Randomized Phase II Study of First-Line Cladribine With Concurrent or Delayed Rituximab in Patients With Hairy Cell Leukemia

Abstract

PURPOSE Single-agent purine analog, usually cladribine, has been the standard first-line therapy of hairy cell leukemia (HCL) for 30 years. High complete remission (CR) rates often include minimal residual disease (MRD), leading to relapse and repeated treatments. Rituximab can clear MRD, but long-term results are unknown and optimal timing of rituximab undefined. PATIENTS AND METHODS Patients were randomly assigned to first-line cladribine 0.15 mg/kg intravenously days 1-5 with 8 weekly doses of rituximab 375 mg/m2 begun either day 1 (concurrent, CDAR) or ≥ 6 months later (delayed) after detection of MRD in blood. MRD tests included blood and bone marrow (BM) flow cytometry, and BM immunohistochemistry. RESULTS Sixty-eight patients with purine analog-naïve classic HCL were randomly assigned 1:1 to concurrent versus delayed arms. At 6 months after CDAR versus cladribine monotherapy, CR rates were 100% versus 88% ( P = .11), MRD-free CR rates 97% versus 24% ( P < .0001, primary end point), and blood MRD-free rates 100% versus 50% ( P < .0001), respectively. At 96 months median follow-up, 94% versus 12% remained MRD free. Compared with CDAR, delayed rituximab after cladribine achieved lower rate (67% of 21 evaluable patients; P = .0034) and durability ( P = .0081, hazard radio favoring CDAR, 0.094) of MRD-free CR. Nevertheless, 12 patients in the delayed arm remained MRD free when restaged 6-104 (median, 78) months after last delayed rituximab treatment. Compared with cladribine monotherapy, CDAR led to brief grade 3/4 thrombocytopenia (59% v 9%; P < .0001) and platelet transfusions without bleeding (35% v 0%; P = .0002), but higher neutrophil ( P = .017) and platelet ( P = .0015) counts at 4 weeks. CONCLUSION Achieving MRD-free CR of HCL after first-line cladribine is greatly enhanced by concurrent rituximab and less so by delayed rituximab. Longer follow-up will determine if MRD-free survival leads to less need for additional therapy or cure of HCL.

Development of Recombinant Immunotoxins for Hairy Cell Leukemia

“…A minimum duration of resolved cytopenias was not specified in the guidelines [ 27 ], but four weeks is often used [ 19 , 59 , 60 , 62 , 64 , 65 , 66 ]. We require four weeks for multiple relapsed HCL protocols, but a single assessment for first- or second line HCL treatment, since improvements are more durable after therapy of early HCL [ 66 , 67 ]. The older PR criteria requiring ≤5% circulating HCL is no longer required for PR [ 27 ], although many protocols including ours required ≥50% reduction in peripheral blood HCL cell count [ 19 , 21 , 68 ].…”

“…MRD criteria by immunohistochemistry include CD20+ or DBA44+ cells mostly consistent with HCL by morphology, and B-cells at least as numerous as T-cells [ 72 ]. We have used this older definition of immunohistochemistry MRD [ 67 ] since it is most established, but it lacks sensitivity compared with newer techniques like Pax5/CD103 or Pax5/TRAP double staining [ 40 ]. One might consider the presence of rare Pax5/CD103 or Pax5/TRAP double-stained cells (6–10 cells on the slide of a 1–2 cm core) to be positive for immunohistochemistry MRD.…”

“…This was, to our knowledge, the first report that eradication of MRD in HCL is associated with longer CR duration. The duration of MRD-positive CR in this trial, which was for HCL patients in ≥third line, was shorter than the duration of MRD-positive CR after first-line HCL treatment with cladribine [ 67 ]. We therefore believe it is particularly critical to eliminate MRD in multiply relapsed HCL.…”

“…It should be noted that while MRD was assessed by bone marrow biopsy immunohistochemistry through a central lab, the assessment of MRD-negative CR for purposes of stopping retreatment was performed at each site, where the sensitivity of MRD tests likely differed. Since bone marrow aspirate flow cytometry is more sensitive than bone marrow biopsy immunohistochemistry [ 67 ], centers utilizing only the latter MRD test might have a higher rate of MRD-negative CR. The primary endpoint was to determine the percent of patients who could achieve CR, which required reversal of cytopenias to the level of a hematologic remission (HR), and then document absence of recurrent cytopenias (continued HR) over 180 days.…”

“…On subsequent cycles, spaced 28 days apart, rituximab is begun just prior to Moxe on day 1. Although rituximab is marginally effective in relapsed HCL as a single agent [ 131 ], we recently reported that its addition to first line cladribine results in a marked improvement in MRD-free CR, from 24% to 97% at six months [ 67 ]. In comparing Moxe-rituximab to cladribine-rituximab (CDAR), albeit across trials, it is notable that Moxe as a single-agent has a higher MRD-free CR rate than cladribine [ 64 ].…”