Patients with relapsed/refractory hairy‐cell leukemia

Abstract Background Hairy cell leukemia (HCL) is a rare chronic B‐cell neoplasm with good long‐term prognosis. First and second‐line therapies include purine nucleoside analogues (PNAs) and rituximab, but until recently, limited alternative options were available for patients with two or more relapses. Aim The aim of this study is to describe our real‐life experience with HCL patients in third and fourth‐line therapies. Methods and Results Data from 49 HCL patients with two or more relapses, including 16 patients with three or more relapses, were collected from the French retrospective HCL cohort covering the period from 1980 until 2011. They were analyzed to assess hematological response, relapse free survival (RFS) and overall survival (OS) after third (L3) and fourth line (L4). The median age at diagnosis was 53 years. PNAs were the most frequently used treatments. As L3 therapy, 29 patients received PNAs (66%) and 15 (34%) other treatments (rituximab [11%] or interferon [7%] alone or in combination [16%]). The distribution of L4 treatments was similar. The overall hematological response rate (OHRR) after L3 was 97% (complete hematological response 86%) with a 40% five‐year cumulative incidence of relapse (CIR), a median RFS of 104 months, and a median OS of 235 months. After L4, the OHRR was 94% with a two‐year CIR of fourth relapse of 27%. Eleven secondary cancers (5‐year cumulative incidence of 12%) were diagnosed in 10 patients. Patients with ≥2 relapses experience frequent further relapses, with increasingly shorter time to next treatment as the number of treatment lines increases. Furthermore, treatment strategies are associated with substantial toxicities. Conclusion All these points lead to the need for novel treatments.


| Design
The initial French retrospective HCL cohort included 487 patients from 36 centers in France diagnosed with HCL between January 30, 1980 andSeptember 20, 2011, with an end of follow-up in December 2012. 18 In January 2018, it was decided to update the database to get follow-up data until June 2018.

| Study centers
A list of 60 French centers known to treat patients with HCL was provided by the French Innovative Leukemia Organization. These centers were sent an e-mail that offered them to participate in the initial survey. Thirty-six of them agreed to take part. When it was decided to update the database, they were contacted again, inviting them to provide follow-up data for their patients. Nineteen centers answered positively. (involving at least one cell type: hemoglobin <10 g/dl, platelets <100 Â 10 9 /L, neutrophils <1 Â 10 9 /L). 19

| Data collection
For each patient, the investigators collected the following information retrospectively from the patients' record: patient's characteristics at baseline including demographics, date of diagnosis, clinical and biological presentation (hemoglobin, platelet count, white blood cell count, neutrophil count, flow cytometry analysis); as well as follow-up data by treatment line with start and end dates for each treatment,

| Statistical methods
Patients' baseline characteristics are described for the following subgroups: L1-L2 (first line and second line of treatment), L3 and L4. Survival curves for OS, RFS and time to next treatment (TTNT) were determined using the non-parametric Kaplan-Meier method. OS was defined as the time between start of L3 or L4 and the date of death or last news (censoring date). RFS was defined as the time between the date of start of the treatment line (L3 or L4) and the date of relapse or death, event-free patients being censored at the date of last news. TTNT was defined as the time laps between start of L3 or L4 and the start of next treatment line or death, event-free patients being censored at the date of last news. Cumulative incidences of relapse (CIR) were determined along with its confidence intervals (95% CI) considering death as a competing risk. Hematological response to treatment was assessed by the investigators and hematological response rates after L3 and L4 are provided. CHR was defined as the disappearance of organomegaly and normalization of the hemogram (a bone marrow evaluation was not mandatory). PHR was defined as the reduction of organomegaly by at least 50%, the disappearance of cytopenias, and <5% circulating hairy cells. Overall hematological response rate (OHRR) was defined as the sum of CHR and PHR rates. SPSS ® (version 16.0) and R ® (version 3.5.3) softwares were used for the statistical analyses.

| RESULTS
We analyzed the data from 49 patients with two or more relapses (18% of the updated cohort of 279 patients) from 12 French centers.

| Outcomes after L3
After excluding the five patients with second relapse who never received an L3 treatment, the five-year CIR after L3 treatment was

| Outcomes after L4
For the 16

| Secondary cancers
Ten patients (10/44, 23%) experienced at least one secondary cancer, corresponding to an overall five-year cumulative incidence of second cancers of 12% (95% CI 4-24%). A total of 11 secondary cancers were reported, seven solid cancers (four non-melanoma skin cancers, one prostate cancer, one kidney cancer, and one esophagus cancer) and four hematological malignancies (two myelodysplastic syndromes, one monoclonal gammopathy of unknown significance and one diffuse large B cell lymphoma).

| DISCUSSION
We analyzed the data of patients with two and more relapses in the updated 279 patients of the French retrospective HCL cohort. 21 We also analyzed the data of patients with three and more relapses. The long-term prognosis of these patients with multiple relapsing HCL is reasonably good, even if not as good as the prognosis of the average HCL patients from the whole cohort.
More than one third (36%) of L3 treated patients relapsed with a Our data emphasize the need of further real-life data for HCL patients with two or more relapses. The impact of new and future therapies needs to be assessed in further clinical and observational studies using modern methods of assessment including marrow response and MRD.

ACKNOWLEDGMENTS
We would like to thank the medical department of Innate Pharma for their participation to the design of this article. We would like to thank all the participating centers.

CONFLICT OF INTEREST
The authors have stated explicitly that there are no conflicts of interest in connection with this article.

ETHICAL STATEMENT
The study was performed in accordance with the Declaration of Helsinki.
Patients signed an informed consent at the time of the initial survey.

AUTHOR CONTRIBUTIONS
All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, J.P. and X.T.; Methodology, J.P. and X.T.; Investigation, J.P. and X.T.; Formal Analysis, J.P. and X.T.; Resources, J.P. and X.T.; Writing-Original Draft, J.P. and X.T.; Writing-Review & Editing, J.P. and X.T.; Supervision, J.P. and X.T.; Data Curation, J.P. and X.T.; Project Administration, J.P. and X.T.; Software, J.P. and X.T.; Validation, J.P. and X.T.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.