OS and Time to Richter Transformation Linked With Age in Adolescent and Young Adults With CLL

Hua-Jay J. Cherng, MD

Age was associated with overall survival (OS) and the time to Richter transformation in adolescent and young adult (AYA) patients with chronic lymphocytic leukemia (CLL), according to findings from a single-institutional, retrospective study published in the British Journal of Haematology.

The results showed that there was a significant difference in OS when sub-stratifying patients into younger than 30, 30 to 34, and 35 to 39 years age groups (P = .049). The HR for OS was 1.72 (95% CI, 1.10-2.70) when comparing patients aged less than 30 years vs 35 to 39 years, and 2.33 (95% CI, 0.83-6.25) when comparing patients aged less than 30 years vs 30 to 34 years.

Moreover, younger age (P = .02), del(11q) or del(17p; P = .03), complex karyotype (P = .02) and CD38 positivity (P = .03) were associated with a shorter time to developing Richter transformation. The probability of being free from Richter transformation at 5 years from diagnosis was 86%, 92%, and 99% for patients aged less than 30, 30 to 34 and 35 to 39 years at diagnosis, respectively.

“CLL presents very rarely in AYA patients younger than 40. Here, we found that the same validated prognostic biomarkers, such as IGHV mutation status and FISH abnormalities, used for all CLL patients could also predict outcomes in this rare subset, which included AYA patients treated with novel oral targeted therapies. Richter transformation into an aggressive lymphoma and need for allogeneic stem cell transplant were significant sources of mortality for this young population,” said Hua-Jay J. Cherng, MD, of The University of Texas MD Anderson Cancer Center, in a statement to OncLive.

Patients included in the review included those with a diagnosis of CLL or small lymphocytic lymphoma (SLL) who had been evaluated at least once at The University of Texas MD Anderson Cancer Center.

Patients with monoclonal B-cell lymphocytosis were excluded. AYA patients, defined as those aged between 15 and 39 years old at the time of diagnosis, were selected from all patients diagnosed between January 1, 2000, and December 31, 2019.

Complex karyotype was defined as 3 or more chromosomal abnormalities. Second primary malignancies were defined as any neoplasm diagnosed after CLL diagnosis, excluding non-melanoma skin cancers. Novel oral targeted therapy was defined as any therapy containing an oral targeted agent, including a BTK inhibitor, BCL-2 inhibitor, or PI3K inhibitor.

The majority of patients were between the ages of 35 and 39 years (n = 159; 70%) and male (n = 140; 62%). Moreover, most patients had mutated IGHV (n = 82; 52%) and non-complex karyotype (n = 114; 84%).

Of 6074 patients who had been diagnosed with CLL between the prespecified period and seen at MD Anderson, 227 (3.7%) AYA patients were selected for analysis.

The median age at the time of diagnosis was 37 years (range, 17-39). The median follow-up time from diagnosis was 7.1 years (range, 0.1-19.3) with a data cutoff of June 30, 2020.

Six (3%) patients had a first-degree relative with CLL. A total of 161 (71%) patients received CLL treatment, and the median time to first treatment was 2.2 years. A total of 39 patients died, and the 5- and 10-year OS rates were 90% and 78%, respectively.

Beta 2-microglubin of at least 3.5 mg/L was the only significant predictor of OS in the reduced model (HR, 2.34; 95% CI, 1.63-3.38; P < .001) because of the small number of death events.

Reduced model multivariate analysis indicated that beta 2-microglubin of at least 3.5 mg/L (HR, 1.72; 95% CI, 1.36-2.16; P <.001), Rai stage I to IV vs 0 (HR, 2.01; 95% CI, 1.07-3.79; P =.03), and del(17p) or del(11q) vs del(13q) or negative FISH (HR, 1.89; 95% CI, 1.03-3.45; P =.04) were significantly associated with a shorter time to first treatment.

There were no differences in baseline characteristics or rate of receipt of oral targeted therapy between the age groups.

The presence of TP53, NOTCH1, SF3B1, POT1, BIRC3 or MYD88 mutations by next-generation sequencing was not associated with outcomes, likely because of the small numbers of patients with available pre-treatment somatic gene mutation data.

Of the 161 treated patients, 72 (45%) patients received oral targeted therapy at any time during their disease course. A total of 30 of the 72 oral targeted therapy-treated patients (42%)

received an oral targeted therapy as part of their first treatment.

Within the subgroup of the 72 patients who received oral targeted therapy at any time, hemoglobin of less than 11 g/dl (P <.001), presence of del(17p) or del(11q; P =.037), complex karyotype (P <.001) and CD38 positivity (P =.057) were associated with shorter OS.

The median time to second treatment from start of first-line therapy was 4.2 years.

There was a significant difference in time to second treatment when sub-stratifying by type of first-line therapy (P <.001).

The HR for oral targeted therapy vs purine/alkylator combination therapy was 0.51 (95% CI, 0.12-2.19) and for oral targeted therapy vs other therapies was 0.42 (95% CI, 0.20-0.85).

“The advent of oral targeted therapy in CLL has revolutionized treatment, including for AYA patients. We did find that patients treated with oral targeted therapy in the first-line setting enjoyed the longest time to second treatment. However, this advantage was not statistically significant compared with classic chemoimmunotherapy regimens such as FCR. AYA patients are much more likely to tolerate chemotherapy better than their older counterparts. For now, some clinicians may still offer FCR to young patients with low-risk disease as a treatment option,” said Cherng.

A total of 18 (8%) patients underwent allogeneic stem cell transplant (allo-SCT), 4 for Richter transformation and 14 for relapsed or refractory disease. Patients with del(11q) or del(17p; P = .006) were more likely to undergo allo-SCT in their treatment course. A total of 10 (4%) patients developed Richter transformation a median of 2.7 years (range, 0-16) after their diagnosis of CLL.

The median OS after diagnosis of Richter transformation was 8 months. Therapy-related myelodysplastic syndromes/acute myeloid leukemia (t-MDS/AML) developed in three (1%) patients; they had received fludarabine, cyclophosphamide, and rituximab (Rituxan) chemoimmunotherapy 2.8, 3.3 and 10.3 years prior to diagnosis of t-MDS/AML. A second primary malignancy occurred in eight (4%) patients a median of 9.0 years from CLL diagnosis.

“Our findings stress the importance of vigilance for disease-related complications such as second cancers and Richter transformation and therapy-related complications such as MDS and AML. The risk of developing these [diseases] increases over time. AYA patients may live a long time with respect to their CLL, so age-appropriate cancer screening and monitoring for other complications is needed,” said Cherng.

Of the total of 39 patients who died, 19 (49%) developed Richter transformation and/or underwent allogeneic stem cell transplant, and 4 (10%) developed t-MDS/AML or a second primary malignancy. Of the 6 patients younger than 30 years who died, 5 (83%) developed Richter transformation and/or underwent allogeneic stem cell transplant, and none developed t-MDS/AML or a second primary malignancy.

“It is worth taking a look at this data again with longer follow-up so we can again investigate how AYA patients are doing on newer oral therapies compared with chemotherapy,” concluded Cherng.

Reference

Cherng HJJ, Jammal N, Paul S, et al. Clinical and molecular characteristics and treatment patterns of adolescent and young adult patients with chronic lymphocytic leukaemia. BJHaem. Published May 10, 2021. doi:10.1111/bjh.17498