Page 1429 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 78 Hairy Cell Leukemia 1275

markers of the disease, such as serum-soluble CD25, CD22, and has been refuted by other reports. The reported second cancers
CD307, have been evaluated and shown to be reliable for disease include melanoma, prostate cancer, gastrointestinal cancers, and
monitoring. 30 non-Hodgkin lymphomas. Whether these second malignancies are
Rituximab has been evaluated for eradication of MRD assessed by related to the primary disease itself or to its treatment has also been
flow cytometry and consensus primer PCR; whether such elimination debated. A number of long-term studies of patients treated with
of MRD can translate to a longer relapse-free survival is unclear. 9,24 pentostatin or cladribine have not shown a statistically significant
Sigal and colleagues reported that patients with HCL may harbor increased risk for second malignancies. It remains unclear whether the
MRD and even morphologically evident disease many years after immunosuppressive effects of nucleoside analogs play a role in such
initial therapy without experiencing overt relapse, raising the question susceptibility to developing a second malignancy or whether disease-
of whether eradication of MRD should be the goal of therapy in related factors or perhaps increased monitoring of these patients are
9
HCL. However, several studies have suggested that patients who important.
achieve a morphologic CR have a better outcome than those with
lesser responses. Whether this can be extrapolated to complete eradi-
cation of detectable disease remains to be established. FUTURE DIRECTIONS
Over the past decade, success in the treatment of HCL has led to
Treatment of Disease Relapse diminished interest in developing new therapeutic strategies for treat-
ing this uncommon leukemia, with research confined to a few special-
Despite the success of the nucleoside analogs in achieving generally ized centers interested in the biology and pathogenesis of this disease.
durable responses in the majority of patients, they are not considered Recent reports unraveling the biologic and molecular aspects of the
2
to be curative, with about 40% of patients relapsing by 10 years disease have kindled a significant resurgence of interest. Further
10
after treatment. Second and third courses of nucleoside analogs studies into other aspects of the disease, such as the role of microen-
have been used, either with the same or the alternate agent used to vironment, BCR signaling, and the complex interaction of various
treat relapsing disease. However, CRs are less frequent with subse- signaling pathways will likely provide better therapeutic tools and
quent courses. Because a single course of cladribine or pentostatin strategies. 2
+
can suppress CD4 lymphocytes for a substantial period of time,
concerns about the use of multiple courses of these agents have
been raised. 18 REFERENCES
Rituximab has the advantage of sparing T-lymphocytes and has
shown significant activity in patients with relapsed disease (see Table 1. Foucar K, Falini B, Catovsky D, et al: Hairy cell leukemia. In Swerdlow
78.6). However, the overall response rate is relatively low, particularly SH, Campo E, Harris NL, editors: WHO classification of tumors of
in studies using only 4 weekly doses of rituximab. Recent studies of haematopoietic and lymphoid tissues, ed 4, Lyon, 2008, International
combination therapy with rituximab and nucleoside analogs have Agency for Research on Cancer (IARC).
reported high response rates, improved activity in variant HCL, and 2. Tiacci E, Liso A, Piris M, et al: Evolving concepts in the pathogenesis of
second CR durations longer than the first CR achieved with nucleo- hairy-cell leukaemia. Nat Rev Cancer 6:437, 2006.
side analogs alone. 31,32 Immunotoxins such as BL22 and HA22 have 3. Forconi F, Sahota SS, Raspadori D, et al: Hairy cell leukemia: at the
been studied in cases of relapsed disease, produce high responses, and crossroad of somatic mutation and isotype switch. Blood 104:3312,
have limited toxicity; however, they are not, as yet, widely available. 2004.
Bendamustine, a novel molecule with structural features of both 4. Arons E, Roth L, Sapolsky J, et al: Evidence of canonical somatic
an alkylating agent and a purine nucleoside analog, has been used hypermutation in hairy cell leukemia. Blood 117:4844, 2011.
by one group for the treatment of relapsed and refractory disease. 5. Basso K, Liso A, Tiacci E, et al: Gene expression profiling of hairy cell
Anecdotal reports have circulated about the use of other agents such leukemia reveals a phenotype related to memory B cells with altered
as alemtuzumab. BCRs signaling kinase inhibitors such as ibrutinib expression of chemokine and adhesion receptors. J Exp Med 199:59,
have shown significant promise in the treatment of a number of 2004.
lymphoid neoplasms and are being investigated in patients with 6. Tiacci E, Trifonov V, Schiavoni G, et al: BRAF mutations in hairy-cell
33
relapsed disease and HCLv. The identification of BRAF V600F as leukemia. N Engl J Med 364:2305, 2011.
a universal aberration in patients with HCL and the availability of 7. Falini B, Tiacci E, Liso A, et al: Simple diagnostic assay for hairy cell
BRAF inhibitors for the treatment of solid tumors such as melanoma leukaemia by immunocytochemical detection of annexin A1 (ANXA1).
led to the investigation of this agent in patients with relapsed HCL Lancet 363:1869, 2004.
34
with promising early reports. The BRAF mutation, BRAFV600E 8. Matutes E, Wotherspoon A, Brito-Babapulle V, et al: The natural history
constitutively activates the mitogen activated kinase pathway in and clinico-pathological features of the variant form of hairy cell leuke-
virtually all patients with HCL. Two phase II trials of the BRAF mia. Leukemia 15:184, 2001.
35
inhibitor, vemurafenib, have been reported. The treated patients 9. Sigal DS, Sharpe R, Burian C, et al: Very long-term eradication of
had relapsed or were refractory to treatment with purine analogs. minimal residual disease in patients with hairy cell leukemia after a single
The drug was administered orally at a dose of 960 mgms orally course of cladribine. Blood 115:1893, 2010.
twice a day for 16 to 18 weeks. The overall response rate was 96% 10. Else M, Dearden CE, Matutes E, et al: Long-term follow-up of 233
to 100% with a CR rate of 35% to 42% All patients had evidence patients with hairy cell leukaemia, treated initially with pentostatin
of MRD at the end of treatment. The progression-free survival rate or cladribine, at a median of 16 years from diagnosis. Br J Haematol
was 73% and the overall survival was 91%. Myelosuppression was 145:733, 2009.
minimal and the most common adverse effects were rash, arthralgias 11. Piro LD, Carrera CJ, Carson DA, et al: Lasting remissions in hairy-cell
or arthritis. These studies suggest that BRAF inhibitors are promis- leukemia induced by a single infusion of 2-chlorodeoxyadenosine. N Engl
ing agents for HCL patients that are unresponsive or refractory to J Med 322:1117, 1990.
purine analogs. The role of these agents in treating patients with 12. Lauria F, Bocchia M, Marotta G, et al: Weekly administration of
HCL will need further studies and longer follow up. 2-chlorodeoxyadenosine in patients with hairy-cell leukemia: a new treat-
ment schedule effective and safer in preventing infectious complications.
Blood 89:1838, 1997.
Incidence of Second Malignancies 13. Robak T, Jamroziak K, Gora-Tybor J, et al: Cladribine in a weekly versus
daily schedule for untreated active hairy cell leukemia: final report from
Early studies suggested an association between HCL and develop- the Polish Adult Leukemia Group (PALG) of a prospective, randomized,
ment of second malignancies, but this link is controversial and multicenter trial. Blood 109:3672, 2007.