84
R. J. Kreitman et al.
weeks. Other than HUS, dose limiting toxicity (DLT) on the phase I trial was limited to a cytokine release syndrome in one patient who had fever, bone pain, hypotension, and weight gain (vascular leak syndrome; VLS) but no pulmonary edema, resolving in 3 days. The cycle 1 maximum tolerated dose (MTD) was 40 mg/kg every other day for three doses (QOD63), and the CR rate was significantly higher when patients began BL22 at least at this dose level. Since HUS was only observed with retreatment at 3– 4-week intervals, the phase II trial was designed to test the efficacy of one cycle of 40 mg/kg QOD63, retreating only those with stable disease (SD) or PR not achieving resolution of blood counts to the levels needed for CR. With one cycle of BL22 in 36 phase II patients with HCL enrolled, 25% achieved CR and 25% achieved PR. Fifty-six percent of patients were retreated, resulting in final response rates of 47% CRs and 25% PRs. Dose-limitingHUS was observed in only two patients on trial, and in two patients treated by special exemption. It was found that HUS resolved completely without plasmapheresis, which was consistent with documentation of adequate levels of the protease ADAMTS13 in the plasma of patients, thus not requiring removal of an inhibitor. Since the CD22 was present at such high density on the HCL cells (median 44 000 sites/cell), the pharmacokinetics of BL22 was strongly affected by tumor burden. Accordingly, plasma BL22 levels usually increased on the cycles given after patients responded. High levels of neutralizing antibodies that prevented retreatment were observed in four (11%) patients. CR rates were higher in patients with spleen diameters5200 mm than in those with either larger
spleens or prior splenectomy (p¼0.019), due to either more advanced disease in the latter group, or more limited tumor penetration of BL22 into bone marrow or splenic tissue. Thus, BL22 activity against relapsed/refractory HCL was confirmed, with best responses achieved before spleens were either re- moved or allowed to grow to massive size.
Targeting CD22 with higher affinity
Response to BL22 in chronic lymphocytic leukemia (CLL) was more limited than in HCL, attributed to the relatively low CD22 expression in CLL (median 1250 sites/cell) and the significant off-rate of BL22. To allow more toxin molecules binding to CLL cells to become internalized, the affinity was increased and off-rate decreased by mutation of hot-spot (RGYW) residues in the complementarity determining regions (CDRs) [10]. By phage display selection, a mutant was developed with THW replacing SSY at positions 100, 100a, and 100b of the VH CDR3, resulting in 15-fold improvement in binding affinity, leading to
improvement in cytotoxicity toward primary CLL as well as HCL cells. In phase I testing of CAT-8015, also called HA22 and moxetumomab pasudotox, the first 28 patients tested achieved a CR rate of 43%, and of the 25 patients receiving 10–50 mg/ kg QOD63, 48% achieved CR. No DLT was observed in this trial, although two patients with minor laboratory abnormalities (creatinine and plate- let abnormalities limited to grade I) were diagnosed as grade 2 HUS. Thus, CAT-8015, a higher-affinity version of BL22, achieved responses in HCL, and may be less toxic than BL22, possibly by decreasing off-target binding and non-specific toxicity.
Use of rituximab in early hairy cell leukemia
While purine analogs alone may not be able to eradicate HCL, since MRD detected after cladribine
is always strongly CD20þ(4100 000 sites/cell), it may be possible to eradicate MRD using rituximab, providing it is timed correctly. Used as a single agent, rituximab has achieved 10–60% CR rates in multiple trials, but overall, those patients who needed treat- ment because of cytopenias and had at least one prior course of purine analog had an ORR of 39%, with 20% CRs. The largest trial of rituximab alone achieved 13% CRs and 13% PRs [11]. However, Ravandi et al. reported a 100% CR rate, most without MRD, in 13 patients with early HCL (0–1 prior courses of purine analog) treated with eight weekly doses of rituximab beginning 1 month after five daily doses of cladribine [12]. To determine
whether rituximabþcladribine should replace cla- dribine alone as the standard treatment of HCL, we initiated a randomized trial in which patients with HCL with 0–1 prior courses of cladribine are treated with five daily doses of cladribine (days 1–5) with eight weekly doses of rituximab begun either on day 1 or at least 6 months later as soon as MRD is detectable in the blood. Although one would expect MRD to be lower at 6 months after cladribine if rituximab were begun on day 1 (the primary endpoint), there are several potential advantages to waiting for 6 months before beginning rituximab, including: (1) since minimum HCL burden is achieved at *6 months after a 5–7-day course of cladribine, rituximab may be best able to reach all HCL cells at that point, (2) since rituximab requires immune mechanisms for killing, cladribine, which kills B- and T-cells, may block efficacy, (3) infusional reactions from rituximab, which often require ster- oids, are not observed when delayed at least 6 months, and steroids may partially block rituximab efficacy, and (4) patients who are neutropenic immediately after cladribine might have added toxicity with immediate rituximab due to prolonged
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100 |
Page 101 |
Page 102 |
Page 103 |
Page 104 |
Page 105 |
Page 106 |
Page 107 |
Page 108 |
Page 109 |
Page 110 |
Page 111 |
Page 112 |
Page 113 |
Page 114 |
Page 115 |
Page 116 |
Page 117 |
Page 118 |
Page 119 |
Page 120 |
Page 121 |
Page 122