Late Effects Arise Irrespective of High-Dose Chemotherapy and ASCT Status in MCL

Sara Ekberg

Intensive first-line treatment with high-dose chemotherapy and autologous stem cell transplant (ASCT) was not associated with higher rates of late effects compared with outcomes from less intensive therapies in patients with mantle cell lymphoma (MCL), according to findings from a population-based study. The results also showed that patients with MCL had a higher rate of outpatient visits, hospitalizations, and bed days vs healthy comparators.

When compared with matched comparators from the general population, patients with MCL had a rate of outpatient visits during follow-up that was 2 times higher (incidence rate ratio [IRR], 2.0; 95% CI, 1.8-2.2). Furthermore, rates of inpatient visits for those with MCL were 7 times higher (incidence rate ratio for inpatient visits, 7.2 [95% CI, 6.3-8.3] and incidence rate ratio for bed days was 8 times higher, 8.3 [95% CI, 6.8-10.1]) 12 months after MCL diagnosis.

“Studies of late effects by different MCL therapies are of interest as new treatments are introduced and the role of [high-dose chemotherapy plus] ASCT is questioned, and may provide a basis for novel treatment strategies and improvements in supportive care and follow-up,” lead study author, Sara Ekberg, of the Uppsala University and Uppsala Akademiska Hospital, and colleagues, wrote.

The current standard of care for younger patients with MCL is rituximab (Rituxan) with dose-intensified cyclophosphamide, vincristine, doxorubicin, and prednisone (R-CHOP) and high-dose cytarabine, followed by high-dose chemotherapy and ASCT, also known as the Nordic MCL2 protocol. However, the benefit of chemoimmunotherapy with consolidating high-dose chemotherapy plus ASCT in this era of novel targeted agents is still to be determined.

Additionally, population-based studies that include patients treated with high-dose chemotherapy and ASCT are necessary to determine the magnitude and panorama of the late effects of MCL outside the context of clinical trials.

This population-based study aimed to describe the late effects experienced by patients with MCL treated with or without high-dose chemotherapy and ASCT.

This study cohort included all patients with MCL recorded in the Swedish Lymphoma Register between the ages of 18 and 69 years who received a diagnosis between 2000 and 2014 (n = 620). A total of 247 patients were treated with high-dose chemotherapy plus ASCT and 373 of whom were not.

Patients in the study cohort were matched 1:10 with healthy comparators (n = 6200) from the general population based on birth year, sex, and lymphoma-free status at the date of the patient’s MCL diagnosis. The median age was 65 years (range, 22-69) for non–HD-ASCT patients and 58 years (range, 32-69) for HD-ASCT patients. The median age of the comparators was 63 years (range, 22-70).

Patients with MCL were classified as HD-ASCT patients if they had received high-dose chemotherapy and ASCT within 12 months of diagnosis. Patients were classified as non–HD-ASCT if they had not received this therapy within 12 months of diagnosis.

Regarding comorbidity, as measured per the Charlson Comorbidity Index, in the non–HD-ASCT group, 57.1% (n = 213), 13.4% (n = 50), and 29.5% (n = 110) had a comorbidity index of 0, 1, or 2 or greater, respectively. In the HD-ASCT group, 76.9% (n = 190), 8.9% (n = 22), and 14.2% (n = 35) had a comorbidity index of 0, 1, or 2 or greater, respectively. Of the comparators, 75.3 (n = 4669), 11.5% (n = 715), and 13.2% (n = 816) had a comorbidity index of 0, 1, or 2 or greater, respectively.

In general, the HD-ASCT patients received R-maxi-CHOP alternated with rituximab plus cytarabine, as well as consolidative high-dose chemotherapy with carmustine, etoposide, cytarabine, and melphalan (BEAM) or carmustine, etoposide, cytarabine, and cyclophosphamide (BEAC) prior to transplant. The non–HD-ASCT patients mostly received R-CHOP plus cytarabine, R-CHOP, rituximab plus bendamustine, or chlorambucil alone. A total of 14 patients received rituximab maintenance.

Among the HD-ASCT patients, 47% underwent transplant within 6 months of diagnosis, and 83% underwent transplant within 12 months of diagnosis, leading to the selected cutoff date of 12 months for the classification of the HD-ASCT group.

Investigators followed patients and comparators through the Swedish Patient Register and Cause-of-Death-Register from 12 months after diagnosis or matching until death or December 31st, 2017. Patients and comparators who died before the start of follow-up were excluded from the landmark analysis.

HD-ASCT patients had a slightly higher rate of outpatient visits during the first 5 years after diagnosis compared with non–HD-ASCT patients (IRR, 1.3; 95% CI, 1.0-1.6). Additionally, HD-ASCT patients had lower rates of inpatient visits 5 to 10 years after diagnosis compared with non–HD-ASCT patients, with an IRR of 0.6 (95% CI, 0.4-0.9). The total rates of bed days were similar between the 2 groups, at 1.1 (95% CI, 0.7-1.6) and 1.0 in the HD-ASCT and non–HD-ASCT groups, respectively.

After 10 years of follow-up, the rates of outpatient visits and hospitalizations were similar between HD-ASCT and non–HD-ASCT patients. Regarding outpatient visits, the IRR were 0.7 (95% CI, 0.5-1.1) and 1.0 for the HD-ASCT and non–HD-ASCT groups, respectively.

The short-term complications, defined as those that occurred within 60 days after transplant in HD-ASCT patients, included blood and blood-forming organ diseases (27.5%), infectious diseases (26.3%), circulatory system diseases (14.2%), and digestive system diseases (9.3%). Other common complications included respiratory system diseases (6.1%), skin and subcutaneous tissue diseases (5.7%), endocrine diseases (4.9%), and genitourinary system issues (4.0%). Musculoskeletal system diseases and mental complications were rare, occurring in 2.4% and 0.8% of patients, respectively. The median duration of hospitalization after high-dose chemotherapy plus ASCT was 22 days; 2 patients (0.8%) in this group died within 60 days after transplant.

The long-term complications investigated among all patients and comparators included the first specialist outpatient visit, hospitalization, or death at least 12 months after diagnosis within any of the 15 mutually exclusive disease groups defined by the investigators. Additionally, investigators quantified all specialist outpatient visits, bed days, and hospitalizations starting from 1 year after diagnosis to illustrate the total health care burden.

When compared with the matched comparators, the patients with MCL had higher relative risks and health care burdens for blood and blood-forming organ diseases (comparators, HR, 1.00 vs non–HD-ASCT, HR, 9.84 [95% CI, 6.91-14.00]; HD-ASCT, HR, 5.80 [95% CI, 3.42-9.84]), respiratory system diseases (comparators, HR, 1.00; non–HD-ASCT, HR, 4.38 [95% CI, 3.53-5.42]; HD-ASCT, HR, 5.26 [95% CI, 4.08-6.77]), and infectious diseases (comparators, HR, 1.00; non–HD-ASCT, HR, 4.66 [95% CI, 3.62-5.99]; HD-ASCT, HR, 5.62 [95% CI, 4.20-7.52]). These rates were seen irrespective of high-dose chemotherapy and ASCT treatment status. These patterns were also observed in the sensitivity analysis at 9, 18, and 24 months after diagnosis.

The most common respiratory disorders included influenza, upper respiratory infections, and pneumonia. The most common infectious diseases were bacterial infections, although HD-ASCT patients had a higher incidence of viral infections than non–HD-ASCT patients. The most common blood and blood-forming organ diseases were anemia, immunodeficiency, idiopathic thrombocyte platelet deficiency, and other diseases.

The rates of secondary malignancies, including melanoma, neoplasms of the skin, prostate cancer, and malignant neoplasm in the urinary tract, were comparable between HD-ASCT and non–HD-ASCT patients.

Deaths from causes other than MCL occuring at least 12 months after diagnosis were rare in both MCL patient groups. The 5-year cumulative probabilities of MCL-specific death were 23% (95% CI, 18%-30%) and 32% (95% CI, 26%-38%) in HD-ASCT and non–HD-ASCT patients, respectively. A standardized analysis showed no evidence of difference in cumulative probabilities of MCL-specific death between the 2 groups when subgroup differences were eliminated.

“Avoiding efficient MCL treatment because it is more demanding and possibly causes late effects may seem reasonable in the short term, but our results indicate that the vast majority of long-term healthcare needs in patients up to 70 years is related to the lymphoma. This calls for continued efforts to improve treatment efficacy in MCL,” the study authors concluded.

Reference

Ekberg S, Smedby KE, Albertsson-Lindblad A, et al. Late effects in mantle cell lymphoma patients treated with or without autologous stem cell transplantation. Blood Adv. Published online August 16, 2022. doi:10.1182/bloodadvances.2022007241