Long-term follow-up results of phase II study of cladribine combined with rituximab in the treatment of variant hairy cell leukemia announced

Variant hairy cell leukemia (HCLv) is a distinct subtype of B-cell leukemia that shares morphological features with classic HCL but differs biologically
.

Compared with HCL, HCLv was less responsive to purine analog monotherapy and had worse overall survival (OS)
.

There are no prospective studies evaluating purine analog monotherapy in HCLv; however, retrospective studies have shown that the complete remission (CR) rate of first-line cladribine in HCLv is only 7%, and repeated use of purine analogs reduces the remission rate and The duration of remission was further reduced
.

Rituximab in combination with purine analogs can improve response rate and duration of response
.

A phase II study from MD Anderson Cancer Center showed favorable efficacy of cladribine plus rituximab (CDAR) in HCLv, but lacked long-term results
.

Therefore, Dai Chihara et al.
updated the results of a phase II trial of CDAR in HCLv and explored for the first time the impact of MRD and TP53 mutations on long-term survival outcomes
.

>>>Research methods Patient inclusion criteria: diagnosed with HCLv, received 0-1 courses of cladribine and rituximab, due to cytopenia (neutropenia <1×109, hemoglobin <10g/dL , or platelets <100 × 106/L), lymphocytes >5 × 109/L, symptomatic splenomegaly, or patients with recurrent infections require treatment
.

Patients with severe cytopenias were not excluded, and those receiving treatment for infection were also eligible
.

During 1 to 5 days, cladribine 0.
15 mg/kg was given intravenously, and rituximab 375 mg/m2 was given at the same time, 8 times a week
.

Primary endpoint is CR rate, secondary endpoints include MRD assessment by blood and bone marrow aspirate flow cytometry and bone marrow biopsy immunohistochemistry (IHC) to determine MRD negativity after first and second courses of rituximab therapy survival rate
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>>>Study Results Twenty patients were enrolled (Table 1), with a median age of 67 years (range 42-86 years)
.

Seven of the 19 evaluable patients (37%) had an unmutated IGHV4-34 gene
.

The median time from diagnosis to CDAR administration was 12.
4 months (range, 1.
9-147.
7 months)
.

Table 1 Patient profile At 4 weeks after CDAR treatment, 9 of 18 (50%) evaluable patients achieved MRD-negative CR (95% CI, 26-74) and 17 of 20 (85%) Bone marrow biopsy was negative by IHC, and 13 of 19 evaluable patients (68%) achieved negative blood MRD
.

At 6 months after CDAR treatment, 18 of 20 patients (90%) were in CR; according to IHC, all 18 patients were MRD-negative, 16 (80%) were MRD-negative, and 17 (85%) were MRD-negative ) was negative for blood MRD
.

Of the 16 patients who achieved MRD-negative CR, 9 (56%) developed MRD-positive, median MRD-negative CR duration was 70.
1 months, and the other 7 patients maintained MRD-negative CR for 21-120 months (median 29.
1 months) (Figure 1A)
.

Among the 17 patients who achieved blood MRD negativity after CDAR treatment, the median survival was 70.
0 months (Fig.
1B)
.

There are currently 7 patients with negative blood MRD for a duration of 27-139 months (median 59.
1 months)
.

Figure 1 shows 11 patients who received delayed rituximab dosing (Figure 2), all due to detectable MRD in the blood, ranging from 6-82 months from CDAR to rituximab delayed dosing (Figure 2).
median 4.
8 months)
.

These 11 patients included 9 patients with positive blood MRD (Fig.
1B), in addition to 2 patients who remained positive for blood MRD after CDAR
.

Delayed administration of rituximab resulted in negative blood MRD in 7/11 patients; 5/7 patients had a negative MRD in bone marrow after 6 months of delayed administration of rituximab
.

Notably, one patient who achieved MRD-negative CR with delayed rituximab dosing was not MRD-negative with early CDAR use
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Of the 5 patients who achieved MRD-negative CR with delayed dosing of rituximab, 3 became MRD-positive again after 12 months, 12 months, and 36 months, and 2 patients at 37 months and 36 months.
Still MRD negative at 42 months
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Of the 11 patients who received delayed rituximab dosing, 5 patients subsequently received other treatments for disease progression, and 1 patient died due to disease progression without receiving other treatments
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The median time from rituximab dosing delay to disease progression in 6 patients was 13 months (range, 6-30 months)
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Figure 2 As shown in Figure 1C, the 5-year PFS rate was 63.
3% (95% CI, 37.
9-80.
6), and remission events could be prolonged by delayed administration of rituximab
.

The 5-year OS rate was 73.
9% (95% CI, 48.
2-88.
2)
.

The 10-year PFS and OS rates were 44.
3% (95%CI, 17.
7-68.
3) and 57.
6% (95%CI, 29.
1-78.
1), respectively
.

As shown in Figure 1D, the median time from progression to death was 29.
7 months (95% CI, 0-40.
6)
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No association was observed between prior splenectomy or purine analogs and PFS or OS
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Five of the 19 evaluable patients (26%) had TP53 mutations (patients 4, 7, 8, 9, and 13) (Table 2)
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Table 2 Overall, CDARs were well tolerated
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Since HCLv patients have higher normal blood counts than typical HCL patients, the frequency of cytopenias observed is relatively low
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Only one patient developed febrile neutropenia and anemia requiring blood transfusion
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Grade 4 thrombocytopenia occurred in 2 patients, and only 1 patient received prophylactic platelet transfusions
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>>>Study Conclusions This prospective trial showed that CDAR has a high efficacy in patients with early HCLv, especially those who achieved MRD-negative CR
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However, more than one in two patients relapses and there is still an unmet need, especially for those who do not achieve MRD-negative CR or have TP53 mutations
.

These findings must be validated in future studies
.

References: Dai Chihara, Evgeny Arons, Maryalice Stetler-Stevenson et al.
Blood Adv (2021) 5 (23): 4807–4816.
https://doi.
org/10.
1182/bloodadvances.
2021005039.
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