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Clinical Cancer Research Vol. 9, 976-980, March 2003
© 2003 American Association for Cancer Research

Clinical Trials

Development of Varicella-Zoster Virus Infection in Patients with Chronic Myelogenous Leukemia Treated with Imatinib Mesylate

Gloria N. Mattiuzzi1, Jorge E. Cortes, Moshe Talpaz, James Reuben, Mary Beth Rios, Jianjin Shan, Dimitrios Kontoyiannis, Francis J. Giles, Issam Raad, Srdan Verstovsek, Alessandra Ferrajoli and Hagop M. Kantarjian

Departments of Leukemia [G. N. M., J. E. C., M. B. R., J. S., F. J. G., S. V., A. F., H. M. K.], Bioimmunotherapy [M. T.], Infectious Diseases [D. K., I. R.], and Hemtopathology [J. R.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: Infection with Varicella-Zoster virus (VZV) is an exceptionally rare complication of chronic myelogenous leukemia (CML) without stem cell transplantation. We report 16 patients with CML who developed VZV infection during imatinib mesylate therapy.

Patients and Methods: From July 1998 until February 2002, 771 patients were included in 11 imatinib mesylate studies for all CML phases in the Departments of Leukemia and Bioimmunotherapy at The University of Texas M. D. Anderson Cancer Center. Sixteen patients developed VZV infection. Charts and follow-up information of were reviewed and analyzed.

Results: Sixteen patients (2%) developed a VZV infection [15 episodes of herpes zoster (HZ), 1 varicella]. The baseline characteristics of the 16 patients with infection do not differ significantly from those who did not develop VZV infection, except for time from diagnosis of CML to imatinib (median: 55 versus 25 months, P = 0.0056) and the number of prior therapies (3 versus 1, P < 0.001). All patients received therapy with antiviral agents with good response. Six patients developed postherpetic neuralgia.

Conclusions: Our results suggest that imatinib therapy in CML is associated with low incidence of HZ infection. VZV infection is more frequent with longer duration of CML disease and with prior therapy, does not disseminate, responds well to therapy, and does not mandate a recommendation for HZ prophylaxis in such patients.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
VZV2 infection is a serious infection in immunosuppressed patients, particularly those with defects in cell-mediated immunity. This infection is usually confined to a skin dermatome but may disseminate and become life threatening (1, 2, 3, 4) . It is estimated that there are ~500,000 cases of HZ/year in the United States among immunocompetent hosts (5) . Patients with cancer and high-risk for VZV infections include those with lymphoma, acute leukemia, and patients undergoing SCT (6 , 7) . Predisposing factors include the use of corticosteroids, exposure to radiation therapy (7) , local surgery (7) , splenectomy (8) , and immunosuppressive therapy.

CML accounts for 15–20% of adult leukemias (9) and is characterized by excessive proliferation of myeloid progenitors cells. The disease typically follows a biphasic or triphasic course. A CP that typically lasts 3–4 years is followed by a transitional stage referred to as AP, which ultimately terminates in a BP of either myeloid or lymphoid phenotype (8) . The cytogenetic-molecular hallmark of CML is the Ph abnormality, generating an abnormal Bcr-Abl fusion protein with constitutively elevated tyrosine kinase activity (10) . Whereas Ph is typically thought of as the lesion in CML-CP, additional cytogenetic and molecular abnormalities accumulate during progression to the CML-BP. Imatinib (STI 571; Gleevec) is a potent and specific inhibitor of the Bcr-Abl tyrosine kinase, which is at the core of the leukemogenic activity of the CML cells. Imatinib is very active in patients with CML-CP and CML-AP, inducing superior cytogenetic response rates and durable remissions compared with previous therapies such as IFN-{alpha} (11 , 12) .

Patients with CML-CP are at low risk for developing infectious complications compared with patients in CML-AP or CML-BP who may be at higher risk because of the more immunosuppressive nature of the cytotoxic chemotherapy these patients receive and their compromised marrow status (13) .

Infection with VZV is an exceptionally rare complication in patients with CML, except those undergoing SCT (4 , 7 , 14 , 15) .

We report herein on 16 patients with CML who developed VZV infections while receiving imatinib mesylate (imatinib, STI571; Gleevec).


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
From July 1998 until February 2002, 11 imatinib studies for all CML phases (early or late CP, AP, or BP) were conducted in the Departments of Leukemia and Bioimmunotherapy at The University of Texas M. D. Anderson Cancer Center. Seven hundred seventy-one patients were included in these studies. A total of 16 patients developed VZV infections (15 patients had HZ and 1 patient had varicella). The charts and follow-up information of these 16 patients were individually reviewed and analyzed. Basic demographic information included age, gender, date of CML diagnosis, treatment immediately preceding imatinib, CML phase at start imatinib and at the moment of HZ or varicella.

HZ was defined as vesicular lesions beginning with a dermatomal localization. Cutaneous dissemination of HZ was defined as the subsequent appearance of six or more extradermatomal skin lesions. Visceral dissemination was defined as histological or cultural evidence of internal organ involvement or as clinical evidence of internal organ involvement in the absence of other identified pathogens. Varicella was defined as a vesicular eruption with a generalized onset and with no dermatomal localization at any time during the course of disease.

Accelerated phase of CML was considered if one of these parameters was present: peripheral blood blasts > 15%; peripheral blood blasts and promyelocytes > 30%; peripheral blood basophils > 20%; platelet count < 100 cells x 109/liter unrelated to therapy; and cytogenetic karyotypic evolution. BP of CML was defined as the presence of >30% of blasts in peripheral blood or bone marrow or the documentation of extramedullary disease (16) . The response criteria for therapy with imatinib in CML have been described previously (17) .

CHR was considered if the patient achieved complete normalization of peripheral blood counts, WBC count < 10 x 109/liter, and no immature cells (blasts, promyelocytes, myelocytes). Within CHR, a cytogenetic response was consider complete if there were no Ph-positive cells, partial if there were between 1 and 34% of Ph-positive cells; major response was defined if complete or partial response was documented; minor response was defined with the presence of <90% Ph-positive cells.

Partial hematological response was the same as for CHR but with persistence of immature peripheral cells or thrombocytosis < 50% of pretreatment levels but > 450 x 109/liter or persistent splenomegaly but <50% of pretreatment level.

Patient baseline characteristics and the overall response to imatinib between the two groups were evaluated by {chi}2 or Fisher’s exact test. Distributions were compared between categories using Mann-Whitney U test.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Among 771 patients with CML treated with imatinib, 16 patients (2%) developed an episode of VZV infection (15 episodes of HZ and 1 varicella) with an incidence of 5.25 cases/100 patient years. The baseline characteristics of the 16 patients with infections did not differ significantly from those who did not develop VZV infection with regard to gender, age, CML status at start of imatinib and pretreatment levels of hemoglobin, platelet count, WBC count, absolute neutrophil and lymphocyte counts, and serum creatinine and albumin (Tables 1Citation and 2Citation ). Of note, 10 of 16 patients (63%) with VZV infection had CP CML. The median time from diagnosis of CML to imatinib therapy was significantly longer in patients with VZV infection (55 months, range: 1–78 months) compared with patients who did not develop this infection (25 months, range: 0–320 months; P = 0.006). Similarly, patients with VZV infections had received a higher median number of prior therapies (IFN-{alpha}, homoharringtonine, and so on) compared with those without such infections (median number of treatments were 3 versus 1 in patients, respectively; P < 0.001). None of the 771 patients received antiviral prophylaxis while on treatment with imatinib (Tables 3)Citation .


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  		Table 1 Characteristics of 771 patients with CML treated with imatinib mesylate: 16 with VZV infection and 755 without infection

 

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  		Table 2 Characteristics of 771 patients with CML treated with imatinib mesylate: 16 with VZV infection and 755 without infection

 

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  		Table 3 Characteristics of 16 patients with CML and VZV infection

 
Evaluation of CML response to imatinib did not reveal any significant differences between the two patient populations. Of these 16 VZV patients, only one was in BP at the start of imatinib and is the only one who developed disseminated cutaneous varicella infection. The median time of onset of VZV infection after initiation of imatinib was 7 months (range: 0.3–29 months). There was no seasonal variation in the incidence of VZV infection and no epidemiological evidence of nosocomial transmission. Two of 16 patients with VZV infection had received previous SCT. One patient had undergone an allogeneic SCT in January 1987, whereas the other patient had undergone an autologous SCT in 1993, failed to engraft and subsequently underwent an autologous SCT the same year. Both patients received imatinib therapy during 2000.

HZ infection was localized in 15 patients and included the following dermatomes: thoracic (7 patients, 43%); trigeminal (3 patients, 19%); and sacral (2 patients, 13%). One patient each had involvement in the sacral, lumbar, and perirectal areas and one in the forehead. One patient appeared to have disseminated cutaneous VZV infection. All patients received therapy with antiviral agents at doses active against VZV (acyclovir, valacyclovir, penciclovir, and gancilcovir) with good response, and none had recurrence of the infection. Six patients (37%) developed postherpetic neuralgia lasting from 3 weeks to 24 months (Table 4)Citation .


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  		Table 4 VZV infection

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our study suggests that imatinib therapy for CML is associated with a risk of developing localized dermatomal VZV infection and postherpetic neuralgia. A longer diagnosis of CML and extensive prior therapy appear to predispose patients, including those in CP, to this infection. Extensive prior therapy may contribute to weakening the immune system of these patients, rendering them more vulnerable to VZV infection, particularly when antiviral prophylaxis is not provided.

In the absence of evidence for nosocomial transmission in our patients, reactivation of latent viral infection appears to be the mechanism of disease in these patients. After primary infection, the VZV becomes dormant and may reactivate, particularly in the presence of defects in cell-mediated immunity (including a low number of CD4-positive cells; Refs. 18 , 19 ). Preliminary unpublished studies conducted at our institution suggest that imatinib suppresses the CD4 cell population (20) . If confirmed, this finding could, at least partly, explain the increasing risk of VZV reactivation in our group of patients.

This is the first report of VZV infection in CML patients not undergoing intensive cytotoxic chemotherapy or SCT. Historically, patients with CML are reported to be at low risk for serious infectious complications, particularly during the CP of CML (13) . In the absence of antiviral prophylaxis, the incidence and severity of VZV infection in patients with CML treated with imatinib appears to be significantly lower than that observed with other immunosuppressive therapies for CML (such as allogeneic SCT; Refs. 3 , 21 ). It is noteworthy that IFN-{alpha} may be protective against herpes viral infections (22, 23, 24) and that hydroxyurea, commonly used for treatment of CML, may also exhibit antiviral properties (25–27).

The extensive use of such agents with antiviral properties in patients with CML could possibly explain the previously described low incidence of VZV infection in this patient population. Although most of VZV cases were observed in the setting of patients with prior extensive treatment, our preliminary experience in untreated patients suggests that VZV infection may still occur in that setting.

Because of the very low risk of VZV infection in CML patients treated with imatinib, the limited extent of the infection and the excellent response to therapy, routine prophylaxis of VZV infection is not recommended in this setting. Early diagnosis and treatment of such infections is, however, strongly recommended, given the significant incidence of postherpetic neuralgia, and the potential risk for fatal infection if therapy is delayed. Antiviral prophylaxis is, however, indicated in those patients receiving imatinib and who have a prior history of VZV infection or significant exposure to individuals with this infection. A better understanding of the risk factors for VZV infection in this setting may, in the future, provide better tools (such as CD4 count) to guide prophylaxis against this serious infection.

Because of the observation of VZV infections in patients treated with imatinib, it would be important to continue long-term monitoring of such patients who will be receiving extended therapy with imatinib. This is because of the potential that such patients may develop more severe immunosuppression and related complications (e.g., PCP, other viral infections, lymphomas, and so on).

In summary, our study suggests that imatinib therapy in CML has been associated with a new infectious event, the development of a low incidence of HZ infections (2%, cumulative 5.25/100 patients/year). This occurrence of HZ infections may be because of suppression of CD4 cells by imatinib, is more frequent with longer duration of CML disease and with prior therapy, does not disseminate, is not life-threatening, respond wells to therapy, and does not mandate a recommendation for HZ prophylaxis in such patients. However, careful longer follow up of patients with CML (and other tumors) on imatinib therapy is needed.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom requests for reprints should be addressed, at Department of Leukemia, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 428, Houston, TX 77030. Phone: (713) 745-2723; Fax: (713) 745-4612; E-mail: gmattiuz{at}mdanderson.org Back

2 The abbreviations used are: VZV, Varicella-Zoster virus; HZ, Herpes Zoster; SCT, stem cell transplantation; CML, chronic myelogenous leukemia; CP, chronic phase; AP, accelerated phase; BP, blastic phase; Ph, Philadelphia chromosome; CHR, complete hematological response. Back

Received 8/ 9/02; revised 10/30/02; accepted 10/30/02.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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