Successful Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Shwachman-Diamond Syndrome (SDS) Using a Reduced-Intensity Conditioning (RIC) Regimen: 41

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Successful Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Shwachman-Diamond Syndrome (SDS) Using a Reduced-Intensity Conditioning (RIC) Regimen: 41
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  Case Report  Successful Allogeneic Hematopoietic Stem Cell Transplantationof a Patient Suffering from Type II Congenital Dyserythropoietic Anemia A Rare Case Report from Western India  GaurangModi, 1 SandipShah, 1 IrappaMadabhavi, 1 HarshaPanchal, 1  ApurvaPatel, 1 UrmilaUparkar, 1  AshaAnand, 1 SoniaParikh, 1 KinnariPatel, 1 KamleshShah, 1 andSwaroopRevannasiddaiah 2 󰀱 Department of Medical and Paediatric Oncology, GCRI, Ahmedabad, Gujarat 󰀳󰀰󰀰󰀱󰀶, India 󰀲 Department of Radiotherapy, Government Medical College, Haldwani, Uttarakhand 󰀲󰀶󰀳󰀱󰀳󰀹, India Correspondence should be addressed to Irappa Madabhavi; irappamadabhavi@gmail.comReceived 󰀲󰀵 October 󰀲󰀰󰀱; Revised 󰀱󰀳 December 󰀲󰀰󰀱; Accepted 󰀳󰀰 December 󰀲󰀰󰀱Academic Editor: Ramon TiuCopyright © 󰀲󰀰󰀱󰀵 Gaurang Modi et al. is is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the srcinal work is properly cited.e most frequent form of congenital dyserythropoiesis (CDA) is congenital dyserythropoietic anemia II (CDA II). CDA II is arare genetic anemia in humans, inherited in an autosomally recessive mode, characterized by hepatosplenomegaly normocyticanemia and hemolytic jaundice. Patients are usually transfusion-independent except in severe type. We are here reporting acase of severe transfusion-dependent type II congenital dyserythropoietic anemia in a 󰀵-year-old patient who has undergoneallogeneic hematopoietic stem cell transplantation (HSCT) at our bone marrow transplantation centre. Patient has had up untilnow more than 󰀱mL/kg/month of packed cell volume (PCV), which he required every 󰀱󰀵 to 󰀲󰀰 days to maintain his hemoglobinof 󰀱󰀰gm/dL and hematocrit of 󰀳󰀰%. His pre-HSCT serum ferritin was 󰀱󰀵󰀰󰀰ng/mL and he was on iron chelating therapy. Donorwas HLA identical sibling (younger brother). e preparative regimen used was busulfan, cyclophosphamide, and antithymocyteglobulin(ymoglobulin).Cyclosporineandshort-termmethotrexatewereusedforgra󰀀versushostdisease(GVHD)prophylaxis.Engra󰀀ment of donor cells was quick and the posttransplant course was uneventful. e patient is presently alive and doing welland he has been transfusion-independent for the past 󰀳󰀳 months a󰀀er HSCT. 1. Introduction Congenital dyserythropoietic anemia (CDA) is a rare blooddisorder, similar to the thalassemias. CDA is one of many types of anemia, characterized by ineffective erythropoiesis,resulting from a decrease in the number of red blood cells(RBCs) in the body and a less than normal quantity of hemoglobin in the blood. Traditionally, CDA have beenclassified into 󰀳 major types (CDA I, CDA II, and CDAIII); recently, additional variants have been described. CDAtype II (CDA II) is the most frequent type of congenitaldyserythropoietic anemias.Congenital dyserythropoietic anemia type II is a genetichyporegenerative anemia characterized by ineffective ery-thropoiesis and distinct morphological abnormalities of theerythroblasts in the bone marrow (BM). Type II congenitaldyserythropoietic anemia (CDA II) is an autosomal recessivedisorder characterized by hemolytic jaundice, mild to mod-erate hepatosplenomegaly, and normocytic anaemia [󰀱, 󰀲]. Most of the patients are transfusion-independent except for󰀱󰀰 to 󰀲󰀰% of the cases, who are transfusion-dependent; thiscould account for the severity of the clinical outcome [󰀳,]. Management usually includes blood transfusion, ironchelating therapy, and splenectomy. Transfusion-dependentpatients usually require allogeneic HSCT (hematopoieticstem cell transplantation) from HLA identical donor. Only few published case reports of allogeneic HSCT in CDApatients are available. 2. Case Report Child was apparently asymptomatic till the age of 󰀳 years.He complained of lethargy and weakness for one to twomonths prior to presentation. His routine investigations Hindawi Publishing CorporationCase Reports in Hematology Volume 2015, Article ID 792485, 4 pageshttp://dx.doi.org/10.1155/2015/792485  󰀲 Case Reports in Hematology showed hemoglobin (Hb) of 󰀵gm/dL, indirect hyperbiliru-binemia, and mild-moderate hepatosplenomegaly. He hadunremarkable birth and family history. His peripheral smearwas showing severe microcytic hypochromic anemia withanisocytosis, poikilocytosis, and low MCV. A󰀀er ruling outhemolytic causes of anemia including thalassemia, sicklingdisease, and G󰀶PD deficiency, patient underwent marrow aspiration and biopsy. It showed erythroid hyperplasia andfeature of dyserythropoiesis such as binucleation (󰀲󰀰%),multinucleation, and karyorrhexis. e other cell lines werenormal. e genetic analysis of the patient’s peripheral bloodrevealed SEC󰀲󰀳 B gene mutation by real-time polymerasechain reaction (RT-PCR). In view of marrow picture andgenetic mutational analysis, final diagnosis of CDA II wasmade.Attheageof󰀵years,hewasreferredtoourhematology unit for further management. Patient has had up until now more than 󰀱mL/kg/month of packed cell volume (PCV).On examination, he had marked pallor, with stable vitals.Abdominal examination revealed palpable splenomegaly of cm below the le󰀀 costal margin and hepatomegaly of 󰀵cmbelow the right costal margin. His pre-HSCT serum ferritinwas 󰀱󰀵󰀰󰀰ng/mL; he was on regular iron chelating therapy (deferasirox 󰀳󰀰mg/kg) once a day. His renal function testsand liver function tests were within normal range except formild indirect hyperbilirubinemia. Other therapeutic optionssuch as splenectomy were explained to patient’s relatives.Family was reluctant to go for splenectomy. Liver biopsy revealed moderate iron overload and no fibrosis was seen.Allogeneic HSCT (hematopoietic stem cell transplanta-tion) from his HLA-matched sibling was planned for patient.e donor was a 󰀲-year-old younger brother, in whom CDAII was ruled out. e patient had 󰀱󰀰/󰀱󰀰 HLA match by low resolution assay. Cytomegalovirus (CMV) status of both thedonorandrecipientwasnegative.Gra󰀀typewasofperipheralblood stem cells (PBSC). Both patient and donor bloodgroup were AB positive. Pre-HSCT work-up of the patientwas normal. A󰀀er taking written consent regarding HSCT,doublelumenHickmancatheterinsertionwasdonebyexpertanesthetist.Initially, 󰀵 days prior to the start of conditioningtherapy, bone marrow suppression was done with aza-thioprine and hypertransfusion of packed cell volume tomaintain the Hb and hematocrit of 󰀱󰀵gm/dL and 󰀰–󰀵%,respectively. Myeloablativeconditioningregimenof busulfan󰀰.󰀸mg/kg/doseintravenousfor󰀱󰀶doses( − Day󰀱󰀰to–Day 󰀷),cyclophosphamide intravenous 󰀵󰀰mg/kg/day with mesna( − Day 󰀵 to  − Day 󰀲), and antithymocyte globulin (y-moglobulin) intravenous 󰀱.󰀵mg/kg/day ( − Day 󰀳 to –Day 󰀱)was used. Ursodeoxycholic acid 󰀱󰀲mg/kg/day was givenorally from the day before starting the conditioning regimenuntil +Day 󰀹󰀰 a󰀀er transplant to prevent the venoocclusivedisease. Oral cyclosporine 󰀵mg/kg was started from –Day 󰀱and continued for +Day 󰀶󰀰 to prevent gra󰀀 versus hostdisease (GVHD). On Day 󰀰, stem cell infusion was donewith dose of CD󰀳+ cells of 󰀷  ×  󰀱󰀰 6 per kg weight. IVmethotrexatewasgivenon+Day󰀱,+Day󰀳,+Day󰀶,and+Day 󰀱󰀱 as gra󰀀 versus host disease (GVHD) prophylaxis. Initially supportive measures were taken to correct low hemoglobinand platelet count. Engra󰀀mentfor neutrophilswas achievedon +Day 󰀱 with 󰀳 consecutive absolute neutrophils countsof more than 󰀵󰀰󰀰cumm/dL. Engra󰀀ment for platelets wasachieved on +Day 󰀱󰀹 with 󰀳 consecutive platelet counts of morethan󰀵󰀰󰀰󰀰󰀰cumm/dLwithoutanycomponentsupport.󰀱󰀰󰀰% donor chimerism for both myeloid and lymphoid cellswas achieved by +Day 󰀵.Patient was given prophylactic antibacterial, antifungal,and anti- P. jirovecii  treatment during HSCT procedure.Engra󰀀ment of donor cells was prompt and the post-HSCTduration was uneventful. No acute or chronic gra󰀀 versushost disease (GVHD) was noted. Cyclosporine and acyclovirwerecontinuedfor󰀶and󰀱󰀲months,respectively.Post-HSCTserialcompletebloodcountsandhemoglobinofpatientwerenormalizedon+Day󰀰andhewasnevergivenPCV(packedcellvolume)orplateletssincethen.irty-threemonthsa󰀀erHSCT, the patient is alive with normal hemoglobin level andis not receiving any immune suppressive therapy at present.Ironchelatingtherapywasstopped󰀳monthsa󰀀ertransplant,when the serum ferritin level was noted to be less than󰀱󰀰󰀰󰀰ng/mL. Now, he is almost 󰀸 years old, under regularsurveillance at our transplant centre without any symptoms. 3. Discussion e congenital dyserythropoietic anemia (CDA) comprises agroup of rare hereditary disorders, characterized by ineffec-tiveerythropoiesisasthepredominantmechanismofanemiaand by distinct morphological abnormalities of the majority of erythroblasts in the bone marrow. e term was first usedby Crookston et al. [󰀱󰀱]. e diagnosis should be suspectedin any case of congenital anemia with features of hemolyticanemia. Various types of CDA are noted of which the mostfrequent form is type II. Approximately 󰀳󰀷󰀰 cases of CDAIIare reported till date. Although this disorder is consideredto be congenital, it is interesting that this type of anemia canbe diagnosed in all age groups. e molecular defects in thegene SEC󰀲󰀳B (loci is 󰀲󰀰p󰀱󰀱.󰀲󰀳) are the confirmatory criteriafor the diagnosis of the CDA II [󰀱󰀲]. Erythrocytes of CDA IIpatients lyse in acidified serum (Ham test) because of an IgMclass antibody that recognizes an antigen present on CDA IIcells but absent on normal cells. So the acronym HEMPAS(hemolytic anemia with a positive acidified serum test) wascommonly used as a synonym for CDA II [󰀱󰀳].Only 󰀱󰀰–󰀲󰀰% of the patients have severe anemia; in thatcase, management focuses mainly on supportive care withthe use of transfusions, iron chelating therapy, allogeneicHSCT, and rarely splenectomy. Iron accumulates steadily throughout life, with kinetics similar to untreated hereditary hemochromatosis [󰀱], and at present management of ironoverload should follow guidelines for thalassemia. Parents of our patient did not want lifelong blood transfusion, regulariron chelating agents, or risk of infection susceptibility a󰀀ersplenectomy. HSCT was the only curative option to avoid theabove complications.Curative therapy for CDA focuses on the use of HSCTusing fully matched sibling donors [󰀸]. Some of the CDA IIcaseswhichhavebeenmanagedsuccessfullywithHSCTwith  Case Reports in Hematology 󰀳 T󰁡󰁢󰁬󰁥 󰀱: HSCT done in various types of CDA.Year Author Type of CDA󰀱󰀹󰀹󰀶 Ariffin et al.[󰀵] Type not documented󰀲󰀰󰀱󰀲 Iolascon etal. [󰀳] CDA II with thalassemia trait󰀲󰀰󰀰󰀲 Ayas et al.[󰀶] CDA I󰀲󰀰󰀰󰀲 Remacha etal. [󰀷] CDA II with a negative Ham test󰀲󰀰󰀱󰀲 Buchbinderet al. [󰀸]Unrelated hematopoietic stem celltransplantation in a patient withcongenital dyserythropoietic anemia(CDA) and iron overload󰀲󰀰󰀱 Russo et al.[󰀹]Successful hematopoietic stem celltransplantation in a patient with CDA II󰀲󰀰󰀱 Braun et al.[󰀱󰀰]Successful treatment of an infant withCDA II by intrauterine transfusions andpostnatal stem cell transplantation excellent results were mentioned in the literature. It has beenreportedtobecurativeinafewseverecasesofCDAincludingtransfusion-dependent CDA type I, CDA type II, Ham test-negative CDA type II, and an unclassified CDA (Table 󰀱).HSCT was successful in some children with exceptionally severe anemia [󰀱󰀵]. So there is a paucity of literature availableto guide us through the application of HSCT in this case.In many instances, a matched sibling donor is not availableand conventional conditioning may be poorly tolerated inmany patients. Lucarelli et al. described risk stratification of thalassemia patients which is defined by the following risk factors: (󰀱) hepatomegaly   > 󰀲cm, (󰀲) portal fibrosis of any degree, and (󰀳) inadequate compliance with the chelatingagents. Class 󰀱 means no risk factors, Class 󰀲 had one or tworisk factors, and Class 󰀳 included all 󰀳 risk factors. We hadassigned our patient to Class 󰀲 status (in view of presence of hepatomegaly) in which HSCT has also been reported as theonly viable curative option [󰀱󰀶].In developing countries like SEAR regions with financialconstraints and limited resources, CDA II patients can bebenefited best with the use of myeloablative conditioningregimen,infusionofhighstemcelldose,andallthemeasureswhich would lead to reduced infection rate and duration of hospital stay. We have demonstrated a successful and safeapplication of aggressive iron chelating agents before HSCTfollowed by successful HSCT. 4. Conclusion Due to rarity of disease, no definitive treatment guidelinesare available but allogeneic HSCT should be consideredin severe cases. As in thalassemia early and regular ironchelating agents in CDA before HSCT give better results. Inthe developing world with limited resources and financialconstraint, severe case of CDA can be managed successfully with allogeneic HSCT by using myeloablative conditioningregimen, infusing high CD󰀳+ stem cell dose, to ensureearlyengra󰀀ment;appropriateandadequateGVHDmeasurewould contribute to reducing infection rate and duration of hospital stay. Highlights: Learning Points (i) e congenital dyserythropoietic anemia (CDA) is agroup of rare hereditary disorders, characterized by ineffective erythropoiesis and specific morphologicabnormalities of erythroblasts in the bone marrow.(ii) Traditionally, CDA have been classified into 󰀳 majortypes (CDA I, CDA II, and CDA III); recently,additional variants have been described.(iii) e diagnosis of CDA should be suspected in any case of congenital anemia with features of hemolyticanemia.(iv) e molecular defects in the gene SEC󰀲󰀳B (loci is󰀲󰀰p󰀱󰀱.󰀲󰀳) are the cause of CDAII.(v) ere is a paucity of literature available to guide themanagement of CDA.(vi) Allogeneic HSCT is the only curative strategy avail-able in severe transfusion-dependent CDA patients. Conflict of Interests e authors declare that there is no conflict of interestsregarding the publication of this paper. References [󰀱] K. Y. Wong, G. Hug, and B. C. 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