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`Vol. 333 No. 9
`
`CORRESPONDENCE
`
`595
`
`CORRESPONDENCE
`
`ADDITIONAL CORRECTIONS: INTERFERON FOR
`HEMANGIOMAS OF INFANCY
`
`To the Editor: Inaccuracies in our paper “Interferon Alfa-2a
`
`Therapy for Life-Threatening Hemangiomas of Infancy”
`1
`prompted a careful review. On the basis of our reanalysis and
`an interim review by a standing faculty committee of the Har-
`vard Medical School, we submitted a revised Table 1, pub-
`lished as a correction notice.
` The final review of this commit-
`2
`tee concluded that ambiguities in method, presentation, and
`conclusions should be clarified and that errors remained that
`should be corrected.
`In our original description of the assessment of outcomes,
`we never stated that lesions were measured; however, the use
`of the terms “dimensions” in the Methods section and “per-
`centages” in the Methods section and the table could have
`implied a quantitative method. It is not possible to quantify
`precisely the tumors we were describing, because of their het-
`erogeneity in size, shape, and anatomical location. Therefore,
`the Methods section should have read: “Premature regression
`was defined as an obvious decrease of 50 percent or more in
`the
` [not
`] of the hemangioma.” We estimated
`size
`dimensions
`the percent change by comparing pretreatment photographs,
`radiographs, or endoscopic examinations with those obtained
`after treatment; the assessment was adjusted according to
`clinical status for most patients. We used the combination of
`methods appropriate for each patient but did not weight the
`contributions of each method formally. For example, in Pa-
`tient 2, who had Kasabach–Merritt syndrome, 70 percent re-
`gression was estimated subjectively on the basis of the reduc-
`tion in the size of the lesion as shown by photography, the
`
`diminished turgor of the lesion, and reversal of coagulopathy.
`In Patient 14, 60 percent regression was estimated subjective-
`ly on the basis of the 100 percent regression of the airway le-
`sion shown by endoscopy and magnetic resonance imaging
`(MRI), modified because of residual mediastinal disease (seen
`on MRI) and the patient’s clinical status. For clarification, we
`now include a table showing the methods used to estimate the
`response in each patient (Table 1).
`In all patients, the period of assessment began at the start
`of interferon treatment. In the Methods section of our paper,
`we stated incorrectly, “Premature regression . . . was sus-
`tained for at least six months during treatment or after the
`withdrawal of the medication.”
` To clarify: Patients 8, 16, 19,
`1
`and 20 required less than 6 months of treatment; they were
`assessed at 3 months, 3 months, 4 months, and 5.25 months,
`respectively. Follow-up procedures were not performed if they
`required general anesthesia and were not clinically indicated
`— i.e., MRI was not performed for Patients 4 and 20, and en-
`doscopy was not performed for Patient 8. Clinical assess-
`ments alone were used, in these instances, to document sus-
`tained regression.
`We also stated incorrectly in the Methods section, “To be
`eligible for the study, infants had to have a life-threatening or
`vision-threatening hemangioma that failed to respond to a
`two-week course of corticosteroid therapy. . . .”
` Therapeu-
`1
`tic doses of corticosteroids were given before interferon ther-
`apy to 15 patients, for one month during interferon therapy to
`Patient 1, and for seven weeks during interferon therapy to
`Patient 12.
` Patient 1 died and Patient 12’s hemangioma grew
`2
`while she was receiving both drugs. Patients 3 and 14 began
`receiving interferon after 12 days of corticosteroids, not 14
`days, because of their worsening conditions. Interferon alone
`was given to Patients 10, 13, and 16.
` In 15 patients for whom
`2
`corticosteroids failed, interferon was initiated during the pe-
`riod when the dose of corticosteroid was being tapered, since
`it was not considered safe to discontinue the latter abruptly.
`We stated incorrectly in the Methods section, “A complete
`blood count and tests of hepatic . . . function were per-
`formed monthly.” We were unable to obtain monthly labora-
`tory studies for 18 patients; therefore, we cannot reach any
`conclusions about toxic effects. We must add to the record,
`
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`Taro Pharmaceuticals, Ltd.
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`596
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`Aug. 31, 1995
`
`induced amenorrhea is associated with a 40 percent reduction
`in the rate of relapse, the analysis carried out by Bonadonna
`et al. in 78 patients had a power lower than 40 percent.
`The authors’ statement that “drug-induced amenorrhea is
`not an important predictor of response” contradicts almost
`all published studies and is not supported by their own data
`— which, incidentally, show a 22 percent reduction in the risk
`of relapse at 20 years. Nine of 10 published studies, some of
`them large,
` reported longer periods of relapse-free survival
`2-5
`in patients with drug-induced amenorrhea than in those with-
`out it. The difference was statistically significant in eight
`studies. In one of these studies, the prognostic role of drug-
`induced amenorrhea was also confirmed in terms of overall
`survival.
`4
`Although these findings do not necessarily imply that the
`main effect of chemotherapy in premenopausal patients is due
`to chemical castration, they do indicate that the predictive
`role of drug-induced amenorrhea should not be denied.
` D
` M
`, M.D.
`L
`ASTRO
`EL
`UCIA
`M
` C
`, M.D.
`OSTANTINI
`ASSIMO
`Istituto Nazionale per la
`Ricerca sul Cancro
`A
` B
`, M.D.
` R
`IANCO
`AFFAELE
`NGELO
`University of Naples Medical School
`
`80131 Naples, Italy
`
`16132 Genoa, Italy
`
`1. Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant
`cyclophosphamide, methotrexate, and fluorouracil in node-positive breast
`cancer — the results of 20 years of follow-up. N Engl J Med 1995;332:901-6.
`2. Bianco AR, Del Mastro L, Gallo C, et al. Prognostic role of amenorrhea in-
`duced by adjuvant chemotherapy in premenopausal patients with early breast
`cancer. Br J Cancer 1991;63:799-803.
`3. Goldhirsch A, Gelber RD, Castiglione M. The magnitude of endocrine effects
`of adjuvant chemotherapy for premenopausal breast cancer patients. Ann On-
`col 1990;1:183-8.
`4. Tormey DC, Gray R, Abeloff MD, et al. Adjuvant therapy with a doxorubicin
`regimen and long-term tamoxifen in premenopausal breast cancer patients:
`an Eastern Cooperative Oncology Group trial. J Clin Oncol 1992;10:1848-
`56.
`5. Ludwig Breast Cancer Study Group. A randomized trial of adjuvant combi-
`nation chemotherapy with or without prednisone in premenopausal breast
`cancer patients with metastases in one to three axillary lymph nodes. Cancer
`Res 1985;45:4454-9.
`
`To the Editor: The article by Bonadonna and colleagues is a
`
`welcome addition, since it involves a relatively long follow-up.
`I was confused, however, by two things in this article. The au-
`thors state that “48 of 179 patients in the control group were
`disease-free at 20 years,” yet only 44 of 179 patients in the
`control group were even alive at 20 years. Also, the authors
`discuss the “ease of administration and the virtual absence of
`severe acute toxicity” in relation to the chemotherapy regimen
`administered, yet only 42 of the 207 patients in the chemo-
`therapy group received at least 85 percent of the planned
`dosages.
`
`Wilmington, OH 45177
`
`M
`
`, M.D.
` D. N
`EWMAN
`ICHAEL
`Clinton Memorial Hospital
`
`To the Editor: In his editorial on breast-sparing surgery for
`
`breast cancer (April 6 issue),
` Henderson says, “Local failure
`1
`is a particularly difficult consequence of therapy for most pa-
`tients because it is readily apparent and is thus a constant re-
`minder that the tumor is no longer curable.” This is incorrect.
`In 1991, the National Surgical Adjuvant Breast and Bowel
`Project concluded that local failure is curable, saying that “lo-
`cal recurrence is a marker of risk for, not a cause of, distant
` Besides the studies cited by Henderson, other
`metastases.”
`2
`studies with 10 years of follow-up have supported this conclu-
`
`Table 1. Methods Used to Assess Outcomes of Interferon Alfa
`Treatment.
`*
`
`P
`
`HOTOGRAPHY
`
`MRI
`
`CT
`
`US
`
`E
`
`NDOSCOPY
`
`HEM
`
`C
`LINICAL
`S
`TATUS
`
`XXX
`
`XXXXXXXXXX
`
`XXX
`
`XX
`
`XXXX
`
`X X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`XX
`
`X X
`
`XXX
`
`X X
`
`XXX
`
`XXX
`
`
`C
`AND
`ONDITION
`P
` N
`.
`O
`ATIENT
`
`Coagulopathy
`
`1234
`
`Cervicofacial
`
`56789
`
`10
`11
`12
`13
`14
`Periorbital
`15
`16
`17
`Visceral
`18
`19
`20
`
`*CT denotes computed tomography, US ultrasonography, and HEM the evaluation of coag-
`ulopathy. Clinical status denotes the turgor and color in Patients 1, 2, 3, 10, 11, 15, and 16; the
`airway opening in Patients 5, 6, 7, 8, 9, 10, 13, and 14; improved cardiac status in Patients 6,
`12, 18, and 19; and decreased ulceration in Patients 7 and 17. Patient 13 was originally given
`a diagnosis of hemangioma on the basis of MRI; the oral lesions improved, whereas the skin
`lesions persisted, and a biopsy of the latter showed venous malformation (January 1993).
`
`however, that four patients, not one, had transient neutrope-
`nia, and eight patients had liver aminotransferase levels two
`to five times their pretreatment levels. Patient 15 was hyper-
`active for one day after receiving a gradually escalated dose
`of interferon to 6 million units per square meter of body-sur-
`face area. Furthermore, Patient 14 missed 13 doses of inter-
`feron during six months of therapy.
`We are embarrassed by our errors and regret them. We
`apologize to the readers for any misunderstanding and thank
`our colleagues for their assistance in correcting our report.
`A
`.
` E
`, M.B., C
`.B., D.P
`HIL
`H
`J
` M
`, M.D.
`OHN
`ULLIKEN
`J
` F
`, M.D.
`UDAH
`OLKMAN
`Children’s Hospital
`
`LAN
`
`ZEKOWITZ
`
`Boston, MA 02115
`
`1. Ezekowitz RAB, Mulliken JB, Folkman J. Interferon alfa-2a therapy for life-
`threatening hemangiomas of infancy. N Engl J Med 1992;326:1456-63.
`2. Correction to: Interferon alfa-2a therapy for life-threatening hemangiomas of
`infancy. N Engl J Med 1994;330:300.
`
`ADJUVANT CHEMOTHERAPY IN BREAST CANCER
`
`To the Editor: Bonadonna et al. (April 6 issue)
` addressed
`1
`the effect of drug-induced amenorrhea on the outcomes of
`78 premenopausal patients treated with cyclophosphamide,
`methotrexate, and fluorouracil (CMF) (Table 2 of the article).
`In 50 patients who had drug-induced amenorrhea and in 28
`patients who did not, the rates of 20-year relapse-free survival
`were 39 percent and 30 percent, respectively. The authors
`concluded that there was no significant difference in relapse-
`free survival between these two groups. We estimated the
`hazard ratio for relapse-free survival between women with
`drug-induced amenorrhea and those without it from 10 pub-
`lished studies. The hazard ratio ranged from 0.39 to 0.86,
`with a median of 0.56. Therefore, if we assume that drug-
`
`The New England Journal of Medicine
`Downloaded from nejm.org on April 18, 2017. For personal use only. No other uses without permission.
` Copyright © 1995 Massachusetts Medical Society. All rights reserved.
`
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`2 of 8
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`Taro Pharmaceuticals, Ltd.
`Exhibit 1034
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`Vol. 333 No. 9
`
`CORRESPONDENCE
`
`597
`
` No reliable data support a contrary conclusion. In the
`sion.
`3,4
`study by Jacobson et al. (also in the April 6 issue),
` recurrent
`5
`disease confined to the ipsilateral breast developed in 19 pa-
`tients, who were treated with salvage mastectomy. The pro-
`jected rate of disease-free survival at 10 years is 67 percent.
`This is not significantly different from that of all the women
`initially treated with lumpectomy and radiation therapy. I
`found no data in Stablein’s reanalysis of National Surgical
`Adjuvant Breast and Bowel Project Protocol B-06 suggesting
`that lumpectomy compromised survival.
` But that trial did
`6
`not record the size of each recurrent tumor. Clearly, a recur-
`rent tumor that exceeds the size of the primary lesion be-
`comes an added survival threat. How does Henderson con-
`clude that local failure is incurable?
`R
`
`, M.D.
` A. E
`VANS
`1011 Augusta Dr.
`Houston, TX 77057-2015
`1. Henderson IC. Paradigmatic shifts in the management of breast cancer.
`N Engl J Med 1995;332:951-2.
`2. Fisher B, Anderson S, Fisher ER, et al. Significance of ipsilateral breast tumor
`recurrence after lumpectomy. Lancet 1991;338:327-31.
`3. Crile G Jr, Esselstyn CB Jr. Factors influencing local recurrence of cancer af-
`ter partial mastectomy. Cleve Clin J Med 1990;57:143-6.
`4. Nemoto T, Patel JK, Rosner D, Dao TL, Schuh M, Penetrante R. Factors af-
`fecting recurrence in lumpectomy without irradiation for breast cancer. Can-
`cer 1991;67:2079-82.
`5. Jacobson JA, Danforth DN, Cowan KH, et al. Ten-year results of a compari-
`son of conservation with mastectomy in the treatment of stage I and II breast
`cancer. N Engl J Med 1995;332:907-11.
`6. Stablein DM. Reanalysis of NSABP Protocol B06. Cancer-Fax News from
`the National Cancer Institute. ID #400027. Potomac, Md.: EMMES Corpora-
`tion, March 1, 1995.
`
`ICHARD
`
`The authors reply:
`
`To the Editor: Del Mastro et al. attempt to reintroduce the
`concept of a “prognostic” role for drug-induced amenorrhea
`following adjuvant chemotherapy in premenopausal women.
`Amenorrhea depends on the patient’s age and the total dose
`of alkylating agents. Before this side effect begins, patients
`are at risk for relapse while still menstruating. There are a
`few techniques for taking this problem into account. In our
`medical records we reported the date of the last menstrual
`period for every patient; we therefore used a time-dependent
`model to analyze our data.
` Although we had a limited num-
`1
`ber of patients, in this model the relative risk of relapse for
`women in whom amenorrhea developed was 0.87 (95 percent
`⫽
`confidence interval, 0.48 to 1.51; P
`0.65). We emphasize
`that in contrast to other studies in which amenorrhea was
`found to be a favorable prognostic factor, our protocol involved
`CMF chemotherapy alone — that is, without the addition of ta-
`moxifen, prednisone, or fluoxymesterone (Halotestin).
`2,3
`To answer Dr. Newman: we made clear in the Methods
`section, as well as at the bottom of Table 1, that in the anal-
`ysis of relapse-free survival second malignant conditions
`other than contralateral breast cancer and deaths due to oth-
`er causes were not considered events. At 20 years, 125 of the
`179 patients in the control group have died of progressive
`breast cancer, 10 have died of other causes, 6 are alive with
`breast cancer, and 38 are alive and free of disease. Adjuvant
`CMF chemotherapy was indeed easy to administer, it was al-
`ways given on an outpatient basis, and it was devoid of life-
`threatening toxicity. Acute hematologic and nonhematologic
`toxic effects were always mild to moderate and reversible.
`We have detailed the reasons why only a minority of our pa-
`tients received the optimal dose of CMF
` — among them,
`4
`that drug doses were calculated on the basis of ideal rather
`than actual body surface, that low starting doses of chemo-
`therapy were used in women over 60 years of age, that some
`patients refused to complete the planned treatment cycles
`
`for psychological reasons, and that doses were adjusted down-
`ward to avert side effects.
`
`20133 Milan, Italy
`
`G
`, M.D.
` B
`ONADONNA
`IANNI
` V
`, B.S.
`P
`ALAGUSSA
`INUCCIA
`Istituto Nazionale per lo Studio
` e la Cura dei Tumori
`
`1. Cox DR. Regression models and life-tables. J R Stat Soc [B] 1972;34:187-
`220.
`2. Bianco AR, Del Mastro L, Gallo C, et al. Prognostic role of amenorrhea in-
`duced by adjuvant chemotherapy in premenopausal patients with early breast
`cancer. Br J Cancer 1991;63:799-803.
`3. Tormey DC, Gray R, Abeloff MD, et al. Adjuvant therapy with a doxorubicin
`regimen and long-term tamoxifen in premenopausal breast cancer patients: an
`Eastern Cooperative Oncology Group trial. J Clin Oncol 1992;10:1848-56.
`4. Bonadonna G, Valagussa P. Dose-response effect of adjuvant chemotherapy
`in breast cancer. N Engl J Med 1981;304:10-5.
`
`To the Editor: Dr. Evans contests the point that a local or re-
`
`gional recurrence in skin, lymph nodes, or muscle has the
`same prognostic effect on survival as recurrence at a distant
`site. I believe that confusion regarding this point, as with so
`many other issues of contention concerning breast cancer,
`arises from the relation between treatment and outcome. It is
`true that some patients with local recurrences have long sur-
`vival times after treatment with surgery, radiotherapy, or
`both; the duration of survival can be decades. This is also true
`for some patients with distant recurrences. The critical ques-
`tions are whether there is a relation between the treatment
`and the survival and whether any patient with recurrent dis-
`ease is “curable.”
`There is marked variation in the behavior of breast can-
`cers. The disease may recur within a few months or up to 40
`years after the first treatment. Similarly, survival after recur-
`rence may vary from a few months to several decades. There-
`fore, an individual physician may treat a few patients who do
`well by chance alone and conclude that the treatment causes
`the good outcome. However, such claims based on a small
`number of patients have been refuted by properly controlled
`trials. It is in this context that the observations on the use of
`screening mammography followed by mastectomy and those
`on mastectomy or radiotherapy or both followed by adjuvant
`systemic therapy are so remarkable. No other interventions
`have been demonstrated to prolong survival to the same de-
`gree. Certainly there are no similar data for the treatment of
`recurrent breast cancer, including local recurrences.
`A new cancer found entirely within the breast after radio-
`therapy does not appear to behave like a local recurrence, but
`rather like a new cancer in the contralateral breast after mas-
`tectomy. If the new cancer is of the same stage or a lower one
`than the original cancer, the patient’s prognosis remains
`largely unchanged.
`1
`
`San Francisco, CA 94143
`
`I. C
`
`, M.D.
` H
`ENDERSON
`RAIG
`University of California,
`San Francisco
`
`1. Harris JR, Recht A, Amalric R, et al. Time course and prognosis of local re-
`currence following primary radiation therapy for early breast cancer. J Clin
`Oncol 1984;2:37-41.
`
`DEFERIPRONE IN IRON OVERLOAD
`
`To the Editor: Olivieri et al. (April 6 issue)
` are to be con-
`1
`gratulated on their work on deferiprone, which, in addition to
`demonstrating the drug’s efficacy in iron chelation, is the
`only study so far to have addressed some of the controversies
`surrounding the use of the drug.
`2-5
`Our experience with autoimmune phenomena has not been
`
`The New England Journal of Medicine
`Downloaded from nejm.org on April 18, 2017. For personal use only. No other uses without permission.
` Copyright © 1995 Massachusetts Medical Society. All rights reserved.
`
`
`3 of 8
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1034
`
`

`

`598
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`Aug. 31, 1995
`
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`confined to just one case of fatal drug-induced systemic lupus
`erythematosus.
` We have found a significantly higher in-
`2
`cidence of antinuclear antibodies in patients with thalasse-
`mia treated with deferiprone (7 of 27) than in those not re-
`ceiving the drug (2 of 63, P<0.01). Antibodies to histones
`were detected in four of the seven patients with antinuclear
`antibodies who were receiving deferiprone and in neither of
`the two not receiving the drug.
` In one patient, both types of
`6
`autoantibodies had disappeared five months after the discon-
`tinuation of treatment with deferiprone, and in another pa-
`tient, who had no antibodies to histones, antinuclear antibod-
`ies had disappeared four months after the discontinuation of
`treatment.
`6
`The disparity between our findings in Indian patients
`4,6
`and those in the patients described by Olivieri et al. is strik-
`ing. Deferiprone is an orphan drug that has to be manufac-
`tured locally for each group investigating it. Is it possible
`that a difference in the manufacturing process or final for-
`mulation of the drug accounts for the difference in the ad-
`verse reactions? This issue needs to be addressed, because
`deferiprone has recently been made commercially available
`for routine use in India. Careful post-marketing surveillance
`is essential, especially on the part of the Indian regulatory
`authorities, because in India the package insert for defer-
`iprone does not recommend immunologic investigations in
`the case of joint problems.
`
`Sutton, Surrey SM2 5PT,
`United Kingdom
`
`Bombay 400 056, India
`
`J. M
`, M.D.
`EHTA
`, M.D.
`S. S
`INGHAL
`Royal Marsden Hospital
`B.C. M
`, F.R.C.P., D.S
`.
`C
`EHTA
`Nanavati Hospital
`
`1. Olivieri NF, Brittenham GM, Matsui D, et al. Iron-chelation therapy with oral
`deferiprone in patients with thalassemia major. N Engl J Med 1995;332:918-
`22.
`2. Mehta J, Singhal S, Revankar R, Walvalkar A, Chablani A, Mehta BC. Fatal
`systemic lupus erythematosus in patient taking oral iron chelator L1. Lancet
`1991;337:298.
`3. Mehta J, Singhal S, Mehta BC. Oral iron chelator L1 and autoimmunity.
`Blood 1993;81:1970-2.
`Idem.
`Deaths in patients receiving oral iron chelator L1. Br J Haematol 1993;
`85:430-1.
`Idem.
` Future of oral iron chelator deferiprone (L1). Lancet 1993;341:80.
`5.
`6. Mehta J, Chablani A, Reporter R, Singhal S, Mehta BC. Autoantibodies in
`thalassaemia major: relationship with oral iron chelator L1. J Assoc Physi-
`cians India 1993;41:339-41.
`
`4.
`
`To the Editor: Oral deferiprone is a potentially important
`
`agent in the treatment of iron overload in patients with thal-
`assemia, but the toxic effects of the drug require further in-
`vestigation before it is recommended for general use. Defer-
`iprone had minimal side effects in the trial by Olivieri et al.;
`none of the 21 patients had neutropenia, and only 1 reported
`joint pain. A multicenter trial from India, however, reported
`that substantial proportions of the patients had joint pain
`(28.8 percent) and minor gastrointestinal problems (20 per-
`cent); neutropenia occurred in three patients (2.1 percent).
`1
`Similar findings were reported by Kontoghiorghes.
`2
`In a trial of oral deferiprone in 20 patients with thalasse-
`mia, my colleagues and I observed a rapid initial decrease in
`the serum ferritin level within 3 months after the start of ther-
`⫾
`⫾
`1611 to 1746
`1044 ng per milliliter), fol-
`apy (from 3355
`⫾
`⫾
`lowed by a gradual decrease (from 1746
`1044 to 1251
`1011
`ng per milliliter) over the next 12 months.
` Gastrointestinal
`3
`problems developed in 30 percent of the patients, joint pain
`in 30 percent, and neutropenia in one patient (5 percent). We
`have studied the response pattern for only 15 months. It is
`
`possible that shorter cycles of deferiprone therapy, rather
`than continuous administration, can improve compliance and
`reduce the incidence of toxic effects.
`D
`
`, M.B., B.S.
` A
`DHIKARI
`EBASIS
`Memorial Sloan-Kettering
` Cancer Center
`
`New York, NY 10021
`
`1. Agarwal MB, Adhikari D, Marwaha RK, Gogtay JA. Multicentre clinical
`studies with the oral iron chelator (deferiprone, L-1:Cipla Ltd) in transfusion
`dependent thalassaemia — the Indian experience. Presented at the Sixth In-
`ternational Conference on Oral Chelation in the Treatment of Thalassaemia
`and Other Diseases, Nijmegen, the Netherlands, January 27 and 28, 1995. ab-
`stract.
`2. Kontoghiorghes GJ. Update of worldwide iron chelation therapy with L-1
`(Deferiprone). Presented at the Sixth International Conference on Oral Che-
`lation in the Treatment of Thalassaemia and Other Diseases, Nijmegen, the
`Netherlands, January 27 and 28, 1995. abstract.
`3. Adhikari D, Basu Roy T, Chandra S, Adhikari SK. Analysis of fall in serum
`b
`ferritin after chelation of iron with deferiprone (L-1) in
`thalassaemia and
`b
`haemoglobin E
` thalassaemia. Curr Sci 1995;68:839-40.
`
`To the Editor: Nathan’s editorial on deferiprone (April 6 is-
`
`sue)
` refers to the use of the drug in a “London hospital with-
`1
`out sufficient studies of toxic effects in animals and without
`Hider’s approval.” These studies were carried out at the Roy-
`al Free Hospital with the approval of both the Department of
`Health and the Royal Free Ethical Committee.
` These phase
`2,3
`1 trials laid the foundation for all subsequent clinical studies
`of deferiprone throughout the world. The clinical side effects
`of idiosyncratic agranulocytosis, arthropathy, zinc deficiency,
`and nausea were all first described in these London studies
`and have recently been reviewed.
` The side effects of defer-
`4,5
`oxamine, like those of deferiprone, could not have been reli-
`ably predicted from animal studies.
`Nathan states that the frequency of agranulocytosis and
`arthropathy associated with deferiprone is not yet known. A
`substantial literature, based on observations in several hun-
`dred patients, reports on both these phenomena.
` The in-
`4,5
`cidence of agranulocytosis has been estimated at 1.6 per-
`cent, and the incidence of less severe neutropenia at 2.4
`percent. The incidence of joint symptoms has ranged from
`0 to 38.5 percent among trials, with an overall incidence of
`18 percent. The incidence of these side effects may well
`depend on the age, sex, and ethnic group of the patients;
`the type of bone marrow disease; the patients’ iron status;
`the dose of deferiprone given; and the period of exposure to
`the drug.
`
`6
`Nathan also states that deferiprone does not readily reduce
`excessive body iron stores “below a certain level.” This is also
`true of deferoxamine; in patients with thalassemia major re-
`ceiving long-term treatment with deferoxamine, iron stores
`are 5 to 10 times larger than normal.
`Nathan asks whether enough is known about the pharma-
`cologic properties of deferiprone. More studies could be un-
`dertaken, but there are already several detailed reports that
`have recently been reviewed.
` He suggests that deferiprone,
`7
`like desferithiocin, may cause renal side effects. However, no
`such effects have been reported in any of the patients receiv-
`ing long-term treatment with deferiprone. Finally, Nathan
`questions whether adolescents will swallow enough of the oral
`chelator to allow its appropriate use. Olivieri et al. have clear-
`ly shown that compliance with deferiprone therapy is far su-
`perior to that with deferoxamine.
`It is clear that not all patients will be able to tolerate defer-
`iprone. The side effects of nausea, arthropathy, and neutrope-
`nia or agranulocytosis have caused patients in all trials to dis-
`continue the drug. Nevertheless, for about 75 percent of the
`
`The New England Journal of Medicine
`Downloaded from nejm.org on April 18, 2017. For personal use only. No other uses without permission.
` Copyright © 1995 Massachusetts Medical Society. All rights reserved.
`
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`4 of 8
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`Taro Pharmaceuticals, Ltd.
`Exhibit 1034
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`Vol. 333 No. 9
`
`CORRESPONDENCE
`
`599
`
`patients in large studies, long-term compliance has been ex-
`cellent, and the drug is potentially life-saving for patients who
`cannot afford deferoxamine or comply with the required reg-
`imen or who are allergic to the drug.
`A.V. H
`.
`, D.M., D.S
`C
`OFFBRAND
`B. W
`, M.D.
`ONKE
`Royal Free Hospital
`London NW3 2QG,
`School of Medicine
`United Kingdom
`1. Nathan DG. An orally active iron chelator. N Engl J Med 1995;332:953-4.
`2. Kontoghiorghes GJ, Aldouri MA, Sheppard L, Hoffbrand AV. 1,2-Dimethyl-
`3-hydroxypyrid-4-one, an orally active chelator for treatment of iron over-
`load. Lancet 1987;1:1294-5.
`3. Kontoghiorghes GJ, Aldouri MA, Hoffbrand AV, et al. Effective chelation of
`iron in beta thalassaemia with the oral chelator 1,2-dimethyl-3-hydroxypyrid-
`4-one. BMJ 1987;295:1509-12.
`4. al-Refaie FN, Hoffbrand AV. Oral iron chelation therapy. Recent Adv Haema-
`tol 1993;7:185-216.
`Idem.
` Oral iron-chelating therapy: the L
`1
`tol 1994;7:941-63.
`6. Agarwal MB, Gupte SS, Viswanathan C, et al. Long-term assessment of effi-
`cacy and safety of L
`, an oral iron chelator, in transfusion dependent thalas-
`1
`saemia: Indian trial. Br J Haematol 1992;82:460-6.
`7. al-Refaie FN, Sheppard LN, Nortey P, Wonke B, Hoffbrand AV. Pharmacoki-
`) in patients with iron overload.
`netics of the oral iron chelator deferiprone (L
`1
`Br J Haematol 1995;89:403-8.
`
` experience. Baillieres Clin Haema-
`
`5.
`
`Dr. Nathan replies:
`
`To the Editor: Though Drs. Hoffbrand and Wonke believe
`that the incidence of myelotoxicity associated with defer-
`iprone therapy is 2 percent, we really do not know what the
`incidence is. It is certainly no more than 10 percent; how
`close the actual incidence is to 2 percent or 10 percent will be
`known in the fullness of time, when the larger study by Oliv-
`ieri et al., now in progress, has been completed.
`I do not agree with Hoffbrand and Wonke’s comments
`about deferoxamine and iron stores. The toxicity of deferoxa-
`mine is largely due to its capacity to deplete iron even when
`iron stores are already low, which is why deafness and other
`serious central nervous system effects can occur if the dose of
`deferoxamine is not lowered as iron stores fall.
`I did not suggest that deferiprone would cause renal toxic-
`ity. I used desferithiocin as an example of an active oral iron
`chelator that was a disappointment.
`In my editorial, I stated that deferiprone is as important an
`option as marrow transplantation. But we just do not have
`enough experience with the drug to know whether it will pro-
`vide protection from heart disease in the long term. I am con-
`cerned that the rapid clearance of deferiprone from the blood
`after an oral dose has been administered will leave the heart
`unprotected. We need better kinetic studies of iron and the
`drug if we are to understand the risks and benefits.
`Finally, readers might have noted an inadvertent but im-
`portant error in the editorial (a correction notice was pub-
`lished in the May 11 issue).
` On page 953, in line 25 of the
`1
`right-hand column, the text should have read “when the con-
`centration of the drug in body fluids,” not “when the concen-
`tration of iron in body fluids.”
`
`, M.D.
` G. N
`ATHAN
`Children’s Hospital
`Boston, MA 02115
`1. Correction to: An orally active iron chelator. N Engl J Med 1995;332:1315.
`
`AVID
`
`D
`
`PROTECTION AGAINST TETANUS
`
`To the Editor: The serologic survey by Gergen et al. (March
`23 issue)
` corroborates earlier studies showing that more than
`1
`half of Americans over the age of 50 lack what are considered
`protective levels (>0.15 IU per milliliter) of tetanus antitoxin.
`
`Although serologic surveys often predict the epidemiologic
`features of a disease, the incidence of tetanus is far better pre-
`dicted by a history of inadequate primary immunization with
`tetanus toxoid. Almost all cases occur in persons who never
`completed a primary imm