1. Healthcare

From www.bloodjournal.org by guest on February 6, 2015. For personal use only.
CORRESPONDENCE
3244
Pure Red Cell Aplasia: Its Clinical Association and Treatment
To the Editor:
Lacy et all recently reported a series of 47 patients with pure red
cell aplasia (PRCA). The characteristics of their patients included a
high frequency (9/47 [19%]) of T-large granular lymphocyte leukemia (T-LGLL), the occurrence of clonal karyotypic aberrations in a
proportion of cases (4/47 [SS%]), and a good response to cyclophosphamide (13/25 [52%]). Although their report provides a number of
interesting findings on PRCA, there are still some unresolved issues.
TThe highfrequency of T-LGLL in theirseriesisintriguing.
LGLL is a relatively rare lymphoproliferative disorder in the West.
Furthermore,whereastheassociationbetweenPRCAandB-cell
chronic lymphocytic leukemia is better defined, PRCA
has been infrequentlyobserved in T-LGLL,withonlysporadic
cases beingdescribed.* On the other hand, the close association between T-LGLL
andPRCAhasbeenwelldescribedinboththeJapaneseand
Chinese.”Oshimi et a14 reported PRCA in 65% of their cases of TLGLL,whereaswefound
a frequency of12.5% in a series of 16
Chinese patients with PRCA.’ Therefore, the ethnic origin of the patients is an importantconsiderationindeterminingtherelationship
between PRCA and T-LGLL, because different clinicopathologic and
epidemiologic factorsmay be involved. It would therefore be important
to know the ethnic origin of the patients in the series of Lacy et al.’
Inthe series ofLacy et al,’ four patients were shown to have
cytogenetic abnormalities. The presence of clonal cytogenetic abnormalities predicted a poor response to treatment, leading to the postulation that these cases might in fact represent a form of myelodysplasia. The currently used diagnostic criteria for PRCA do not
distinguish between erythroid aplasia secondary to other systemic
diseases or as a result of an intrinsic clonal disorder of erythropoiesis,
although it is contentious if the latter should actually be classified
as PRCA. It is therefore important to separate these two categories
of PRCA, because immunosuppression will not only be ineffective
in clonal myelopoietic disorders but also may even accelerate transformation. It would be important for Lacy et all to provide adequate
follow-up data on these cases.
Lacy et al’ suggested that cyclophosphamide and cyclosporin were
among the most effective therapeutic agents for PRCA. However,
it is noteworthy that no follow-up information was given for some
of their cases in terms of the needand duration of maintenance
treatment, whether the patients could be taken off therapy, and the
relapse rate of these patients on and off treatment. Because PRCA
From www.bloodjournal.org by guest on February 6, 2015. For personal use only.
3245
CORRESPONDENCE
is a disease marked by relapses, the absence of this information
makes it difficult to judge the appropriate choice of treatment. Furthermore, no discussion on the relative merits of treatment with
cyclophosphamide and cyclosporin has been made in their report.
The use of cyclophosphamide, which is an alkylating agent, an immunosuppressant, and a known bladder carcinogen, is significantly
related to the subsequent development of malignancies, particularly
This increased risk had been shown to
those of urothelial
persist up to 17 years after cessation of treatment. Cyclosporin has
also been shown to increase the incidence of secondary malignancies.* This is thought to be related to the immunosuppressive effect
rather than an intrinsic mutagenic property of the drug.' The safety
of both forms of treatment will need to becompared, but physicians
should be aware of these complications. Finally, whether the concomitant presence of T-LGLL predicted a good response of PRCA
to treatment might be related to how well the leukemia was controlled. It is important to know whether the patients with T-LGLLassociated PRCA had received concomitant antileukemic therapy.
Recently, we have seen two patients with T-LGLL complicated by
PRCA (unpublished observation). Treatment with antithymocyte
globulin resulted in adequate control of the T-LGLL and, hence,
remission of the PRCA in one patient, whereas the other patient was
refractory to all types of treatment for the T-LGLL and remained
transfusion-dependent from the PRCA.
K.F. Wong
Depament of Pathology
Queen Elizabeth Hospital
Hong Kong
Y.L. Kwong
Department of Medicine
Queen Mary Hospital
Hong Kong
REFERENCES
1. Lacy MQ, Kurtin PJ, Tefferi A: Pure red cell aplasia: Associa-
tion with large granular lymphocyte leukemia andthe prognostic
value of cytogenetic abnormalities. Blood 87:3000, 1996
2. Loughran TP Jr: Clonal diseases of large granular lymphocytes.
Blood 82:1, 1993
3. Kwong YL, Wong KF, Chan LC, Liang RHS, Chan JKC, Lin
CK, Chan TK: Large granular lymphocyte leukemia-A study of
nine cases in a Chinese population. Am J Clin Pathol 103:76, 1995
4. Oshimi K, Yamada 0, Kaneko T, Hishinarita S, Iizuka Y,
Urabe A, Inamori T, Asano S, Takahashi S, Hattori M, Naohara T,
Ohira Y, Togawa A, Masuda Y, Okubo Y, Furusawa S, Sakamoto
S, Omine M, Mori M, Tatsumi E, Mizoguchi H: Laboratory findings
and clinical courses of 33 patients with granular lymphocyte-proliferative disorders. Leukemia 7:782, 1993
5. Kwong YL, Wong KF, Liang RHS, Chu YC, Chan LC, Chan
TK: Pure red cell aplasia: Clinicopathologic features and treatment
results of 16 cases. Ann Hematol 72:137, 1996
6. Radis CD, Kahl LE, Baker GL, Wasko MC, Cash JM, Gallatin
A, Stolzer BL, Aganval AK, Medsger TA Jr, Kwoh CK: Effects of
cyclophosphamide on the development of malignancies and on long
term survival of patients with rheumatoid arthritis. A 20-year follow
up study. Arthritis Rheumatol 38:1120, 1995
7. Travis LB, Curtis RE, Glimelius B, Holowaty ET, Van Ieeuwen
FE, Lynch CF. Hagenbeek A, Stovall M, Banks PM, Adami J:
Bladder and kidney cancer following cyclophosphamide therapy for
non-Hodgkin's lymphoma. J Natl Cancer Inst 87:524, 1995
8. Gaya SB, Rees AJ, Lechler RI, Williams G, Mason PD: Malignant diseases in patients with long-term renal transplants. Transplantation 59:1705, 1995
9. Ryffel B, Mihatsch MJ, Fisher GL: Immunosuppression and
cancer: The cyclosporin case. Drug Chem Toxicol 15:95, 1992
Response: Pure Red Blood Cell Aplasia: AssociationWith Large Granular Lymphocyte Leukemia andthe
Prognostic Value of Cytogenetic Abnormalities
We appreciate the letter by Wong and Kwong regardingour recent
report on PRCA.' We reported on a series of 47 patients with PRCA
and more than 90% of these patients were white. It should be noted
that T-cell receptor gene rearrangement studies were performed in
only 14 of the 47 patients and that the reported overall frequency of
19% maybe an underestimation. In two previous reports, we described
68 patients with T-cell LGL disorder and 10 patients with chronic
natural killer cell lymphocytosis identified at our Institution over a
IO-year
The overall incidence of these disorders is increasing
at both our institution and other centers because of increased awareness. Therefore, LGL disorders may not be as rare as suggested.
We agree that the current diagnostic criteria do not distinguish
clonal PRCA as a separate entity. Additional studies are necessary
to confirm our observation regarding patients with PRCA and detectable clonal cytogenetic abnormalities. As stated in our previous report, none of the four patients with PRCA and cytogenetic abnormalities responded to immunosuppressive therapy including prednisone,
oral cyclophosphamide, antithymocyte globulin, and cyclosporine
A.' One of these patients developed pathologically evident refractory
anemia with excess blasts after a follow-up period of 18 months.
This was manifest by peripheral blood leukopenia and 3%circulating
blasts. The bone marrow showed substantial dysmegakaryopoiesis
and excess blasts. The second patient died of bacterial pneumonia
at 19 months from the diagnosis of PRCA. The third patient is now
3 years from diagnosis and still requires blood transfusions. We
were unable to obtain a follow-up on the fourth patient, who was
from another country.
All of the patients treated with cyclophosphamide or cyclosporine
had prompt responses in 1 to 3 months. In the majority of these
cases, the drugs were tapered and an effort was made to discontinue
treatment after 3 to 6 months of therapy. In general, patients who
were tapered offthe cyclosporine relapsed in 1 to 2 months and
required ongoing maintenance therapy. However, unmaintained remissions were noted in some patients treated with cyclophosphamide, but late relapses have been frequent.
We agree with Wong and Kwong that long-term complications
from cyclophosphamide and cyclosporine should be discussed with
the patients and, as is true with every situation, the risks and benefits
have to be weighed in deciding particular forms of therapy. Currently, our treatment of PRCA is similar to our treatment of symptomatic patients with T-LGL leukemia? Therefore, none of our patients received additional antileukemic therapy other than
corticosteroids and/or oral cyclophosphamide.
Ayalew Tefferi
Martha Q. Lacy
Paul J. Kurtin
Mayo Clinic/Foundation
Rochester, M N
REFERENCES
1. Lacy M, Kurtin PJ, Tefferi A: Pure red cell aplasia: Association
with large granular lymphocytic leukemia and the prognostic role
of cytogenetic abnormalities. Blood 87:3000, 1996
From www.bloodjournal.org by guest on February 6, 2015. For personal use only.
3246
2. Dhodapkar MV, Li CY, Lust JA, Tefferi A, Phyliky R L Clinicalspectrum of CD3(+) clonallargegranularlymphocyte (LGL)
proliferations. Blood 84:1620, 1994
CORRESPONDENCE
3. Tefferi A, Li CY, Witzig TE, Dhodapkar MV, Okuno SH,
Phyliky F&: Chronic natural killer cell lymphocytosis: A descriptive
clinical study. Blood 84:2721, 1994
From www.bloodjournal.org by guest on February 6, 2015. For personal use only.
1996 88: 3245-3246
Response: pure red blood cell aplasia: association with large
granular lymphocyte leukemia and the prognostic value of
cytogenetic abnormalities [letter]
A Tefferi, MQ Lacy and PJ Kurtin
Updated information and services can be found at:
http://www.bloodjournal.org/content/88/8/3245.citation.full.html
Articles on similar topics can be found in the following Blood collections
Information about reproducing this article in parts or in its entirety may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests
Information about ordering reprints may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#reprints
Information about subscriptions and ASH membership may be found online at:
http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American
Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.