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Blood, 15 February 2002, Vol. 99, No. 4, pp. 1486-1488
BRIEF REPORT
Unusual viral infections (progressive multifocal
leukoencephalopathy and cytomegalovirus disease) after high-dose
chemotherapy with autologous blood stem cell rescue and
peritransplantation rituximab
Stuart L. Goldberg,
Andrew L. Pecora,
Robert S. Alter,
Mark S. Kroll,
Scott D. Rowley,
Stanley E. Waintraub,
Kavita Imrit, and
Robert A. Preti
From the Adult Blood and Marrow Transplantation
Program, Hackensack University Medical Center, NJ; Centra State Medical
Center, Freehold, NJ; and Progenitor Cell Therapy, Hackensack, NJ.
 |
Abstract |
Efforts to reduce relapse of non-Hodgkin lymphoma after autologous
transplantation have included ex vivo stem cell selection and/or
peritransplantation immunotherapy. The late infectious and immunologic
consequences of these maneuvers are not well understood, although an
increase in early cytomegaloviral disease after CD34+ stem
cell selection and an alteration in immunoglobulin and T-cell recovery
after peritransplantation rituximab has been noted. We report the first
2 cases of progressive multifocal leukoencephalopathy caused by
JC papovavirus after autologous peripheral blood stem cell
transplantation and a case each of cytomegalovirus retinitis and
pneumonitis. All 4 patients experienced significant impairment of CD4
T-cell recovery, placing them at risk for these unusual viral
infections. The clustering of cases is concerning because all occurred
shortly after the introduction of peritransplantation rituximab into
treatment protocols (4 of 62 immunotherapy recipients compared
with 0 of 276 without; z = 3.595;
P < .001), although a direct association with this CD20
B-cell-directed therapy remains speculative.
(Blood. 2002;99:1486-1488)
© 2002 by The American Society of Hematology.
| |
Introduction |
Immune reconstitution after autologous stem cell
transplantation may be delayed by ex vivo cellular manipulations and/or
peritransplantation immunotherapies. Although an increase in early
viral infections, including cytomegaloviral (CMV) disease, has been
noted after CD34-selected autografting, little is known about the late
infectious consequences of stem cell selection.1-3
Rituximab (Genentech, South San Francisco, CA; IDEC Pharmaceuticals,
San Diego, CA), a monoclonal antibody directed against
CD20+ cells, is being investigated as an in vivo purging
agent before stem cell collection and may have a role in the treatment
of minimal residual disease after transplantation.4 The
immunologic effects and infectious complications related to rituximab
in the peritransplantation setting, or even when used in conjunction
with standard dose chemotherapy, also remain unclear.
We recently observed 2 cases of progressive multifocal
leukoencephalopathy and a case each of CMV retinitis and pneumonitis occurring in lymphoma patients 9, 20, 5, and 12 months after undergoing autologous peripheral blood stem cell (PBSC) transplantation. These
cases represent our first experiences with JC papovavirus after
transplantation and CMV retinitis/pneumonitis postautologous transplantation. All occurred after the introduction of
peritransplantation rituximab into our treatment protocols. Since 1991 we have treated 338 adult lymphoma patients with a conditioning regimen
consisting of high-dose carmustine 600 mg/m2, etoposide
1600 mg/m2, cytarabine 24 g/m2, and
cyclophosphamide 90 mg/kg (BVAC). The 4 cases of viral infection occurred among the 62 patients receiving peritransplantation rituximab (6.4%) compared with no cases among the 276 not receiving
immunotherapy (z = 3.595; P < .001).
| |
Study design |
A 34-year-old woman presented in January 1999 with stage
IIB mediastinal thymic B-cell non-Hodgkin lymphoma. She was treated with CHOP (cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone) chemotherapy and consolidative radiotherapy. In October 1999 she experienced a widespread relapse that involved the lungs, pericardium, bone, spleen, kidneys, liver, and adrenal glands. She
received debulking chemotherapy with one cycle of DICE (dexamethasone, ifosfamide, carboplatin, and etoposide) and one cycle of DICEP (dose-intensive cyclophosphamide, etoposide, and cisplatin). In December 1999 she received high-dose chemotherapy with BVAC rescued by
an infusion of 3.62 × 106 CD34 cells/kg unmanipulated,
cryopreserved autologous PBSCs. Hematopoietic engraftment, facilitated
by filgrastim, with a neutrophil count above 500/µL occurred on day
21 after transplantation. Subsequently, she received 4 weekly cycles of
rituximab 375 mg/m2. In August 2000 (9 months after
transplantation), while still in remission, she developed right
upper-extremity weakness. Evaluation for thromboembolic disease was
negative. Over the next several months her neurologic status
deteriorated with the development of a right hemiparesis, ataxia, and
dysarthria. Magnetic resonance imaging in late September 2000 revealed
areas of white matter disease consistent with a demyelinating process.
Polymerase chain reaction analysis of spinal fluid in October 2000 confirmed JC viral DNA. She was HIV negative. Her total lymphocyte
count was 216/µL with 89/µL CD4+ and 41/µL
CD8+ cells. Peripheral B cells included decreased
CD19+ (4/µL) and CD20+ cells (4/µL) as well
as CD56+ cells (97/µL). Quantitative serum
immunoglobulins revealed an immunoglobulin (Ig)G of 627 mg/dL, IgA 58 mg/dL, and IgM 19 mg/dL. Despite treatment with continuous infusion
interleukin 2 and intermittent cidovir she died in March 2001.
A 42-year-old woman presented in January 1992 with a stage III marginal
zone non-Hodgkin lymphoma. She received CVP (cyclophosphamide, vincristine, and prednisone) chemotherapy and entered remission. Her
first relapse in December 1995 responded again to CVP, which was
changed to C-MOPP (cyclophosphamide, mechlorethamine, vincristine, procarbazine, and prednisone) in June 1996. A second relapse in a
para-aortic node in August 1998 was treated with 2 cycles of DICE and
concurrent rituximab 375 mg/m2. In January 1999 she
underwent high-dose chemotherapy with BVAC and was rescued with
0.91 × 106/kg CD34 selected (Isolex 300i, Nexell
Therapeutics, Irvine, CA) autologous PBSCs. Neutrophil recovery
facilitated by filgrastim occurred on day 11. She received 2 additional
cycles of rituximab during the second posttransplantation month. Her
posttransplantation course was complicated by cyclophosphamide-induced
cardiomyopathy in April 1999, Clostridium difficile colitis
in September 1999, and varicella zoster dermal infection in March 2000. In August 2000 (20 months after transplantation), while still in
complete remission, she noted visual changes and right-sided ataxia.
Magnetic resonance imaging confirmed white matter disease and
polymerase chain reaction of the spinal fluid revealed JC viral DNA.
Laboratory studies in October 2000 revealed depressed quantitative
immunoglobulins with an IgG of 163 mg/dL, IgA of 17 mg/dL, and IgM 2 of
mg/dL. Peripheral blood analysis in December 2000 revealed
lymphocytosis (3934/µL), but depressed CD4+ (551/µL)
with elevated CD8+ (2596/µL) and normal CD19+
(315/µL) and CD20+ (315/µL) counts. HIV serologies were
negative. Without therapy she has made slow recovery, although she
remains with significant muscular weakness and left visual field
defects. Immunologic studies in June 2001 (30 months after
transplantation) continued to reveal low CD4+ (462/µL)
and elevated CD8+ (1437/µL) cells with IgG of 866 mg/dL.
A 42-year-old man with diffuse large cell, B-cell non-Hodgkin lymphoma
stage IIB involving Waldeyer ring received CHOP plus consolidative
radiotherapy. Four years later he experienced a left supraclavicular
relapse that responded to DICE salvage therapy. Subsequently, he
underwent BVAC autologous CD34 selected (2.91 × 106
cells/kg) PBSC transplantation. Neutrophil engraftment occurred on day 13. He received 2 cycles of rituximab before and 2 cycles after
transplantation. His posttransplantation course was complicated by bischloroethylnitrosourea pneumonitis requiring steroid therapy. In
May 2000 (5 months after transplantation and 2 months into steroid
therapy) he noted visual changes. Ophthalmologic evaluation revealed
CMV retinitis. He was lymphopenic (1200/µL) with a CD4 count of
12/µL and CD8 count of 420/µL, suppressed IgG 365 mg/dL, IgM
29 mg/dL, and low-normal IgA 70 mg/dL. HIV serologies were negative.
A 66-year-old man with diffuse large cell, B cell non-Hodgkin lymphoma
stage IVB achieved a partial response to 6 cycles of CHOP chemotherapy.
He received rituximab 375 mg/m2 twice followed by DICE
salvage therapy. Subsequently, in February 1999 he underwent BVAC
autologous PBSC transplantation (2.62 × 106 CD34
cells/kg unmanipulated) and achieved neutrophil engraftment on day 20. Six months after transplantation he developed a perirectal abscess with
varicella zoster, requiring prolonged antiviral therapy. Ten months
after transplantation he developed profound thrombocytopenia. Staging
studies failed to demonstrate lymphoma recurrence, and bone marrow
immunophenotyping revealed 7% lymphoid cells with 0% CD19, 1% CD20,
21% CD4, and 6% CD8 cells. The thrombocytopenia was subsequently
refractory to prednisone 1 mg/kg, intravenous immunoglobulin,
azathioprine, and staph A column, and during treatment (1 year after
transplantation) he developed dyspnea and confusion and suddenly died.
At autopsy he was found to have CMV pneumonitis and multiple cerebral hemorrhages.
Approval for these studies was obtained from the Hackensack University
Medical Center's institutional review board. Informed consent was
provided according to the Declaration of Helsinki.
| |
Results and discussion |
Progressive multifocal leukoencephalopathy (PML) is an uncommon
demyelinating disease of the central nervous system caused by JC
papovavirus. Primary JC viral infection during childhood, which occurs
in 75% of the population, results in lifelong viral latency in the
kidneys and B-cell lymphocytes.5 Clinical disease is
hypothesized to occur when infected B cells become activated during
periods of immunosuppression and subsequently enter the brain, where
astrocytes and oligodendrocytes support JC virus replication that
result in neurologic damage.6 Inflammatory responses to
the JC virus by T cells within PML lesions are associated with
transient stabilization of symptoms.7 Death within 6 months is common. JC viral reactivation is typically observed among
patients with severe immunodeficiency states such as a general
impairment of Th1-type T-helper function.8 In the HIV
population, PML is strongly correlated with depressed CD4+
lymphocyte counts.9 Rare cases of PML have been reported
among patients with lymphoma.10-12 Although urinary
excretion of the related BK polyomavirus is common after blood and
marrow transplantation, less than 10 cases of PML have been noted after
allogeneic bone marrow transplantation,13,14 autologous
bone marrow transplantation,15-18 and autologous purged
marrow transplantation.19 Our cases represent the first
reports after autologous PBSC transplantation.
CMV is a well-described infection among allogeneic transplantation
recipients and individuals with T-cell deficiencies. Although viral
reactivation occurs with similar frequencies after allogeneic and
autologous transplantation, clinical disease occurs in only 2% to 8%
of autologous marrow recipients.20,21 A comparative study
noted an increased odds ratio of 17.0 of CMV disease among recipients
of CD34-selected peripheral blood stem cells (7 of 31 patients) versus
recipients of unselected peripheral blood stem cell support (10 of 237 patients).3 Clinical disease after hematopoietic stem cell
transplantation typically involves a pattern of early (first 3 months)
pneumonitis and enteritis (including all 17 patients in the above
study) rather than retinitis that is more common among patients with
HIV disease and severe T-cell deficiencies.22
The failure of our patients to obtain late immunologic reconstitution
after autologous PBSC transplantation in the absence of relapse or
other clinical problems is unusual. T-cell CD3+
repopulation typically occurs by 2 to 4 months. Low CD4/CD8 ratios, related to both low numbers of CD4+ and elevated
CD8+ with low levels of naive CD4+ CD45RA cells
may exist during the first 6 months but return to baseline by 1 year.
T-cell function, as measured by mitogen studies and mixed lymphocyte
reactions, returns to baseline by 1 year.23 Even the
introduction of CD34+ selection techniques to reduce
potential tumor contamination does not greatly influence long-term
immunologic reconstitution after PBSC infusions, with no significant
differences in the kinetics of CD4+, CD8+,
CD45RA+, and CD45RO+ cells.24,25
CD19+ B-cell numbers return to baseline within 3 months,
but in vivo function measured by immunoglobulin levels typically
requires more than 6 months after both selected and unselected infusions.
CD20, the target of rituximab, is expressed on virtually all mature
peripheral blood and lymphoid tissue B cells, but not by resting or
activated T cells, monocytes, or granulocytes; thus, T-cell recovery in
the setting of peritransplantation rituximab might be suspected to be
unaffected.26 However, preliminary studies have suggested
delayed immune reconstitution with the combination of rituximab and
CD34-selected transplantation. Among recipients of CD34-selected,
B-cell antibody-purged stem cell infusions receiving
posttransplantation rituximab, decreased IgG levels were noted in 10 of
20 patients at 6 months and 6 of 11 at 1 year. T-cell recovery was also
impaired with CD4 counts less than 200/µL observed in 12 of 20 patients at 6 months and in 4 of 11 at 1 year.27 A second
study of CD34-selected autographs with pretransplantation rituximab
noted 5 of 13 patients with T-helper counts less than 200/µL at 6 months, and 8 of 8 CMV-seropositive patients developing reactivation
CMV-DNA in blood at least once after transplantation.28
Our cases of PML and CMV disease suggest that the addition of
peritransplantation rituximab, which results in delayed T-cell
reconstitution after autografting, may have serious consequences for
late clinical infectious disease.
| |
Footnotes |
Submitted June 26, 2001; accepted October 5, 2001.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Stuart L. Goldberg, 20 Prospect Ave, Suite 400, Hackensack, NJ 07601; e-mail: sgoldberg{at}humed.com.
| |
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Top
Abstract
Introduction