CLEVELAND CLIN!’C FOUNDA:T~ON
`
`COOPER CLINIC
`
`GEISINGER MEDICAL CEN’FE,R
`
`GUTHRIECLINIC
`
`HENRY FORD HOSPITAl:.
`
`JO’SLIN,CLINtC
`
`LAHEY CLINIC FOUNDATION
`
`LOVELACE MEDICAL CEN’,TER
`
`MARSNFIELD CLINIC
`
`MAYO;,CLINtC. ,=
`
`OCHSNER CLINIC
`
`PALO ALTO MEDICAL CLINIC
`
`SCOTT AND WHITE CLINIC
`~CRIPPS ~LINIC AND RESEARCH FOUNDATION
`
`Sandoz Inc.
`Exhibit 1019-0001
`
`JOINT 1019-0001
`
`

`
`urrent
`lin
`Pract ic e
`
`FRANZ H. MESSERLI, M.D.
`EDITOR
`
`1987
`W.B. SAUNDERS COMPANY
`Philadelphia London Toronto
`Sydney Tokyo Hong Kong
`
`Sandoz Inc.
`Exhibit 1019-0002
`
`JOINT 1019-0002
`
`

`
`W. B. Saunders Company: West Washington Square
`Philadelphia, PA 19105
`
`Library of Congress Cataloging in Publication Data
`
`Current clinical practice
`
`1. Internal medicine. 2. Medicine, Clinical.
`L Messerli, Franz H. [DNLM: 1. Medicine. WB 100 C976]
`
`RC46. C95 1987 616 86-6512
`
`ISBN 0-7216-1460-4
`
`Editor: John Dyson
`
`Developmental Editor: Carole Morrison
`
`Designer: Terri Siegel
`
`Production Manager: Bill Preston
`
`Manuscript Editor: David Harvey
`
`Illustration Coordinator: Walt Verbitski
`
`Indexer: Ella Shapiro
`
`Current Clinical Practice
`
`ISBN 0-7216-1460-4
`
`© 1987 by W. B. Saunders Company. Copyright under the Uniform Copyright Convention. Simul-
`taneously published in Canada. All rights reserved. This book is. protected by copyright: No part of it
`may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, eJectronic,
`mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Made
`in the United States of America. Library of Congress catalog card number 86-651Z
`
`Last digit is the print number: 9 8 7 6 5 4 3 2 1
`
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`
`

`
`BLOOD AND
`NEOPLASTIC DISORDERS
`
`ERNEST BEUTLER
`JAMES K. WEICK
`
`1 . BONE MARROW
`TRANSPLANTATION IN
`
`ANEMIA
`Wayne Spruce
`SCRIPPS CLINIC AND RESEARCH FOUNDATION
`
`ETIOLOGIC CONSIDERATIONS
`
`Until the advent of bone marrow transplantation,
`severe aplastic anemia was associated with a high mor-
`tality:rate. ~Most patients would succumb within the
`first six months of the onset of their disease. Treatment
`with anabolic steroids and corticosteroids had,~in most
`cases, been disappointing and most patients died of
`hemorrhagic or infectious complications. The presenting
`symptoms of marrow aplasia are a result of.the, marrow
`failure and are usually easy bruising, spontaneous
`bleeding, and/or infection.
`Severe aplastic anemia is a ~elatively uncommon
`disorder with an inddence of about 65 per million in
`adults over 65 years of age and 4 per:million in children.
`Approximately 25% of cases occur in individuals under
`the age of,20 years and 30% in patieots over the age of
`60 years. Males and females are equally affected. While
`there are well:described congenital forms of marrow
`aplasia including Fanconi~s anemia, the majority of the
`cases are acquired. A variety of etiologic.agents, includ-
`ing chemicals, drugs, ionizing radiation, and infections
`has been implicated. Occasionally pregnancy and thy-
`momas have been. associated with marrow failure, and
`paroxysmal noctttrnal hemoglobinurea may occasionally
`present with pancytopenia. The best known drug as-
`sociation is the rare but often fatal association with
`chloramphenicol. Benzine and insecticides are chemical
`agents that have been implicated in cases of aplastic
`anemia. In spite of the multitude of possible etiologic
`agents, the majority of patients present with no clear-
`cut cause of their marrow failure.
`
`DIAGNOSTIC CRITERIA
`
`The criteria for severe marrow aplasia include a
`markedly hypocellular marrow and peripheral blood
`with any two of the three following findings: ~ neutro-
`phil count of less than 500/dl, a platelet count of less
`than 20,000/dl, and a corrected reticulocyte count of less
`than 1%. Bone marrow aspirations are not adequate to
`make the diagnosis and a bone marrow biopsy is man-
`datory ....
`
`PATHOPHYSIOLOGY
`
`Since aplastic anemia is not a single disease, the
`pathophysiology cannot be explained with a single
`concept. Theoretically, marrow failure could be ex-
`plained as failure of the pleuripotential stem cell, or a
`failure of its microenvironment. Until recently it was
`felt that most cases of marrow failure resulted from an
`isolated failure of the stem cell. HoweVer, clinical ex-
`perience in human marrow transplantation indicates
`that at least in some cases the cause may reside in the
`immune system. There are many-well-documented
`cases of spontaneous autologous’marrow recovery after
`unsuccessful attempts at marrow grafting. In addition,
`at least half of identical twin transplants have failed
`when no immunosuppression was used. Also; a grow-
`ing number of individuals have been successfully
`treated with antithymocyte globulin (ATG). These ob-
`servations implicate an immune mechanism in at least
`some patients.
`
`PHARMACOLOGIC AND IMMUNOLOGIC
`THERAPY
`
`Most of this chapter will deal with bone marrow
`transplantation as the treatment for severe aplastic ane-
`mia; however, a brief description of other forms of
`therapy will also be presented.
`
`STEROIDS
`Treatment with androgens such as testosterone and
`oxymetholone was reported to result in remission of
`severe marrow aplasia in small numbers of patients in
`the early 1960s. These reports were not confirmed in
`lar~ger numbers of patients, and more recent studies in
`the 1970s showed that they provided no advantage over
`modern supportive care. Likewise, corticosteroids in
`291
`
`Sandoz Inc.
`Exhibit 1019-0004
`
`JOINT 1019-0004
`
`

`
`292
`
`V~-BLOOD ANL) NEOPLASTIC DISORDERS
`
`conventional doses (1 to 2 mg/kg) and immunosuppres-
`sive ~trugs such as cydophosphamide have been re-
`ported to be effective in small numbers of patients.
`Confirmation in larger numbers of patients is lacking.
`
`ANTIrHYMOCYTE GLOBULIN
`Since Mathe’s original report on autologous marrow
`recovery in three out of seven patients treated with
`antithymocyte globulin (ATG) in 1970, there have been
`many other studies confirming its efficacy used alone,
`with haplo-identical marrow, or with androgens. The
`doses of ATG and the source of the material have varied
`greatly from study to study. However, the response
`rate in most series is between 40% and 70%. Many
`patients do not respond completely; however, the ma-
`jority of them are transfusion free. The role of haplo-
`identical marrow and androgens remains unclear. The
`use of large doses of methylpredisolone (20 mg/kg)
`along with ATG by the Swiss group has shown re-
`sponses in 15 of 16 patients so treated. In most series
`of patients, the time to response has varied from a few
`weeks to several months and relapses have been seen
`in up to: 10% of ~atients.
`The toxic effect of ATG is considerable and includes
`fever, chills, urticaria, and hypotension. In addition,
`platelet counts usually drop and may be difficult to
`support. Many of these side effects can be modified
`with the use of antihistamines and corticosteroids. Many
`patients will develop serum sickness, which can usually
`be prevented or treated with corticosteroids.
`
`[
`
`Bone Marrow Transplantation
`
`HISTOCOMPA TI BI LITY
`HLA System. Early clinical work, primarily in murine
`systems, ~. showed that marrow could be successfully
`transplanted in lethally irradiated animals only when
`they were histocompatible as determined by the H2
`complex.. The human equivalent is called the human
`leukocyte antigen (HLA) system. There is a series of
`closely related loci on the number six. chromosome
`designated HLA-A, B, C, ahd D, which make up the
`human ’histocompatibility .complex. Because of their
`close proximity on the chromosome, they are inherited
`as a unit in a mendelian codominant manner. Thus
`siblings have a 25% chance of being HLA identical. The
`A, B, C, and DR (D-related) loci are determined,by anti:
`HLA antisera, and the D loci by the mixed lymphocyte
`culture. HLA testing can be done at all transplant
`centers and by most major blood bankS. By and large,
`the majority of successful transplants have been per-
`formed between individuals who are HLA identical. At
`present, a patient must have siblings to have a marrow
`transplant for aplastic anemia. There have been occa-
`sional reports of successful transplants using parental
`or unrelated donors who are phenotypically identical to
`the patient, but these are rare.
`
`PATIENT EVALUATION PRIOR TO
`TRANSPLANTATION
`
`Once the diagnosis has been established, a decision
`needs to be made as to whether the patient is a candi-
`
`date for transplantation. HLA typing of the patient and
`family should be done as soon as possible. The results
`of the HLA typing and mixed lymphocyte culture can
`usually be available within a week. Transplantation in
`patients over the age of 40 years is not usually success-
`ful, and these individuals should be considered for other
`forms of treatment.
`During the evaluation period, blood product trans-
`fusions should be given very judiciously to avoid ex-
`posure of the patient to foreign antigens that might lead
`to graft rejection. Donors who are family members
`should be especially avoided. However, if the patient is
`extremely anemic or bleeding, transfusions should be
`given. The use of washed or frozen red cells and single
`donor, unrelated platelets may help to minimize sensi-
`tization. Infections should be treated vigorously; how-
`ever, it may be necessary to go ahead with the transplant
`even in the face of active infections.
`
`PREPARA TIVE REGIMENS
`Work done~ in animal systems showed ihat some
`form of immunosuppression was necessary in order for
`a marrow transplant to be successful. This has proved
`to be true in the human situation as well. Currently
`most centers, including our own, employ cyclophos-
`phamide as. the backbone of the preparative regimen.
`The dose is 50 :mg/kg of lean body weight given intra-
`venously over one hour daily for four days (total dose
`is 200 mg/kg). Most patients experience intense nausea
`and vomiting with the drug that lasts from several
`hours to several days. Other prominent side effects of
`the drug include an antidiuretic effect, hemorrhagic
`cystitis, and very rarely cardiac toxicity. Because of the
`antidiuretic effect and risk of hemorrhagic cystitis, a
`high urine flow must be maintained. A balanced elec-
`trolyte solution containing sodium bicarbonate, potas-
`sium, and furosemide (10 rag/L) is infused at a rate of
`3000 ml/24 hours/m~. In addition, we use continuous
`bladder irrigation with urologic saline at 1. lite¢ perHour
`beginning at the time of the first cyclophosphamide
`infusion and continuing for 24 to 48 hours after the last
`dose of the drug.
`In patients who have not been Sensitized by prior
`blood product transfusions,i this preparative regimen is
`usually adequate to allow engraftment. However, the
`majority of patients with aplastic anemia have required
`some blood component support either with packed cells
`or with platelets prior to coming ~o transplant. In these
`patients there is a definite risk of graft rejection, which
`may be as high as 30%, and additional immunosuppres-
`sion appears to be necessary. Several methods have
`been used to provide additional immunosuppression.
`Our group currently employs total lymph node irradia-
`tion as suggested by the transplant group at the Uni-
`versity of Minnesota. It involves the delivery of 750 rads
`of irradiation to all the major lymph node-bearing areas
`at a rate of approximately 25 rads per minute. The ~otal
`nodal irradiation is delivered 24 hours after the last dose
`of cyclophosphamide. Other centers have used total
`body irradiation from 300 to 600 rads, and others have
`employed additional drugs such as Myleran and pro-
`carbazine; all of these methods have.been successful in
`reducing the graft rejection rate to less than 10%. The
`Seattle group employs unirradiated donor buffy coat
`transfusions after the marrow transplant for four to five
`days. Recently cyclosporine has been reported by sev-
`
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`Exhibit 1019-0005
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`JOINT 1019-0005
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`

`
`eral European centers to be effective in reducing graft
`rejection,
`
`MARROW PROCUREMENT
`Donors should have a complete physical examina-
`tion, complete blood count, liver and renal function
`tests, electrocardiogram, and chest film prior to being
`accepted. In the event of more than one donor, an
`individua! who is younger, of the same sex, and of the
`same blood group as the patient should be chosen.
`The donor is usually admitted to the hospital a day
`before the procedure. On the rnorning of donation the
`patient is taken to’ the operating room and, under
`general anesthesia, the marrow is aspirated from the
`posterior and, if necessary, anterior iliac crests. During
`the aspirating procedure the marrow is mixed with
`tissue culture media (TC 199, Difco Labs) that contains
`5000 units of preservative-free heparin per 100 ml of
`tissue culture media. The total volume of the marrow
`that is taken will depend on the size and weight of the
`patient and donor, and on the cellularity of the marrow.
`Manual cell counts need to be performed during the
`procedure, and the final cell concentration should be
`greater than 3 x 10-8 nucleated cells per~kg of recipient
`weight. Cel! yields below this are correlated with an
`increased incidence of rejection. Once the marrow has
`been co!lected, it is screened through two sizes of metal
`mesh screens placed on the bottom of cut-off syringes
`and then placed in a standard blood transfer pack. If
`there is no major blood group incompatibility between
`the donor and recipient, the marrow is transfused
`immediately.
`
`POST-TRANSPLANT SUPPORTIVE CARE
`
`ENVIRONMENT
`After the marrow infusion, most patients remain
`pancytopenic for three to four weeks. During this period
`of time, patients should be nursed in single rooms and
`individuals involved with the care of the patient should
`observe careful handwashing techniques. Conventional
`reverse isolation techniques are probably of little value.
`Patients nursed in laminar air flow with gut decontam-
`ination and sterile food may have a decreased incidence
`of graft-Versus-host disease (GVHD) and serious infec-
`tions.
`
`HYPERALIMENTA TION
`Because of infections and oral mucositis, most pa-
`tients are unable to meet their caloric needs orally.
`Hyperalimentation is therefore needed in the majority
`of patients. We use standard hyperalimentation solu-
`tions and attempt to provide 80% to 90% of the patient’s
`caloric needs parenterally. ’ .’
`
`TRANSFUSIONS
`In the majority of patients, adequate blood product
`support can be provided with packed red blood cell
`transfusions and random donor platelet transfusions.
`To avoid the risk of engraftment of lymphocytes in
`these products, all blood products are irradiated with
`2500 rads.
`Occasionally patients will become refractory to ran-
`dora donor platelets and require single donor platelets.
`The marrow donor is usually the best donor in this
`situation, although other falnily members may be used.
`
`It is our practice to a~te:rnpt to keep the hemoglobin
`the range of 10 gm!dl and the platelet count above
`20,000.
`
`TRANSPLANI-RE!_ATED COMPLICATIONS
`
`GRAFT REJECTION
`Failure of engraftment, or graft rejection, is a prob-
`lem that is seen priruarily in marrow transplanfation for
`aplastic anemia. In the early series of patients reported
`by Seattle the rejection rate was approximately 30%,
`and other centers reported rates that were even higher.
`In analyzing their data, taro factors were consistently
`related to graft failure: (1) patients who had been trans-
`fused with blood products prior to undergoing prepa-
`ration for transplantation had a much higher rate of
`rejection than those who were untransfused; and (2)
`those patients who receivedgreater than 3 x 10-~ of
`nucleated cells had a much lower rejection rate. Other
`factors such as patient!donor sex or age have .not proved
`to be of significant prognostic value. Several methods
`have been developed to circumvent this problem and
`they have been alluded to in the section on preparat!ve
`regimens.
`
`INFECTIONS
`Infections are the second major post-transplant
`complication. Many patients with aplastic anemia may
`already be infected at the time they come to transplan-
`tation, and the majority of patients will become clinically
`septic within the first few days after receiving their
`marrow graft. Preventive measures are usually not suc-
`cessful in preventing infections in these profoundly
`immunosuppressed patients. The use of laminar air flow
`in conjunction with gut decontamination with nonab-
`sorbable antibiotics and sterile food and linen has been
`shown to decrease infections but has not improved
`survival.
`
`Management
`The most common organisms that infect patients
`during the first 30 post-t~ansplant days are staphylococ-
`cal species, gram-negative gut flora, and fungi. There-
`fore, when patients become febrile, empiric broad-spec-
`trum antibiotics .should be started. It has been our
`practice to start patients on a semisynthetic penicillin
`such as ticarcillin at 3 gm every four hours, an amino-
`glycoside such as gentamicin or tobramycin at 5
`mg!kg/day in three divided doses, and a cephalosporin
`such as cefazolin at 1 gm every six hours. Peak and
`trougE blood levels of the aminoglycoside should be
`obtained to prevent renal toxic effects and ototoxicity
`and to ensure therapeutic blood levels. Prior to the
`institution of antibiotic therapy, patients should have
`blood, urine and throat cultures obtained. Frequently,
`in spite of the clinical appearance of sepsis, no positive
`cultures will be obtained and the antibiotic choice must
`remain empiric. If the patient continues to be clinically
`septic after the institution of triple antibiotic coverage,
`we add amphotericin B, starting at 0.1 mg/kg/day and
`increasing the dose by 0.1 mg/kg!day up to 0.5 to 0.7
`mg/kg!day; when this dose has been reached, the drug
`is given on an every-other-day schedule: The drug is
`administered over three to four hours. In patients who
`have positive cultures, antibiotic choice can, of course,
`be guided by the sensitivity reports. Patients who have
`
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`
`294
`
`persistently positive btood cultures in spite of optimaI~
`antibiotics should be considered for granulocyte trans-
`fusions. To avoid the risk of serious pulmonary reac-
`tions, granulocytes should be separated from ampho-
`tericin by as mucb time as possible. When granulocytes
`are started, they should be continued Until the patient
`is culture negative and the absolute granulocyte count
`is over 500/dl.
`Herpes simplex infections in the ’oral and genital
`regionscan develop during the early post-transplant
`period. The antiviral drug acyclovir given intravenously
`at a dose of 10 mg/kg/dose every eight hours is usually
`effective in suppresging these infections,, Occasionally,
`repeated 10-day courses may be necessary.
`After the granulocyte ~ount has increased to gi~eater
`than 5001dl, the~risk of serious bacterial and fungal
`infections is reduced except in those patients who have
`significant GVHD. These patients often require cortico-
`steroids (2 to 4 mg/kg) and other immun0suppressive
`measures’ to control the. process and, hdnce, ’are at
`continued risk for bacteFial and especially fungal infe&
`lions. In addition, the return of humoral and cellular
`immunity is delayed in these patients, further aggra-
`vating the situation.
`
`INTERSTITIAL PNEUMONIA
`Interstitial pneumonia is a major problem after the
`first 30 post-transplant days. The incidence is lowest in
`those patients who do not receive radiation as part of
`the preparative regimen and in those patients who have
`identical twin (syngeneic) donors. Other risk factors
`include older age and the presence of GVHD. About
`80% of the cases are either idiopathic or related to
`cytomegalovirus (CMV). Rarely other viruses or Pneu.
`mocystis can be the cause of interstitial pneumonia.
`Patients present with steadily increasing hypoxia with
`a paucity of. physical findings. The chest fihn usually
`shows a progressively worsening picture of interstitial
`infiltrates.
`
`Management ~
`Patients with severe GVHD have a very high mor-
`tality rate and to date there has been no effective
`treatment. Antiviral drugs have not.proved effective,
`and the use of high liter immune plasma of globulin
`has not been successful. There has been some early
`evidence that the prophylactic use of high titer CMV
`immune globulin may be effective in preventin, g .the
`development of interstitial pneumonia.
`.... Herpes zoster infections can occur in up to 50% of
`patients following transplantation. The peak incidence
`is at five months. The majority of these patients are still
`very immunocompromised and at risk of cutaneous and
`visceral dissemination.: It is our practice to start ’these
`patients o’n acyclovir in the same doses used for herpes
`simplex infections and to treat for 10 days. ’In most
`patient~ this is adequate treatment. Occasionally, l~a-
`tients will reactivate their disease and require second
`and even third courses of the drug~
`
`G~arr-vr~sus-,osr D,S~ASr (GVHD)
`Acute GVHD. GvHD is the third major complication
`of marrow transplantation. It results from the reaction
`of an immunologically competent donor against an
`
`inm~unologically compromised hos~. The effector cells
`are thought to toe dono>cytotoxic T iymphocytes. Ti~e
`incidence of severe GVHD is between 40% and 70% in
`fully HLA identical allogeneic transplants. The severe
`form is seen in approximately 25% to 30% of patients.
`The target organs are the skin, the gastrointestinal tract,
`and the liver. The clinical manifestations of the disorder
`range from a mild macular skin rash, mild gastrointes-
`tinal discomfort and asymptomatic liver functional
`normalities to a fuhninant and often fatal form with
`~nassive epidermolysis, liver failure, and large quantities
`of diarrhea. Death in these patients is most often from
`intercurrent bacterial, fungal, or viral-infections. A grad-
`ing system for the degree of organ involvement has
`been developed by the Seattle group and is used by
`most transplant centers. Grades 1 and 2 are considered
`the mildest, forms, and grades 3 and 4 are the most
`severe forms, which are associated with the highest
`mortality. Advancing age appears to be the greatest risk
`factor. "
`. Methotrexate given intermittently over the first 100
`post-transplant days has been the most commonly used
`method of attempting to prevent GVHD. It is given at
`15 mg/m~ on the first post-transplant day and at 10
`mg/m~ on day +3, +6, +11, and then weekly there-
`after. Most groups have also added prednisolone at 0.5
`to 2 mg/kg/day to the methotrexate regimen. Antithy-
`mocyte globulin has also been used by some centers
`but the results have been’ inconsistent.
`Cydosporine has been employed by many groups,
`usually starting two to three days prior to marrow
`infusion and continuing for the first three to,six months
`post transplant. However, its place in the prevention
`and treatment of acute GVHD remains to be established.
`Several groups, including our own, have been exploring
`the use of anti-T cell monoclonal antibodies in an
`attempt to remove the T cells from the marrow prior to
`infusion. Preliminary results in fully matched patients
`look promising. Finally, the Seattle group has.reported
`a decreased incidence of grade 2-4 acute GVHD in
`patients cared for in a laminar air flow environment.
`Chronic GVHD. The chronic form of GVHD can
`occur in up to 30% of patients any time after the first
`100 post-transp!an~ g!ays. It may develop as an extension
`of the acute form of the disease, after a quiescent period,
`or de novo. This syndrome may involve multiple organ
`systems including the skin, liver, gastrointestinal tract,
`eyes, lungs, hematopoietic system, and musculoskeletal
`system. The disorder has many of the. characteristics of
`a collagen vascular disease. These patients, as well as
`those with the acute form of the disease have a marked
`delay in the return of their immune function and, hence,
`they are at high risk for developing serious overwhelm-
`ing infections. Most patients suffer from chronic skin
`rashes, hyperpigmentation and hypopigmentation, loss
`of subcutaneous tissues, dry mouth and eyes, chronic
`diarrhea, and liver disease manifested by elevations of
`the transaminases, alkaline phosphatase, and bilirubin.
`Many patients are thrombocytopenic and may have low
`white blood counts, but interestingly, they are not
`usually anemic. Some Suffer from muscle weakness and
`cramps and occasionally joint effusions.
`Treatment has been most successful with the use
`of oral prednisone, usually in doses of I to 2 mg/kg/day.
`Azathioprine in doses of 1.5 mg/kg/day has been used
`
`4
`
`Sandoz Inc.
`Exhibit 1019-0007
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`JOINT 1019-0007
`
`

`
`by the Seattle group in addition to prednisone and
`initially appeared to improve survival; however, a sub-
`sequent randomized trial has failed to confirm their
`earlier results. The latter patients were treated earlier
`and were usually placed on prophylactic trimethoprim-
`sulfamethoxazole, and received more aggressive sup-
`portive care. In any event, the survival of these patients
`has improved in recent years.
`
`FOLLOW-UP
`
`The length of hospitalization will vary for each
`patient and depend on several factors including the
`rapidity of engraftment, the severity of infections, the
`presence of GVHD and its severity, and the nutritional
`status of the patient. Most patients will spend a total of
`40 to 60 days in the hospital. In younger individuals,
`for those in good general condition prior to undergoing
`transplantation, and in those with few complications,
`the period may be shorter. Once individuals are released
`from the hospital, most require close outpatient follow-
`up for at least two additional months. The patient’s
`graft status and GVHD must be monitored closely. It is
`the practice of most transplant centers to keep patients
`under close observation for the first three months after
`marrow transplantation and then to return them to their
`referring physician.
`
`COST
`
`The cost of the procedure can be quite variable,
`depending primarily on the length of stay in the hospital
`and the number of transplant-related complications that
`the patient experiences. In spite of rising medical costs,
`the cost for most transplants has remained relatively
`constant and is in the range of $75,000 to $!00,000.
`When one compares this with the cost of repeated
`hospitalizations to treat complications of severe aplastic
`anemia, it appears tobe cost-effective.
`Because of its complexity, and the need for highly
`trained medical and paramedical support, this is not a
`procedure that is likely to be easily transported to
`community hospitals. At present it is limited to those
`institutions that have the ne4essary experienced staff
`and facilities to care for these patients.
`
`CLINICAL RESULTS AND CONCLUSIONS
`
`Over the last decade the clinical results for alloge-
`neic marrow transplantation have improved. Long-term
`survival ranges from’40% to around 70%. This can be
`attributed to several factors including earlier transplan-
`tation and better supportive care during the period of
`pancytopenia. The development of methods to prevent
`graft rejection has clearly been the most important factor
`in improving the clinical results in aplastic anemia.
`While a great deal of progress has been made over
`this period of time, GVHD and the lack of a histocom-
`patible donor continue to be major problems in the
`field. If one could obviate GVHD, the limitations of age
`and histocompatibflity could be removed. As discussed
`previously, few patients over the age of 40 are success-
`fully transplanted; this is primarily due to the increased
`
`incidence of GVHD. In fact, the mortality associated
`with the procedure rises rapidly after the age of 20.
`There have been occasional reports of successful
`transplant between less than fully matched patients and
`in a few patients using unrelated fully matched donors.
`However, by and large, these attempts have not been
`successful. Attempts at removing donor T cells from the
`marrow have been successful in fully matched patients,
`but the results in mismatched patients have been dis-
`appointing and clearly much more work needs to be
`done in this area. ’These problems are currently being
`worked on in many marrow transplant centers and it is
`hoped we will see some positive results in the near
`future. Until these problems are worked out, individuals
`who are over the age of 40 and those without histocom-
`patible donors should be considered for treatment with
`alternative forms of therapy such as antithymocyte
`globulin.
`
`REFERENCES
`
`Champlin R, Ho W, Bayever E, ~t al: Treatment of aplastic anemia:
`results with bone marrow transplantation, antithymocyte globulin
`and a monoclonal anti T-cell antibody, h* Young N, Levine A,
`Humphries R: Asplasfic Anemia, Stem Cell Biology and Advances
`in Treatment. Alan R. Liss Inc, New York, 1984, pp 227-238.
`Forman S, Hows J: Bone marrow failure. In Blume K, Petz L (eds):
`Clinical Bone Marrow Transplantation. Churchill-Livingstone, New
`York, 1983, pp 2!5-214.
`Ramsay NKC, Kim T, Nesbit ME, et al: Total lymphoid irradiation and
`cyclophosphamide as preparation for bone marrow transplantation
`in severe aplastic anemia. Blood 55:3442346, 1980.
`Spruce W, McMillan R, Beutler E: Bone marrow transplantation for the
`treatment of severe aplasfic anemia. Clin Hemato112:285-310, 1983.
`Storb R, Thomas ED, Buckner CD, et al: Marrow transplantation for
`aplastic anemia. Semin Hematol 21:27-35, 1984.
`Sullivan K: Graft versus host disease, hi Blume K, Petz L (eds): Clinical
`Bone Marrow Transplantation. Churchill-Livingstone, New York,
`1983, pp 91-120.
`Thomas ED, Storb R: Technique for human marrow grafting. Blood
`36:507-515, 1970.
`Young N, Speck B: Antithymocyte and antilympho~yte globulins: clin-
`ical trials and mechanisms of action. In Young N, Levine A,
`Humphries R: Aplastic Anemia, Stem Cell Biology and Advances
`in Treatment. Alan R. Liss Inc, New York, 1984, pp 221-226.
`Zaia JA: Infections. In Blume K, Petz L (eds): Clinical Bone Marrow
`Transplantation. Churchill-Livingstone, New York, 1983; pp 131-
`!68.
`
`2" IRON DEFICIENCY
`
`Virgil F. Fairbanks
`MAYO CLINIC AND MAYO FOUNDATION
`
`DEFINITIONS AND DIAGNOSTIC CRITERIA
`
`Iron deficiency is the condition in which total body
`iron content is less than normal for a person’s age and
`sex. Three stages of iron deficiency are recognized: (1)
`iron depletion, wherein the normal iron storage pools
`of ferritin and hemosiderin are markedly reduced or
`absent but blood hemoglobin and serum iron concen-
`trations are normal and no physiologic effects of iron
`deficiency are demonstrable; (2) iron deficiency without
`
`Sandoz Inc.
`Exhibit 1019-0008
`
`JOINT 1019-0008
`
`

`
`V 13LOOD AND NEOPLASTIC
`
`~nemia, wherein the iron storage pools are absent,
`serum iron concentration may be reduced, and such
`effects~of iron deficiency as decreased work tolerance or
`epithelial changes may be demonstrated although there
`is no anemia or morphotogic change in erythrocytes;
`and (3) iron deficiency anemia.
`In. general, as iron deficiency progresses, it is re-
`fleeted in the sequence of abnormalities in laboratory
`test results shown in Table 1.
`While Table 1 shows the general pattern in.Which
`changes of iron deficiency evolve, exceptions are com-
`mon. It is not unusual for the serum iron concentration
`(SI), total iron binding capacity (TIBC), and transferrin
`saturation to be normal even when anemia and micro-
`cytosis are evide ~nt..Consequently, these assays are of
`limited diagnosti¢ value, Serum ferritin assay, now
`generally ;avoilable, should supplant assay of SI as a
`diagnostic test. Normal values for serum ferritin vary
`between laboratories, depending on the method used.
`For a commonly used immunoradiometric assay, a value
`of 10 ~g/L or less is usually diagnostic of iron deficiency.
`A major limitation of the ferritin assay is that the serum
`ferritin concentration is usually elevated in the presence
`of chronic "disease, such as rheumatoid arth~iJ~!s, infec-
`tions, and malignancies including lymphoma~ and leu-
`kemias, and this elevation may obscure .concomitant
`iron deficiency.
`Review of a Wright-stain4d blood film, when inter-
`preted in the context of the clinical