VH4-34þ Hairy cell leukemia
p¼0.12), or in frequency of unmutated sequences. Thus, VH4-34þ HCL rearrangements had high homology to the germline sequence unrelated to
whether HCLv or HCLc.
Clinical factors prior to treatment in classic hairy cell leukemia and hairy cell leukemia variant, with respect to VH4-34 status
Since leukopenia at presentation is common with HCLc but less so with HCLv [1,2], blood counts at presentation were analyzed for all patients where relevant information was available. As shown in Figure 1(B), absence of leukopenia, defined as a
white blood cell count of 56109/L, was more common in VH4-34þ than -negative patients (93% vs. 40%, p¼0.0006), and also more common in HCLv than in HCLc (83% vs. 40%, p¼0.002). These significant differences were still observed when patients with HCLv were subtracted from the
comparison of VH4-34þ and VH4-34-negative cases (100% vs. 32%, p¼0.002). As shown in Figure 1(B), by rank order analysis, presenting white blood cell
counts were higher for VH4-34þ versus -negative patients (median 9.0 vs. 3.86109/L, p¼0.002). Although the same was true of HCLv vs. HCLc
(median 11.3 vs. 3.56109/L, p50.0001), among just patients with classic disease, VH4-34 positivity correlated independently with presenting white blood
cell count (p¼0.003). Moreover, absence of leuko- penia was more common in HCLv than HCLc even
after VH4-34þ cases were subtracted (80% vs. 32%, p¼0.01), indicating that HCLv and VH4-34 corre- lated independently with lack of leukopenia. Median
neutrophils (2.23 vs. 0.826109/L, p¼0.004) and platelets (105 vs. 686109/L, p¼0.014) were also higher at presentation in VH4-34þ than in other patients with HCL, although differences became
non-significant once HCLv cases were subtracted [9]. In contrast, higher median neutrophil (5.52 vs.
0.716109/L, p¼0.0001) and platelet (136 vs. 616109/L, p¼0.004) counts at presentation were observed in HCLv compared to HCLc even after
VH4-34 cases were subtracted. Thus, VH4-34 positivity was independently associated with higher white blood cells at presentation but not higher
neutrophils or platelets, suggesting that VH4-34þ patients have themisfortune of higher malignant cells in the blood without higher normal blood cells.
Response to treatment and outcome with respect to VH4-34 status
To determine whether VH4-34 status was associated with clinical outcomes, the response to first-line cladribine was assessed when possible, and survival
101
data from diagnosis were obtained on all 82 patients. Failure of first-line cladribinewasmuchmore frequent overall than expected due to the skewed patient population examined, since patients were mainly seeking relapsed/refractory trials. Among just patients withHCLc, the overall response rate(ORR)wasmuch
lower for VH4-34þ than -negative patients (33% vs. 90%, p¼0.006). Among VH4-34-negative patients, ORR was lower withHCLv than with HCLc (50% vs.
90%, p¼0.02), indicating that VH4-34 and HCLv were independently related to lack of response. With
respect to overall survival fromdiagnosis, Figures 1(C) and 1(D) indicate that either VH4-34 (p50.0001) or
HCLv (p¼0.02) correlates with poor outcome. As shown in Figure 1 (E), among patients with HCLc, overall survival (OS) from diagnosis was much shorter
for VH4-34þ than -negative patients (4.7 vs. 26.64 years, p50.0001).However, as shown in Figure 1(F), among VH4-34-negative patients, HCLv was not associated with significantly shorter survivalcompared
to HCLc (21.05 vs. 17.33 years, p¼0.22). Thus, VH4-34 positivity correlates with poor overall survival in HCL, and the lower survival attributed to HCLv
may in part be due to the abundance of VH4-34þ patients within the HCLv population.
Possible mechanisms for poor prognosis with VH4-34þ hairy cell leukemia
VH4-34 is expressed in a variety of other hematologic malignancies, including chronic lymphocytic leukemia (CLL) where it was reported in 159 (8%) of 1967 rearrangements. It was second most common after VH1-69 [10]. However, in CLL, only 33 (21%) out of the 159 VH4-34 rearrangements were unmutated, very different from 13 out of 14 patients with HCL
(p¼961078). VH4-34 is also used by 5–10% of normal B-cells [11] and B-cells mediating autoim- mune disorders, including systemic lupus erythema- tosus, cold agglutinin disease, andmultiple sclerosis. It is possible that VH4-34-expressing B-cells can evade checkpoints that might normally keep normal B-cells from either recognizing self-antigens, or becoming malignant. It is notable that multiple myeloma is
almost never VH4-34þ, possibly because transforma- tion to this malignancy occurs late in the timeline of
B-cell differentiation, and before that point, VH4-34þ B-cells might undergo clonal deletion or anergy [12].
Effective treatment for VH4-34þ hairy cell leukemia and hairy cell leukemia variant
In our series, unmutated VH4-34þ HCL was asso- ciated with failure of initial cladribine therapy in all cases, when given as a single agent. However, several case reports document that rituximab alone can
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