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This review discusses the clinical presentation; epidemiology; laboratory, radiologic, and pathologic features; and treatment options for each of the heavy chain diseases, emphasising the importance of an accurate pathologic diagnosis and correct interpretation of immunologic studies in their identification. 

The Heavy Chain Diseases: Clinical and Pathologic Features 

The FDA has approved treosulfan (Grafapex) plus fludarabine as an injection prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients who are 1 year or older with acute myeloid leukemia or myelodysplastic syndrome, according to a press release from Medexus Pharma.

The approval was based on results from a phase 3 trial (NCT00822393) with the aim to compare the efficacy and safety of treosulfan-based conditioning with intravenous busulfan-based reduced-intensity conditioning. Patients were given 4 x 0.8 mg/kg doses per day of intravenous busulfan on days –4 and –3 plus treosulfan at 10 g/m

 intravenously on days –4, –3, and–2.

The primary end point was event-free survival (EFS). The secondary end point was a comparative evaluation of the incidence of CTC grade 3/4 mucositis or stomatitis between day –6 and day +28.

"We are pleased to report this positive development, which marks a strategically important step forward for our business and, importantly, will now benefit eligible patients across the US," commented Ken d'Entremont, Medexus's chief executive officer.

 "Not only will [treosulfan] make a substantial contribution to allo-HSCT in the US, but it also solidifies Medexus's leadership position in this therapeutic field."

Updated findings highlighted in a news release from the FDA noted that the hazard ratio for overall survival (OS) with treosulfan vs busulfan across all randomly assigned patients was 0.67 (95% CI, 0.51-0.90).

 Additionally, OS hazard ratios were 0.73 (95% CI, 0.51-1.06) in those with AML and 0.64 (95% CI, 0.40-1.02) in the MDS population. 

Results for this trial were previously published in 

 and showed that the primary end point was met at the second planned interim analysis. Overall, 476 patients were enrolled in the trial, with 240 in the busulfan group and 221 in the treosulfan group.

The median follow-up was 15.4 months for those given treosulfan and 17.4 months for those given busulfan. The 2-year EFS rate was 64.0% (95% CI, 56.0%-70.9%) in the treosulfan group and 50.4% (95% CI, 42.8%-57.5%) in the busulfan group (HR, 0.65; 95% CI, 0.47-0.90; 

The most common adverse effects that were grade 3 or higher included abnormal blood chemistry results (15% vs 15%) and gastrointestinal disorders (11% vs 16%) between the treatment arms.

In September 2024, the new drug application for treosulfan was extended by 3 months. The FDA needed additional time to review supplemental analyses on previously submitted data that were requested.

Medexus announces FDA approval of GRAFAPEX (treosulfan) for injection and provides business update. News release. Medexus Pharma. January 22, 2024. Accessed January 24, 2025. https://shorturl.at/FQQ72

Clinical phase III trial treosulfan-based conditioning versus reduced-intensity conditioning (RIC). ClinicalTrials.gov. Accessed January 24, 2025. https://shorturl.at/OJLKM

FDA approves treosulfan with fludarabine as a preparative regimen for alloHSCT in adult and pediatric patients with AML or MDS. News release. FDA. February 6, 2025. Accessed February 6, 2025. https://tinyurl.com/3znkk63b

Beelen DW, Trenschel R, Stelljes M, et al. Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): a randomised, non-inferiority, phase 3 trial. 

. 2020;7(1):e28-e39. doi:10.1016/S2352-3026(19)30157-7

Medexus provides update on treosulfan NDA review process and extended PDUFA goal date. News release. Medexus Pharma. September 16, 2024. Accessed January 24, 2025. https://shorturl.at/5eAuS

Treosulfan plus fludarabine is now approved by the FDA as an injection for allo-HSCT conditioning for patients with AML or MDS. 

FDA Approves Treosulfan Combo Injection for HSCT Conditioning in AML/MDS

Non–clear Cell RCC: First-Line Treatment Options and Guideline Updates (insert the slide for case in this segment)

Video content above is prompted by the following:

Describe the current available first-line treatment options for advanced nccRCC.

What patient, disease, and/or other characteristics do you consider when selecting a first-line agent?

How do the NCCN guideline updates or specific label updates/changes impact your decision makingdecision-making when choosing a preferred regimen?

Medical experts outline the current first-line treatment options for advanced non–clear cell RCC, including the factors influencing agent selection, as well as discuss how recent NCCN guideline updates and label changes affect treatment decisions in community practice.

Video Series

Non–clear Cell RCC: First-Line Treatment Options and Guideline Updates

Although the 70-Gene MammaPrint (MP) assay was not confirmed to be predictive of distant recurrence (DR) in patients with hormone receptor (HR)–positive, early-stage breast cancer, the assay predicted responses to extended letrozole (Femara) therapy (ELT) and identified subsets of patients with low-risk disease who experienced improved outcomes with ELT. These findings from the phase 3 NSABP B-42 study (NCT00382070) were published in the 

Data showed no statistically significant difference in ELT on DR between tumors classified as MP high risk (MP-HR) or low risk (MP-LR; 

 = .38). A statistically significant 10-year benefit of 3.7% was found for DR in MP-LR tumors, (HR, 0.43; 95% CI, 0.25-0.74, 

.002) but a nonsignificant 2.4% benefit was observed for DR with MP-HR tumors (HR, 0.65; 95% CI, 0.34-1.24; 

Compared with the overall population of the B-42 trial (n = 3903), a significantly improved prognosis for DR was noted among those in the translational MP cohort (n = 1866; 

.036). The study authors noted that the relatively low incidence of DR events—especially among tumors classified as ultralow-risk (MP-UL)—limited the study's power to assess this end point and detect significant differences in outcomes following ELT across subgroups.

There was a significant 10-year ELT benefit for disease-free survival (DFS) and breast cancer-free interval (BCFI) for MP-LR tumors not observed in those with MP-HR disease; the interaction between MP and ELT benefit reached statistical significance for these end points (DFS: interaction 

At 10 years, ELT benefit for DR was not statically significant for MP-UL tumors (HR, 0.53; 95% CI, 0.13-2.15; 

 = .37), although a significant effect occurred in low-non-ultralow risk (MP-LNUL) tumors (HR, 0.42; 95% CI, 0.24-0.77; 

 = .003). This difference was not statistically significant (interaction 

 = .89). At 10 years, the DR rate was 4.0%, the DFS rate was 9.5%, and the BCFI rate was 7.9% among those with MP-LNUL tumors. These benefits in the MP-LNUL subgroup were significant and more pronounced compared with those for patients with MP-UL tumors, where the respective 10-year rates were 3%, 1.8%, and 4.1%.

“Overall, these findings may expand the clinical utility of MP beyond prognostic indication because they provide the first evidence suggesting that MP is predictive of [extended endocrine therapy] benefit,” wrote Priya Rastogi, MD, vice-chair for medical affairs at the National Surgical Breast and Bowel Project and medical oncologist at the Magee-Womens Hospital of the University of Pittsburgh Medical Center, with study coinvestigators in the publication.

 “Future analyses incorporating clinicopathologic characteristics could also further optimize patient selection.”

Included in the prospective-retrospective correlative study were eligible patients with clinical follow-up and available untreated primary tumor tissue. Developers in Irvine, California received tumor blocks, and MP test scores were generated and blinded to clinical outcome. These test results were included in the final clinical data set.

Of patients randomly assigned to letrozole or placebo in the B-42 trial (n = 3966), blocks were available for 2338 patients, with a final translational MP cohort consisting of 1866.

The primary end point of the correlative study assessing the predictive abilities of MP was DR. Secondary end points in this analysis included DFS and BCFI. In the original NSABP-B42 trial, the primary end point was DFS.

The median follow-up time for patients included in the MP cohort was 10.4 years. In total, 706 (37.8%) and 1160 (62.2%) patients were MP-HR or MP-LR, with those in the MP-LR group further disaggregated into MP-UL (n = 252, 13.5%) and low-non-ultralow risk (MP-LNUL, n = 908, 48.7%) subtypes.

There were 102 DR and 457 DFS events observed in the translational cohort. A statistically significant ELT benefit for DFS was observed in the MP-LR group (HR, 0.67; 95% CI, 0.52-0.85; 

< .001) but not in the MP-HR group (HR, 1.10; 95% CI, 0.82-1.47; 

 = .55). Furthermore, a 7.8% improvement was observed in patients undergoing ELT for MP-LR tumors vs placebo, contrasting with a –1.6% difference reported in patients undergoing ELT for MP-HR tumors compared with placebo.

In BCFI, the assumption of hazards proportionality was not satisfied between treatment groups for the MP-HR subgroup; a change point of 5.2 years identified a distinguishable statistically significant difference in ELT effect between MP-HR (HR, 2.77; 95% CI, 1.28-5.99; 

= .01) and MP-LR (HR, 0.37; 95% CI, 0.21-0.66; 

< .001) subgroups. Prior to 5.2 years, ELT benefit was similar between MP-HR and MP-LR subgroups.

Rastogi P, Bandos H, Lucas PC, et al. Utility of the 70-Gene MammaPrint assay for prediction of benefit from extended letrozole therapy in the NRG Oncology/NSABP B-42 trial. 

 Published online July 24, 2024. doi:10.1200/JCO.23.01995

Letrozole in treating postmenopausal women who have received hormone therapy for hormone receptor-positive breast cancer. ClinicalTrials.gov. Accessed August 14, 2024. https://tinyurl.com/2dhreevh

NSABP B-42 trial results show that the assay was predictive of extended letrozole therapy response, identifying a patient subset with improved outcomes.

Gene Assay May Predict Extended Letrozole Benefits in Breast Cancer Subsets

An overall survival benefit was observed when patients with resectable esophageal cancer were given perioperative chemotherapy with docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil (FLOT) vs neoadjuvant chemoradiation (CROSS), according to results from the phase 3 ESOPEC trial (NCT02509286) presented during the 

2024 American Society of Clinical Oncology (ASCO) Annual Meeting

At a median follow-up of 55 months, patients in the intention-to-treat population who received the FLOT protocol (n = 221) achieved a median OS of 66 months (95% CI, 36-not evaluable [NE]) compared with 37 months (95% CI, 28-43) among those who were treated with the CROSS protocol (n = 217; HR, 0.70; 95% CI, 0.53-0.92; 

 = .012). The 3-year OS rates were 57.4% vs 50.7%, respectively, and the 5-year OS rates were 50.6% vs 38.7%, respectively.

Additionally, the median progression-free survival (PFS) was 38 months (95% CI, 21-NE) in the FLOT arm compared with 16 months (95% CI, 12-22) in the CROSS arm (HR, 0.66; 95% CI, 0.51-0.85; 

 = .001). The 3-year PFS rates were 51.6% vs 35.0%, respectively, and the 5-year PFS rates were 44.4% vs 30.9%, respectively.

“Many patients in the US and Europe are still treated with the CROSS radiochemotherapy protocol. Our study shows that patients with resectable esophageal cancer should have FLOT chemotherapy before and after the operation in order to optimize the chance of curing their tumors in the long term,” Jens Hoeppner, FAChirg, FACS, MD, the director of the Department of Surgery at University Medical Center, University of Bielefeld, in Detmold, Germany, stated in a press release.

ESOPEC was a prospective multicenter study that enrolled patients with esophageal adenocarcinoma across 25 sites in Germany between February 2016 and April 2020. Eligible patients needed to be at least 18 years old, have received no prior abdominal or thoracic radiotherapy, have an ECOG performance status of 2 or less, and have adequate organ function. Patients were also required to have pretreatment stage cT1N+, M0 or cT2-4a, N0/+, M0 disease. The presence of squamous or other non-adenocarcinoma histology, gastric cancer, clinical stage cT1cN0 and cT4b disease, or metastatic disease excluded patients from enrollment.

Patients were randomly assigned 1:1 to receive either the FLOT or CROSS protocol. Those in the FLOT arm received repeated doses of 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel every 2 weeks over 4 neoadjuvant cycles prior to surgery and 4 adjuvant cycles after surgery. In the CROSS arm, patients received neoadjuvant radiation therapy and concurrent chemotherapy with carboplatin and paclitaxel for 5 cycles in 5 weeks prior to surgery. Following neoadjuvant treatment, patients in both arms waited 4 to 6 weeks before proceeding to surgery.

The primary end point was OS. Secondary end points included PFS, recurrence-free survival, postoperative pathological stage, postoperative complications, and postsurgical quality of life.

At baseline, the mean age of patients in the FLOT and CROSS arms was 63.1 years (standard deviation [SD], 8.6) vs 62.6 years (SD, 9.8), respectively. Most patients in both arms were male (89.1% vs 89.4%), had clinical T-stage cT3-4 disease (79.1% vs 81.9%), and had clinical N-stage cN+ disease (77.8% vs 81.6%). Overall, 191 patients in the FLOT arm underwent surgery compared with 180 patients in the CROSS arm.

Additional findings from ESOPEC showed that the pathological complete remission rates among patients who underwent surgery in the FLOT arm was 16.8% compared with 10.0% in the CROSS arm. In both arms, complete regression (18.3% vs 13.3%) or near complete regression (25.1% vs 39.4%) was observed. Most patients across both arms underwent an R0 resection (94.2% vs 95.0%).

Patients in the predefined protocol population in the FLOT (n = 207) and CROSS (n = 196) arms achieved a median OS of 66 months (95% CI, 38-NE) vs 39 months (95% CI, 29-45), respectively (HR, 0.72; 95% CI, 0.54-0.96; 

 = .023). The 3-year OS rates were 58.1% vs 52.6%, respectively, and the 5-year OS rates were 51.8% vs 40.5%, respectively.

Results from an exploratory subgroup analysis demonstrated that the OS benefit in favor of FLOT vs CROSS was observed in all subgroups examined. The most pronounced benefit was reported in patients aged less than 60 years (HR, 0.57; 95% CI, 0.34-0.95) and those with clinical T-stage T3-4 disease (HR, 0.68; 95% CI, 0.50-0.92).

Most patients in both the FLOT and CROSS arms started neoadjuvant treatment; these patients comprised the predefined protocol population. A majority of patients in both arms completed neoadjuvant treatment (87.3% vs 67.7%) and received neoadjuvant treatment plus surgery (86.0% vs 82.9%). In the FLOT arm, 63.3% of patients received adjuvant treatment and 52.5% completed adjuvant treatment.

In the 90 days post-surgery, 3.2% of patients in the FLOT arm died compared with 5.6% in the CROSS arm. The 30-day postoperative mortality rates were 1.0% vs 1.7%, respectively At the data cutoff, 97 and 121 patients died in these respective arms.

“Perioperative chemotherapy with FLOT plus surgery improves OS compared with neoadjuvant chemoradiation with CROSS plus surgery in patients with locally advanced, resectable esophageal adenocarcinoma. ESOPEC found that perioperative chemotherapy with FLOT should be preferred over neoadjuvant chemoradiation with the CROSS protocol for improving survival in resectable esophageal adenocarcinoma,” Hoeppner concluded in an oral presentation.

Hoeppner J, Brunner T, Lordick F, et al. Prospective randomized multicenter phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (ESOPEC trial).

. 2024;42(suppl 17):LBA1. doi:10.1200/JCO.2024.42.17_suppl.LBA1

Chemotherapy before and after surgery may be new standard treatment for some patients with esophageal cancer. News Release. ASCO. June 2, 2024. Accessed June 2, 2024. https://society.asco.org/about-asco/press-center/news-releases/chemotherapy-and-after-surgery-may-be-new-standard-treatment

Perioperative chemotherapy compared to neoadjuvant chemoradiation in patients with adenocarcinoma of the esophagus (ESOPEC). ClinicalTrials.gov. Updated May 8, 2024. Accessed June 1, 2024. https://clinicaltrials.gov/study/NCT02509286

study was published on June 2, 2024, from the press briefing, and was updated on June 4, 2024, with additional information/data from the oral session.

The combination of perioperative chemotherapy plus FLOT improved overall survival vs neoadjuvant chemoradiation in patients with resectable esophageal cancer. 


Conference

OS Prolonged With Perioperative Chemo Vs Neoadjuvant CRT in Esophageal Cancer 

The FDA has accepted a biologics license application (BLA) for a subcutaneous formulation including nivolumab (Opdivo) and hyaluronidase (rHuPH20) for adult patients with solid tumors for which standard intravenous nivolumab has already received approval, according to a press release from the developers, Bristol Myers Squibb.

If approved, patients would be eligible to receive subcutaneous nivolumab as monotherapy, monotherapy maintenance after receiving prior nivolumab plus ipilimumab (Yervoy), or as part of a combination regimen including chemotherapy or cabozantinib (Cabometyx). The regulatory agency has set a Prescription Drug User Fee Act date of February 28, 2025, for its decision on approving the subcutaneous formulation of the agent.

(Editor's Note: As of May 21, 2024, the FDA updated the Prescription Drug User Fee Act date for subcutaneous nivolumab to December 29, 2024.)

“We believe subcutaneous nivolumab has the potential to make a significant difference in the lives of patients, which is reinforced by the FDA’s acceptance of our application,” Gina Fusaro, PhD, vice president and global program lead at Bristol Myers Squibb, said in the press release.

“[Nivolumab] is a foundational PD-1 inhibitor approved for many different types of cancer, and our continued investment in research that puts patients first remains a priority. If approved by the FDA, the subcutaneous administration of nivolumab would provide patients and their physicians with a new option that delivers the same well-known benefits as [intravenous nivolumab] but with the improved convenience of an injection administered in 3-to-5 minutes rather than a 30-to-60-minute infusion.”

Supporting findings for the BLA came from the 

phase 3 CheckMate-67T trial (NCT04810078),

 in which investigators compared treatment with intravenous vs subcutaneous nivolumab in previously treated patients with advanced or metastatic clear cell renal cell carcinoma (RCC). Updated findings from the CheckMate-67T trial were presented at the 

In the CheckMate-67T trial, 495 patients were randomly assigned to receive either subcutaneous (n = 248) or intravenous (n = 247) nivolumab. ORR was a key secondary end point of the trial.

Regarding the coprimary end point of time-averaged nivolumab serum concentration over 28 days (Cavgd28), treatment with subcutaneous nivolumab demonstrated noninferiority compared with the intravenous formulation with a geometric mean ratio of 2.098 (90% CI, 2.001-2.200).

 Additionally, the subcutaneous formulation exhibited noninferiority with respect to the coprimary end point of trough serum concentration at steady state (Cminss) with a geometric mean ratio of 1.774 (90% CI, 1.633-1.927).

The objective response rate (ORR) was 24.2% with subcutaneous nivolumab vs 18.2% with the intravenous formulation (relative risk, 1.33; 95% CI, 0.94-1.87). Additionally, the median progression-free survival according to blinded independent central review was 7.23 months vs 5.65 months, respectively.

Grade 3/4 adverse effects (AEs) occurred in 35.2% of patients in the subcutaneous arm vs 40.8% of those in the intravenous arm. Additionally, 9.7% and 14.7% of patients in each respective arm had treatment-related AEs, 21.1% and 22.9% had serious AEs, and 6.5% and 6.5% experienced treatment-related serious AEs.

Investigators concluded that the safety profile of subcutaneous nivolumab was comparable with prior reports of the intravenous formulation.

“The data from CheckMate-67T with the subcutaneous formulation of nivolumab co-formulated with recombinant human hyaluronidase represent a groundbreaking advancement in oncology research for physicians and our patients,” Saby George, MD, FACP, a professor of Oncology and Medicine and the director of Network Clinical Trials in the Department of Medicine at Roswell Park Comprehensive Cancer Center said in a press release about these data.

“Having the option to administer immunotherapy subcutaneously could undoubtedly reduce the treatment burden that patients diagnosed with cancer currently [have], as well as help maximize efficiencies within healthcare systems. As it stands, intravenous immunotherapy infusion can take precious time, which we know is an important commodity for patients and the doctors who treat them. That’s why these results indicating noninferiority with subcutaneous nivolumab have the potential to be practice-changing and to improve patients’ treatment experience with one injection that can be given in under five minutes and, in some cases, outside of the infusion center,” George concluded.

U.S. Food and Drug Administration accepts Bristol Myers Squibb’s application for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Bristol Myers Squibb. May 6, 2024. Accessed May 6, 2024. https://bit.ly/3JL8yY1

Data from the CheckMate-67T trial support the biologics license application for subcutaneous nivolumab in multiple solid tumors.

Nancy Lee Harris, MD

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