. Risk at primary presentation was stratified as all completely excised teratomas and stage I gonadal tumors being low risk (LR); stage IV ovarian, stage III-IV extragonadal GCTs as high risk (HR), and the remaining as intermediate risk (IR). SC regimens were: vinblastine-ifosfamide-cisplatin/carboplatin or paclitaxel-ifosfamide-cisplatin/carboplatin, or cisplatin/carboplatin-etoposide-bleomycin. Local therapy was either surgery and/or radiotherapy. The analyzable cohort comprised 50 patients (44 = rel-GCTs; 6 = ref-GCTs) with a median age of 3.8years and male:female ratio of 1.27:1. Primary location was ovary in 16 (32%), testicular in 10 (20%), and extragonadal in the rest (48%). Local, metastatic, and combined progression was noted in 28 (56%), 14 (28%), and eight (16%) patients, respectively, at a median time of 8.5months. At a median follow-up of 60months, the 5-year event-free survival (EFS) and overall survival (OS) of the entire cohort (n=50) were 42.4% and 50.0%, respectively. In patients previously exposed to platinum analogs (n=38), 5-year-EFS and OS were 27.7% and 31.7%, respectively. Local relapses did better when compared to metastatic and combined relapses (5-year EFS: 64% vs. 23% vs. 0%; p=.009). LR and IR tumors did better compared to HR (5-year EFS: 81.5% vs. 49.3% vs. 6.5%; p=.002). Patients with normalization of tumor markers after two cycles had a superior EFS (57.6% vs. 0%; p<.001). Relapsed tumors fared better than primary refractory GCTs (5-year EFS: 48.6% vs. 0%; p<.001). Primary refractory GCTs, extragonadal rel-GCTs, and rel/ref-GCTs with a poor biochemical response did poorly with conventional SC and need alternative treatment strategies. The rel/ref-testicular GCTs had the best chance of salvage despite a second recurrence (5-year EFS and OS: 28.60% and 42.90%, respectively).

Analysis of treatment sequence and outcomes in patients with relapsed malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas originating from cellular components within the nerve sheath. The incidence of MPNST is highest in people with neurofibromatosis type 1 (NF1), and MPNST is the leading cause of death for these individuals. Complete surgical resection is the only curative therapeutic option, but is often unfeasible due to tumor location, size, or presence of metastases. Evidence-based choices of chemotherapy for recurrent/refractory MPNST remain elusive. To address this gap, we conducted a retrospective analysis of our institutional experience in treating patients with relapsed MPNST in order to describe patient outcomes related to salvage regimens. We conducted a retrospective electronic health record analysis of patients with MPNST who were treated at Johns Hopkins Hospital from January 2010 to June 2021. We calculated time to progression (TTP) based on salvage chemotherapy regimens. Sixty-five patients were included in the analysis. Upfront therapy included single or combined modalities of surgery, chemotherapy, or radiotherapy. Forty-eight patients received at least 1 line of chemotherapy, which included 23 different regimens (excluding active clinical studies). Most patients (n = 42, 87.5%) received a combination of doxorubicin, ifosfamide, or etoposide as first-line chemotherapy. Salvage chemotherapy regimens and their TTP varied greatly, with irinotecan/temozolomide-based regimens having the longest average TTP (255.5 days, among 4 patients). Patients with advanced or metastatic MPNST often succumb to their disease despite multiple lines of therapy. These data may be used as comparative information in decision-making for future patients and clinical trials.

Optimal approach to T-cell ALL.

T-lineage acute lymphoblastic leukemia (T-ALL) is curable for most children and adolescent and young adult patients with contemporary frontline chemotherapy regimens. During the past decade, improved survival rates have resulted from the optimization of frontline chemotherapy regimens, the use of minimal residual disease (MRD) assessment for evaluating a patient's risk for relapse, and the intensification of treatment based on the persistence of MRD. Optimization of initial therapy is critical because relapsed T-ALL after initial intensive chemotherapy is incurable for most adult patients. Current T-ALL salvage chemotherapy regimens are minimally effective, and unlike in B-cell ALL, there are no approved antibody therapies or chimeric antigen receptor T-cell therapies for relapsed disease. Immunotherapy and small-molecule inhibitors are beginning to be tested in relapsed T-ALL and have the potential to advance the treatment. Until effective salvage strategies are discovered, however, intensive frontline therapy is required for cure. In this article I review the current frontline chemotherapy regimens for adult patients with T-ALL, summarize the novel targeted and immune therapeutics currently in early-phase clinical trials, and outline how these therapies are helping to define an optimal approach for T-ALL.

Does Choice of Salvage Regimen Impact Stem Cell Mobilization in Hodgkin's Lymphoma?

INTRODUCTION: Salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard of care in the management of relapsed or refractory (R/R) classical Hodgkin lymphoma (HL). Historically, salvage chemotherapy regimens such as ICE (Ifosfamide, carboplatin, and etoposide) and GDP (gemcitabine, dexamethasone, cisplatin) have been used. However, newer regimens such as bendamustine with brentuximab-vedotin (BBV), and BV with nivolumab are being increasingly used owing to their improved efficacy. The impact of the newer regimens on subsequent mobilization and collection of peripheral blood stem cells (PBSCs) for ASCT is not studied in detail. Furthermore, despite its well reported use, the mobilizing agent "plerixafor", which is approved for multiple myeloma and non-Hodgkin lymphoma, is not FDA approved for HL. This creates a logistic barrier in using it in HL patients. METHODS: We conducted a retrospective chart review of patients with R/R HL referred to Karmanos Cancer Institute and considered for ASCT between January 1, 2015, and December 31, 2021. Patients were grouped in two groups based on the pre-ASCT salvage chemotherapy regimen used: ICE/GDP and BBV. We analyzed multiple parameters to study the impact of ICE/GDP versus BBV on mobilization/collection of PBSCs for ASCT in R/R HL. We also describe our institutional experience with the usage of plerixafor in addition to G-CSF for PBSC mobilization. RESULTS: A total of 53 patients with R/R HL who underwent mobilization for ASCT. The salvage regimen was ICE/GDP in 33 (62%) and BBV in 20 (38%) patients. There was no difference in the median age at diagnosis (32 vs 37 years, p=0.59), and distribution of sex (p>0.99), race (p>0.99) and ECOG performance status (p=0.60) (See Table 1). Majority of the patients received ABVD/AVD (Adriamycin, bleomycin, vinblastine, dacarbazine) as their initial treatment (ICE/GDP 91% vs BBV 85%, p=0.06), with a median of 6 cycles (p=0.16), and no difference in the use of radiation therapy (p=0.14). Thereafter, around two-third of the patients underwent salvage chemotherapy for relapsed, and one-third for refractory disease in both arms. The median number of cycles was 2 (1-4) versus 3 (2,4) (p=0.267), and the CR rate was 67% versus 80% in ICE/GDP and BBV respectively (p=0.36). Stem cell mobilization was performed using G-CSF and median peripheral CD34 count (×106) on day 1 of collection was higher at 22.5 (range, 4.12-314) in the ICE/GDP group versus 13.1 (0-97.15) in the BBV group (p=0.049). Twenty (61%) patients in the ICE/GDP had a successful stem cell harvest following G-CSF (>2 million cells/kg) compared to 5 (25%) in the BBV group on first planned day of collection (p=0.02). Among the patients who failed successful stem cell collection with G-CSF on the first day of collection, 6 (46%) received plerixafor in the ICE/GDP and 7 (46%) in the BBV group (See Table 2). Notably, 3 (23%) patients in the ICE/GDP whereas 7 (46%) patients in the BBV group failed the first attempt of mobilization and had to undergo a separate second attempt with GM-CSF, cyclophosphamide and/or plerixafor. The cumulative number of mobilizing agents other than filgrastim used in any attempt was 11 (0.3 per patient) and 15 (0.75 per patient) in ICE/GDP and BBV groups respectively. Furthermore, 2 patients in the BBV group had a failure of adequate mobilization/collection of PBSCs despite more than one attempt, and were unable to proceed with ASCT. One of these patients died of progressive HL. In contrast, all the patients were able to undergo ASCT in ICE/GDP group. There was no difference in the day of neutrophil or platelet engraftment between the two groups. CONCLUSIONS: We conclude that BBV regimen led to poor mobilization and collection of stem cells on the first day, consequently requiring additional mobilization agents/attempts. Although, PBSC collection and subsequent ASCT was eventually successful in a majority of the patients in the BBV group, two patients in our population failed to undergo ASCT given inadequate mobilization/collection. With the increasing utilization of brentuximab-vedotin in salvage as well as in the first line setting, larger studies are needed to study its impact on PBSC collection and ASCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ABVD for Hodgkin Lymphoma in Malawi; Excellent Outcomes but with Persistent Clinical Disparities Compared to High-Income Countries: A Prospective Cohort Study

BACKGROUND: ABVD is a well-established curative-intent therapy for Hodgkin lymphoma (HL) but, to our knowledge, little has been published about therapy or outcomes in sub-Saharan Africa (SSA) where supportive care is more limited, infectious milieu is different, and in our case, radiation therapy was not available. We report mature data from one of the first prospective HL cohorts treated under real-world conditions in SSA. METHODS: Patients ≥15 years with newly diagnosed HL were enrolled in Malawi from Jul 2013 to Dec 2021 and followed for five years if remain in remission; patients not yet achieveing five years or with relapse were censored May 2022. All participants had diagnosis confirmed by immunohistochemistry during telepathology conference between the team in Malawi and UNC Chapel Hill. Two patients were excluded from survival analysis as they were treated with CHOP chemotherapy due to misdiagnosis early in the study period. Staging was done by chest xray, abdominal ultrasound, and bone marrow biopsy. Participants were treated with ABVD chemotherapy and, if HIV+, concurrent antiretroviral therapy (ART). Post-progression therapy is generally limited to salvage chemotherapy regimens without access to radiation or autologous stem cell transplant. RESULTS: 38 participants were enrolled with mean age 29 years (SD 11). Twenty-one (55%) were men, and eleven (21%) were HIV+, of whom eight (73%) were on ART at HL diagnosis. Twenty-five (65%) participants had advanced stage disease and thirteen (35%) had limited stage disease, of whom ten were unfavorable risk and three were favorable risk. Bulky disease (at least one lymph node >10cm) was present in 29 (76%) participants at enrollment. Median CD4 count was 138 cells/mL (IQR 102-298) and 10 (91%) had an HIV viral load <400 copies/mL. Participants received a median six cycles (i.e. twelve doses) ABVD. Grade 3/4 neutropenia occurred in 15 (42%) but there were only two (5%) episodes of neutropenic fever and one episode of grade 3/4 anemia. There were no documented episodes of any grade cardiac or pulmonary toxicity. One patient was lost to follow-up, one patient absconded and died early in therapy, and one patient absconded and died during salvage therapy with median follow up 36 months for patients still alive at administrative censoring. Among patients with evaluable disease (n=34), 27 (79%) achieved a CR, three (9%) achieved a PR, and four (12%) had progressive disease. Among patients with limited stage disease, 2-yr overall survival (OS) and progression-free survival (PFS) were 92% and 80%, respectively. Among patients with advanced stage disease, 2-yr overall survival (OS) and progression-free survival (PFS) were 75% and 61%, respectively (see FIGURE). There was no difference in survival by HIV status. Of eleven deaths during the study period, nine (82%) were due to disease progression, one due to therapy-related sepsis, and one due to other causes. CONCLUSION: Here, we present, to our knowledge, the most complete prospective clinical and outcome data of pathologically confirmed Hodgkin lymphoma in sub-Saharan Africa. Most patients with HL in Malawi, a low-income country, present with advanced or unfavorable risk HL. With standard chemotherapy in the form of ABVD, long-term cure is possible, and in fact, probable, for patients presenting with HL in Malawi. The majority of deaths are attributed to disease progression and not to adverse events. However, there remains a marked disparity between outcomes in Malawi and in high-income countries and improvements through both clinical and implementation research are urgently needed to accelerate diagnosis at a lower stage and to provide therapeutic options for those who fail ABVD. Figure Caption: Overall survival and progression-free survival of Hodgkin lymphoma patients treated with ABVD in Malawi. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Matching-Adjusted Indirect Comparison (MAIC) of Lisocabtagene Maraleucel (Liso-cel) Versus Axicabtagene Ciloleucel (Axi-cel) for Second-Line (2L) Treatment of Patients (Pt) with Refractory/Early Relapsed (R/R) Large B-Cell Lymphoma (LBCL)

Background: Two chimeric antigen receptor (CAR) T cell therapies, liso-cel and axi-cel, demonstrated superior efficacy over salvage chemotherapy and autologous transplant for chemotherapy sensitive disease as 2L therapy in transplant-intended pts with high-risk R/R LBCL, yet no head-to-head clinical trials have compared CAR T cell therapies. A previous MAIC report showed comparable efficacy and an improved safety profile of liso-cel vs axi-cel in 3L+ R/R LBCL (Maloney et al. J Hematol Oncol 2021). Here we conducted a MAIC of treatment effects in the 2L setting for liso-cel vs axi-cel in pts with R/R LBCL. Methods: MAICs were used to estimate population-adjusted relative treatment effects associated with liso-cel for event-free survival (EFS), PFS, ORR, and CR rate (TRANSFORM; NCT03575351; N = 184) vs axi-cel (ZUMA-7; NCT03391466; N = 359), as well as safety (TRANSFORM, N = 183; ZUMA-7, N = 338). Pts from TRANSFORM were excluded from this analysis if they did not satisfy eligibility criteria specified in ZUMA-7 (ie, matching). Individual pt data (IPD) for pts who remained in the TRANSFORM data set were weighted using a method-of-moments propensity score model to match the marginal distribution (ie, mean, variance) of clinical factors among pts from ZUMA-7 (ie, adjustment). Baseline characteristics and outcome measures were revised to align with those defined in ZUMA-7. Efficacy comparisons were anchored through the common comparator, standard-of-care (SOC; with similar protocol-defined salvage chemotherapy regimens in both trials, followed by high-dose chemotherapy and autologous transplant in responders). Hazard ratios (HRs) were used to compare time to event outcomes (EFS, PFS), and odds ratios (OR) were used to compare binary outcomes (ORR, CR rate, safety). Selection and rank-ordering of the treatment effect modifiers were guided by analysis of the TRANSFORM IPD and by a panel of expert clinicians. Factors to match (ie, pts from TRANSFORM were removed) and adjust (ie, pts from TRANSFORM were re-weighted) for efficacy included: central nervous system involvement, absolute lymphocyte count at screening, age, sex, geographic region, secondary age-adjusted International Prognostic Index (sAAIPI) score, sum of the product of perpendicular diameters at baseline, R/R status to 1L therapy, double/triple-hit status, and disease histology. Safety comparisons were unanchored, owing to the absence of CAR T cell-associated toxicities in the SOC arms; factors for safety MAIC included: LVEF < 50% and bilirubin > 1.5 mg/dL at screening, age, and sAAIPI score. Notably, bridging chemotherapy was allowed in TRANSFORM but not in ZUMA-7; it was not practically possible to adjust for this factor given sample size constraints. Results: Unmatched and unadjusted comparisons showed no differences in median (95% CI) EFS for liso-cel (10.1 mo [6.1‒not reached]) vs axi-cel (8.3 mo [4.5‒15.8]; HR, 0.94 [0.58‒1.52]). After matching with ZUMA-7 for pt eligibility, the TRANSFORM sample size was 157; matching and adjusting for the selected effect modifiers resulted in an effective sample size of 69 for the primary efficacy scenario comparisons (sample size unchanged for ZUMA-7). MAIC primary scenario efficacy results for these populations showed no differences (Table). Median (95% CI) EFS after matching and adjustment was 9.5 mo (5.95‒not reached) for liso-cel. Results were consistent for other efficacy parameters of PFS, ORR, and CR rate. Sensitivity scenario comparisons that included additional adjustment factors led to similar results. MAIC safety results demonstrated lower odds of key CAR T cell-associated AEs with liso-cel vs axi-cel: cytokine release syndrome (CRS) any grade (OR, 0.09 [95% CI: 0.04‒0.19]), CRS grade ≥ 3 (OR, 0.10 [0.01‒0.81]), neurological events (NE) any grade (OR, 0.10 [0.04‒0.22]), and NEs grade ≥ 3 (OR, 0.21 [0.06‒0.69]). Conclusions: Findings from this comparative analysis of liso-cel and axi-cel for the 2L treatment of R/R LBCL show comparable efficacy of liso-cel and axi-cel, with more favorable safety outcomes for liso-cel where lower rates of all-grade and grade ≥ 3 CRS and NEs were observed. These results indicate liso-cel may have a better safety profile than axi-cel in 2L+ R/R LBCL and are consistent with those from the 3L+ MAIC analysis. This MAIC will be updated with the TRANSFORM primary analysis dataset when available. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Response to Hypomethylating Agents Plus Venetoclax in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome: Real World Data from a Developing Country

Background: Myelodysplastic syndrome (MDS) is a pre-malignant condition characterized by ineffective hematopoiesis, cytopenias and potential to transform into acute leukemia. Acute myeloid leukemia (AML) is a hematological malignancy deriving from myeloid progenitor cells. About one quarter of patients fail to respond to initial therapy (refractory AML). In addition, around 50% of initial responders relapse after a transient remission (relapsed AML). Commonly used salvage chemotherapy regimens include FLAG, FLAG-Ida, HIDAC and Hypomethylating agents (HMA) with or without Venetoclax. In patients who are ineligible for transplant or with poor functional status and in relapsed/refractory cases, treatment options are minimal. However recent data from Western countries has shown promising results with HMA plus Venetoclax in such patients. No such data is available from Pakistan. Objectives: To assess response of HMA plus Venetoclax in patients with AML and MDS treated at Armed Forces Bone Marrow Transplant Center, Rawalpindi, Pakistan. Methods: Study design: Single arm observational prospective study Research Setting: Armed Forces Bone Marrow Transplant Center, Rawalpindi, Pakistan. Study population: Cases included in study were patients of AML and MDS who received HMA plus Venetoclax. A total of 35 patients (25 AML, 10 MDS) were found eligible and included in the final analysis. The primary outcome measured was response to HMA plus Venetoclax. Results: Out of 25 AML patients 17 (68%) were male and 8 (32%) were female. Median age of patients was 44 (range 20-67). Six (24%) patients had AML MRC, 18 (72%) had AML NOS which included 2 (8%) AML-M0, 1 (4%) AML-M1, 9 (36%) AML-M2, 3 (12%) AML-M4 and 3 (12%) patients with AML-M5 while other 3 patients included 1 (4%) patient each of t-AML and AML transformed from Fanconi anemia and aplastic anemia. One (4%) AML-M2 patient had Monosomy 7 and 1 (4%) AML-M5 had trisomy 8. Three (12%), 16 (64%) and 6 (24%) patients were categorized into favorable, intermediate and high risk respectively. Nine (36%) had relapsed disease including 3 (12%) who had relapsed after allogenic HSCT, 8 (32%) had refractory disease while 7 (28%) were unfit for intensive chemotherapy due to advanced age or poor functional status. Median number of HMA+ Venetoclax cycles given were 3 (range 1-16). Overall response rate (ORR) was 44% (n=11), including 9 (36%) patients with CR and 1 (4%) with CRi. One (4%) patient had partial response (PR). Fourteen (56%) patients were non-responders. Of the 10 patients who responded, 6 (24%) achieved remission after 2 cycles while other 4 achieved remission, 1 (4%) patient each, after 1, 3, 5 and 6 cycles. Two (8%) patients underwent allogenic HSCT after achieving remission, including 1 (4%) who had relapsed after first HSCT and underwent second HSCT after achieving CR with HMA+Venetoclax. Out of 10 MDS patients 8 (80%) were male and 2 (20%) were female. Median age of patients was 51 (range 29-71). Two (25%) patients had MDS-MLD, 6 (60%) MDS-EB2 and 2 (20%) had fibrotic MDS. One (10%), 7 (70%) and 2 (20%) patients had intermediate, high and very high risk disease (as per R-IPSS score) respectively. One (10%) patient had relapsed after allogenic HSCT. Median no of cycles of HMA+Venetoclax given were 2 (range 1-6). Three (30%) patients achieved CR (after 2 cycles each), 2 (20%) had stable disease and 5 (50%) patients were non-responders. Two (20%) patients underwent allogenic HSCT after receiving HMA+Venetoclax (Table:1) Common side effects noted were prolonged cytopenias, febrile neutropenia and infections (cellulitis, perianal infections and fungal infections). No treatment related mortality was noted. Conclusion: HMA plus Venetoclax is effective treatment regimen in relapsed/ refractory AML and MDS, however our population shows inferior results as compared to Western population and further large randomized controlled trials are needed to validate this observation. Key Words: Relapsed AML, refractory AML, MDS, salvage chemotherapy, Hypomethylating agents, Venetoclax Research funding: None Word count: 691 Presentation type: Oral Category: Acute Leukemia/ Myelodysplastic syndrome Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ABCL-012 Salvage Chemotherapy in Refractory/Relapsed Non-Hodgkin Lymphoma Treatment From the Perspective of Developing Country Management

One hundred relapsed or refractory NHL patients were randomly divided into 2 groups receiving either GDP or DHAP for 4 to 6 cycles. The primary endpoints were overall survival and progression-free survival. The secondary endpoints were response to treatment, toxicity profile of each regimen, and quality of life. The overall response rate was 70% in the GDP group and 64% in the DHAP group with no statistically significant difference between them (P = 0.5). There was no significant difference between the groups regarding toxicity profile, except that febrile neutropenia episodes were much less frequent in the GDP group (P = 0.04). Quality of life was significantly better in the GDP group than in the DHAP group (P = 0.04). GDP is as effective as DHAP for relapsed or refractory lymphoma with less toxicity and better quality of life.

Efficacy of different salvage regimens in progressive unresectable pediatric low-grade glioma.

Multiple salvage chemotherapy regimens are used in progressive low-grade glioma (LGG), with no single regimen being more effective than any other. In the present study, different salvage therapies were compared with regard to the response rate, overall survival (OS) rate, event-free survival (EFS) rate and visual outcome in 70 patients with pediatric LGG. Age was found to significantly affect the EFS and OS rates (P<0.001). The visual outcome was the same between the three regimens. The 2-year EFS and OS rates of the vincristine/carboplatin, monthly carboplatin and weekly vinblastine regimens were 64.7 and 70.6%, 71.0 and 85.0%, and 56.0 and 62.7%, respectively (P=0.6 for EFS; P=0.56 for OS). Overall, the present study demonstrated that age had a significant impact on survival. The three salvage regimens used were equally effective with regard to the radiological response and visual outcome. However, further randomized controlled trials are required to detect the optimal salvage therapy.

Novel Salvage Therapy Options for Initial Treatment of Relapsed/Refractory Classical Hodgkin's Lymphoma: So Many Options, How to Choose?

Simple SummaryRelapsed/refractory classical Hodgkin’s lymphoma (cHL) accounts for 10–30% of patients. Historically, such patients were treated with salvage chemotherapy regimens followed by autologous stem cell transplantation. Introduction of novel agents such as brentuximab vedotin and immunotherapy to the treatment algorithm for cHL may change the choice of salvage therapy regimens. The purpose of this article is to review the various salvage regimens used to treat first relapse or primary refractory disease that incorporate novel agents, discuss the recent literature and propose an algorithm to determine the treatment approach for this patient population.The treatment landscape for relapsed/refractory classical Hodgkin’s lymphoma (cHL) has evolved with the introduction of several novel agents. Historically, the standard of care for relapsed cHL was salvage chemotherapy followed by autologous stem cell transplant (ASCT). However, many patients are ineligible for ASCT or will have poor responses to salvage chemotherapy and ASCT. Brentuximab vedotin (BV) and checkpoint inhibitors (nivolumab/pembrolizumab) were initially approved in the post-ASCT setting. However, as a result of excellent responses and durable outcomes in this setting, they are now being studied and explored in earlier lines of therapy. Additionally, these agents are also being studied for post-transplant consolidation and maintenance with promising results in improving progression-free survival. We will review current salvage therapy options involving these novel agents and provide comparisons between regimens to aid the clinician in selecting the appropriate salvage regimen for patients who progress after first-line therapy.

Homoharringtonine combined with cladribine and aclarubicin (HCA) in acute myeloid leukemia: A new regimen of conventional drugs and its mechanism.

Objective The prognosis of children with refractory acute myeloid leukemia (AML) is poor. Complete remission (CR) is not always achieved with current salvage chemotherapy regimens before transplantation, and some patients have no chance of transplantation. Here, we aimed to describe a new regimen of conventional chemotherapy drugs (homoharringtonine, cladribine , and aclarubicin (HCA)) for refractory AML and its mechanism in vitro. Methods We retrospectively collected the clinical data of 5 children with primary refractory AML using HCA as reinduction chemotherapy, and CR rates, adverse reactions, and disease-free survival (DFS) were analyzed. The effects of homoharringtonine, cladribine, and aclarubicin alone or in combination on the proliferation of HL60 and THP1 cells were analyzed by CCK-8 assay. Furthermore, CCK-8 was used to determine the effects of HCA, alone or in combination with apoptosis inhibitors, necroptosis inhibitors, ferroptosis inhibitors, or autophagy inhibitors, on the proliferation of HL60 and THP1 cells and to screen for possible HCA-mediated death pathways in AML cells. The pathway of HCA-mediated AML cell death was further verified by Hoechst/PI staining, flow cytometry, and Western blotting. Results After 2 cycles of conventional chemotherapy, none of the 5 children with AML achieved CR and were then treated with the HCA regimen for two cycles, 4 of 5 achieved CR, and another child achieved CR with incomplete hematological recovery (CRi). After CR, 3 children underwent hematopoietic stem cell transplantation (HSCT), and only 2 of them received consolidation therapy. As of the last follow-up, all 5 patients had been in DFS for a range of 23 to 28 months. The inhibition rate of homoharringtonine, cladribine, and aclarubicin in combination on HL60 and THP1 cells was significantly greater than that of a single drug or a combination of two drugs. We found that inhibitors of apoptosis and necroptosis were able to inhibit HCA-mediated cell death but not ferroptosis or autophagy inhibitors. Compared with the control group, the number of apoptotic cells in the HCA group was significantly increased and could be reduced by an apoptosis inhibitor. Western blot results showed that PARP, caspase-3, and caspase-8 proteins were activated and cleaved in the HCA group, the expression of Bax was upregulated and that of Bcl-2 was downregulated. The expression of apoptosis-related proteins could be reversed by apoptosis inhibition. Compared with the control group, the expression levels of the necroptosis-related proteins RIP1, RIP3, and MLKL were downregulated in the HCA group but were not phosphorylated. The necroptosis inhibitor increased the expression of RIP1 but caused no significant changes in RIP3 and MLKL, and none were phosphorylated. Conclusions HCA, as a new regimen of conventional drugs, was a safe and efficacious reinduction salvage strategy in children with refractory AML before HSCT. HCA exhibits the synergistic growth inhibition of AML cells and induces cell death mainly through apoptosis.