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1536 Part XI: Malignant Lymphoid Diseases Chapter 92: Chronic Lymphocytic Leukemia 1537

and electrolyte monitoring during and after the infusion. Other uncom- type II, IgG antibody with additional structural modifications that
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1
mon toxicities include delayed neutropenia, hepatitis B reactivation, explain its enhanced activity. It binds selectively to the extracellular
interstitial pneumonitis, rash, and serum sickness. Patients with a prior domain of CD20 with reduced internalization. This persistence of the
history of hepatitis B infection should receive monitoring for reactiva- antibody on the cell surface along with a fucosylation in its Fc region
tion while being treated with rituximab or similar agents, with rapid allow for enhanced ADCC through robust engagement of Fc-gamma
implementation of antiviral therapy if reactivation is observed. Fatal receptor type III on effector cells. Another modification in the hinge
cases of progressive multifocal leukoencephalopathy from JC polyoma- region allows for more potent direct cytotoxicity. 239–241 Together, these
virus infection has also been reported with the use of rituximab and modifications translate into a higher efficacy as compared with rituxi-
similar monoclonal antibodies. These infections typically occur during mab in both preclinical and clinical studies. 239–243
treatment or soon after, with virtually all cases observed during the first Obinutuzumab in combination with chlorambucil was compared
year posttherapy. 227,228 to rituximab and chlorambucil and chlorambucil alone in patients with
Ofatumumab Ofatumumab is a fully human, type 1, IgG , untreated CLL in the CLL-11 trial conducted by the German CLL study
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CD20-targeting, monoclonal antibody that binds more effectively to a group. Patients had a median age of 73 years, which is closer to the
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different epitope of CD20 than rituximab. In vitro it was shown to median age of 72 years at diagnosis for CLL patients, and significantly
have improved CDC and ADCC as compared to rituximab. 230,231 Ofa- higher than the median ages of 58 to 62 years which have historically
tumumab is given as a test dose of 300 mg followed by eight weekly been the population that has been enrolled in chemotherapy-based
intravenous infusions of 2000 mg, after which patients can go on a clinical trials for CLL. More importantly, these patients had clinically
maintenance schedule of four monthly infusions of 2000 mg. The half- meaningful comorbid conditions. Treatment of this patient population
life of ofatumumab is 21 days, but the B-cell–depleting effects may last has historically been challenging and no prior chemotherapeutic option,
for up to 7 months after the last infusion. 232 including fludarabine, has improved survival outcomes as compared to
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Early results with ofatumumab as a single agent in patients who chlorambucil alone. The combination of obinutuzumab and chloram-
were refractory to alemtuzumab and/or fludarabine showed encourag- bucil improved ORRs (77.3 percent [obinutuzumab and chlorambucil]
ing ORR of 58 percent in the double refractory group and 47 percent in vs. 65.7 percent [rituximab and chlorambucil] vs. 31.4 percent [chlo-
the fludarabine refractory cohort with bulky disease. Responses were all rambucil]), CR rates (22.3 percent [obinutuzumab and chlorambucil] vs.
partial except for one CR in the fludarabine refractory group. Response 7.3 percent [rituximab and chlorambucil] vs. 0 percent [chlorambucil])
was also short lived and the median duration of response was 7 months and median PFS (26.7 months [obinutuzumab and chlorambucil] vs.
in the fludarabine refractory group and 5.6 months in the double refrac- 16.3 months [rituximab and chlorambucil] vs. 11.1 months [chloram-
tory group with most patients progressing during treatment. These bucil]). Obinutuzumab with chlorambucil also prolonged OS over that
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results led to the approval of ofatumumab in patients with relapsed dis- which was observed with chlorambucil. Notably, the combination also
ease refractory to alemtuzumab and/or fludarabine in 2009. Subsequent resulted in significant improvement in the rate of MRD-negative status
studies compared ofatumumab (300 mg on day 1 followed by eight in both marrow (19.5 percent vs. 2.6 percent) and blood (37.7 percent vs.
weekly infusions of 1000 mg, followed by 1000 mg on day 1 of subse- 3.3 percent) as compared to rituximab and chlorambucil.
quent 28-day cycles, for a maximum of 12 cycles) given in combination Obinutuzumab is generally well-tolerated, but has a high incidence
2
with oral chlorambucil (10 mg/m on days 1 to 7 of each 28-day cycle) of infusion reactions that are seen primarily with the first infusion.
versus chlorambucil alone, in patients with previously untreated CLL Unlike rituximab or ofatumumab where infusion events occur 1 to 2
who required treatment and were not considered candidates for con- hours into therapy, those with obinutuzumab typically occur within the
ventional chemoimmunotherapy. The combination resulted in an ORR first 5 to 10 minutes of starting therapy. These may be minimized by a
of 82 percent versus 68 percent with chlorambucil alone. However, CR test dose, slower infusion rate, and prophylactic steroids, acetamino-
rates were 12 percent versus 1 percent and median duration of response phen, and antihistamines. Tumor lysis is also seen in a small number of
was 22 months versus 13 months in the combination versus chloram- patients, reflecting the higher efficacy of obinutuzumab. Hematologic
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bucil arms, respectively. Based on these results, the combination toxicities, like neutropenia and thrombocytopenia, are also observed.
of ofatumumab and chlorambucil was granted approval in 2014 for All CD20-targeting antibodies increase the risk of hepatitis B virus reac-
the treatment of previously untreated patients with CLL for whom tivation and progressive multifocal leukoencephalopathy.
fludarabine-based therapy is considered inappropriate. The activity of obinutuzumab in patients with untreated CLL is
Ofatumumab has also been studied in the upfront setting in com- very exciting and this antibody is being combined with other novel
bination with FC in smaller phase II studies of a relatively young patient agents and chemotherapy to further improve outcomes in patients with
population (median age: 56 years). This study revealed an ORR of CLL.
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75 percent with 41 percent CRs. The combination of ofatumumab
with pentostatin and cyclophosphamide resulted in a 96 percent ORR Other Antibodies and Antibody-Like Compounds
with 46 percent complete remission rate. 236,237 This compares favorably Multiple antibodies targeting various antigens like CD19 and CD37
to the results seen with the combination of rituximab and chemother- are at various stages of development for the treatment of CLL. 245–247
apy, but large multiinstitution randomized trials are lacking. Advances in antibody manufacturing technology are enabling us to syn-
Ofatumumab is generally well-tolerated, with the most common thesize more potent and bispecific antibodies like blinatumomab, which
reaction being an infusion-related reaction that typically occurs with has already shown promising activity in patients with acute lympho-
the first infusion and includes fevers, rash, fatigue, chills, and dia- blastic lymphoma (ALL) and CLL. 248
phoresis. These reactions tend to get better with subsequent infusions.
Infectious complications are similar to those reported with other CD20
monoclonal antibodies. GLUCOCORTICOIDS
Obinutuzumab Obinutuzumab is a CD20-targeting antibody Glucocorticoids are effective agents in the management of patients with
that was approved in combination with chlorambucil for the initial treat- relapsed CLL and especially patients with del 17p and fludarabine refrac-
ment of patients with CLL in 2014. Obinutuzumab is a fully humanized, tory disease. High-dose methylprednisolone, either as a single agent or

Kaushansky_chapter 92_p1527-1552.indd 1536 9/18/15 10:47 AM