Page 1562 - Williams Hematology ( PDFDrive )

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

in combination with multiple other chemotherapeutic agents, produced with FCR had a significantly higher ORR of 90 percent with a CR rate of
sustained responses in the majority of patients with refractory and high- 44 percent as compared to FC, which resulted in an ORR of 80 percent
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risk disease. High-dose methylprednisolone at 1 g/m for 5 days with and a CR rate of 22 percent. More importantly, this study established
weekly rituximab for three cycles induces response rates as high as 93 the improvement in OS with the addition of rituximab to chemother-
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percent with a CR of 36 percent. Therapy, however, is complicated apy. As a result, rituximab was approved for the treatment of patients
by significant hyperglycemia, fluid retention, and immune suppression with CLL in combination with chemotherapy in 2010. The use of FCR
resulting in increased incidence of opportunistic infections requiring was also associated with a significantly higher risk of cytopenias that
close followup and aggressive supportive care with prophylactic anti- did not result in a higher incidence of serious infectious complications
biotics. The addition of weekly rituximab and decreasing the duration which were similar in both arms as was the treatment-related mortality.
of methylprednisone dose to 3 days resulted in similar responses and All genomic groups appear to benefit from the addition of FCR, except
reduction in the incidence of adverse events. 250,251 Similar results were for those without any common interphase cytogenetic abnormalities
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observed when methylprednisolone was substituted for dexamethasone and those with del 17p. Long-term followup of FCR by both the MD
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40 mg weekly or every 2 weeks for 4 days. Glucocorticoids at lower Anderson group and the German CLL Study Group suggests that the
doses are also very useful in the management of patients with autoimmune patients benefiting most from FCR may be those with IGHV mutated
complications as a result of their CLL. disease where prolonged complete remissions can be obtained. For
patients with IGHV unmutated disease there does not appear to be any
CHEMOIMMUNOTHERAPY evidence of sustained stable remission, with all eventually relapsing and
requiring additional therapy.
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The combining of chemotherapy with targeted antibodies has been a Given the poor tolerability and increased toxicity observed with
major advance in the management of patients with CLL. Multiple thera- the use of FCR in elderly patients and patients with compromised renal
peutic combinations have been developed and validated for use and are function and to enhance efficacy of FCR, multiple variations of the reg-
summarized below. imen were tested with similar results in small cohorts of patients. 265,266
None of these regimens are commonly used and the advent of alterna-
Fludarabine and Rituximab tive agents have made these regimens of limited utility.
The impact of sequential or concurrent administration of rituximab
with fludarabine (FR) was assessed in the Cancer and Leukemia Group Bendamustine and Rituximab
B (CALGB) 9712 randomized study of 104 previously untreated CLL The combination of bendamustine and rituximab (BR) has been tested
patients. Fludarabine was given at 25 mg/m days 1 to 5 every 4 weeks both in patients with relapsed and in patients with untreated CLL. In
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for six cycles, with or without concurrent rituximab 375 mg/m on day 1 the first BR study with relapsed CLL bendamustine was administered to
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of each cycle, and an additional dose on day 4 of cycle 1. Patients in both 78 patients at a dose of 70 mg/m on days 1 and 2 with rituximab 375
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arms received rituximab 375 mg/m weekly for four doses beginning mg/m on day 0 of cycle 1 and 500 mg/m on day 1 of cycles 2 to 6. The
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2 months after completion of fludarabine; thus, patients in the concur- ORR was 59 percent with a CR rate of 9 percent and a median PFS of 14.7
rent arm received 11 total doses of rituximab, compared to four in the months. Minimal activity was observed in patients with del 17p. In the
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sequential arm. ORR was 90 percent versus 77 percent and CR rates subsequent followup study, 117 patients with previously untreated CLL
were 47 percent versus 28 percent in the concurrent versus sequential were treated at the same schedule but with a higher dose of bendamustine
arm, respectively. A retrospective comparison to a fludarabine-only at 90 mg/m on days 1 and 2 and resulted in ORR of 91 percent with CR
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treatment (CALGB 9011) demonstrated improved PFS and OS with rate of 33 percent. In the large, multicenter, CLL10 trial, 564 patients
the use of FR. This regimen had limited efficacy in patients with del with previously untreated CLL, good performance status, and low comor-
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17p and del 11q. The median PFS was 42 months and 27 percent were bidity burden were randomized to FCR or BR. ORR was similar in both
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progression free at 5 years. Notably, there were no cases of treatment- arms at 97 percent but CR rates were higher in the FCR arm at 40 percent
related-myeloid neoplasms occurring before disease relapse. 255 versus 31 percent with BR. MRD rates were also higher with FCR (74 per-
cent vs. 62 percent). Median PFS was 53 months in the FCR arm and 43
Fludarabine, Cyclophosphamide, and Rituximab months in the BR arm. FCR was more toxic and severe neutropenia was
Fludarabine, cyclophosphamide, and rituximab (FCR) chemotherapy more often observed in the FCR arm (87 percent vs. 67 percent) as were
has been studied extensively in patients with previously treated and severe infections (39 percent vs. 25 percent). Treatment-related mortality
untreated CLL. 256–259 Fludarabine was administered at 25 mg/m , cyclo- was 3.9 percent with FCR and 2.1 percent with BR. Given these results,
2
phosphamide at 250 mg/m on days 2 to 4 of cycle 1 and on days 1 to FCR appears to be the more effective therapeutic option for younger
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3 of cycles 2 to 6, and rituximab at 375 mg/m on day 1 of cycle 1 and patients and patients without significant comorbid conditions, and BR can
2
500 mg/m on day 1 of cycles 2 to 6. In the initial single institution, be used for older and unfit patients.
2
phase II experience of 300 untreated CLL patients, this combination
resulted in exciting ORR of 95 percent with CR rate of 72 percent with Other Chemoimmunotherapeutic Regimens
median time to progression of 80 months in patients with untreated Pentostatin and rituximab and pentostatin, cyclophosphamide, and
CLL. However, despite a younger patient population with a median rituximab (PCR) both resulted in promising ORR (91 percent vs. 76
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age of 57 years, FCR resulted in significant and sustained myelosuppres- percent) and CR rates (41 percent vs. 27 percent). 237,270 Importantly, the
sion, with 35 percent of patients experiencing cytopenias 3 months after PCR regimen appeared to be generally well-tolerated in young and older
completing therapy. Notably, therapy-related myeloid neoplasms/ patients and in patients with high-risk genetic features. Levels of Mcl-1,
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myelodysplastic syndromes occurred in 5.1 percent of patients and an antiapoptotic protein, were also shown to be predictive of response
Richter transformation in 9 percent. FCR was subsequently compared and OS. The most common toxicity was neutropenia and thrombo-
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to FC in a large multicenter trial of 817 young patients (median age: cytopenia. Similarly, cladribine and cladribine plus cyclophosphamide
61 years) with previously untreated CLL. The responses observed were also combined with rituximab and resulted in predictable efficacy
262
with FCR were more modest in larger phase III trials. Patients treated and toxicity. 271–273
Kaushansky_chapter 92_p1527-1552.indd 1537 9/18/15 10:47 AM