On 8 April 2013, Multan Khan, Oat 58 years of age, underwent allogeneic bone marrow transplant for severe aplastic anemia. Till now, he is the oldest patient to undergo allogeneic HSCT at our centre.
Multan Khan was diagnosed one year before his transplant and had been heavily transfused with blood components. Before the transplant he has received over 100 red cell concentrate/whole blood units and over 200 random donor platelet units. Other than platelet refractoriness, there was no comorbidity.
Donor was patient’s grand multiparous sister who was about 10 years younger than him. Pretransplant conditioning was given with Flu120/Cy120/ATG20. Post-transplant cyclosporine was used for GVHD prophylaxis. Stem cells source consisted of un-primed bone marrow harvest (BMH) on day zero and GCSF mobilized peripheral blood stem cell (PBSC) harvest on day +4. 8 Cell dose was TNC 2.4 x 10 /kg from 8 BMH and MNC 1.7 x 10 /kg from PBSC. Facility for CD34 positive cells was not available. Neutrophil engraftment was on day +13 & platelet engraftment on day +28.
During early post-transplant period, Multan Khan had an episode of neutropenic fever prior to engraftment. Later on, there was a spell of abnormal behavior and grade II gut GVHD which promptly responded to treatment. After first 3 months, Multan Khan remained generally well with stable blood counts and no chronic GVHD. Immunosuppression was tapered off at one year followed by routine vaccination.
Now 5 years after transplant, at 63 years of age, Multan Khan is fully fit and leading an active life. He is working full time and running a small general store in his village.
Contributed By: Dr Muhammad Farhan, FCPS (Clinical Haem)
Mr. Umair Khan was 23 years of age when he developed progressive pallor. He was initially worked up in Karachi and was diagnosed as a case of very severe Aplastic Anemia. The patient reported to AFBMTC/NIBMT in Jan 2012 and underwent allogeneic bone marrow transplant on 26 Mar 2012 from HLA matched sister. Prior to transplant Mr. Khan has received 30 units of RCC and approximately 30 units of random donor platelets. One year before presentation the patient suffered intraocular bleeding due to injury sustained while playing cricket as a result of which he lost eyesight in his left eye.
Pretransplant work up revealed no comorbidity and good functional status. There was no ABO mismatch. The patient received conditioning with Fludarabine 120 mg/m, Cyclophosphamide 120 mg/kg and ATG (rabbit) 20/kg over 4 days. He received both bone marrow harvest (TNC dose 2.9 x 10 /kg) and PBSC harvest (MNC dose of 1.7 x 8 10 /kg). Engraftment was prompt with neutrophil engraftment was on day +11 and that of platelets on day +14. There was no major complication and except for initial azotemia (max creatinine 202 µmol/l) the patient remained well. There was no acute graft versus host disease.
Three months after transplant Mr. Khan went back to Karachi and his follow up was handed over to a local consultant. Immunosuppression was tapered off one year post transplant, followed by vaccination.
Mr. Khan has recently married and last month he visited us along with his wife. They were on honeymoon trip to northern areas. Mr. Khan looked well and is leading an active life. He works at a managerial post in a private company. We wish a very happy and prosperous life to the newly married couple.
Contributed By: Dr Muhammad Farhan, FCPS (Clinical Haem)
Abdul Mateen was diagnosed as a case of B-Thalassemia Major and received his first transfusion at 9 months of age. Iron chelation was started at 2 years of age. The patient then moved to Jeddah, Saudi Arabia with his family and was treated there till his return to Pakistan in 2008 at 14 years of age. It was then Mateen’s family came to know about bone marrow transplant facility at AFBMTC.
Mateen was found to have a perfect HLA match with his only sibling. Pretransplant work up revealed positive PCR for HCV RNA; ALT was 76 U/l and ultrasound abdomen demonstrated mild texture changes in liver with splenomegaly. There was mild fibrosis on liver biopsy. Serum ferritin was 3118 ng/ml. There was minor ABO incompatibility (Patient’s blood group AYE Positive; Donor’s blood Group OOO Positive). The patient was placed in Pesaro risk class III and conditioning consisted of a 45 days long protocol for B-Thalassemia major with Hydroxyurea, Azathioprine, Fludarabine, Cyclophosphamide and Busulphan. He tolerated conditioning well and was given cyclosporine, methylprednisolone and methotrexate for GvHD prophylaxis. Mateen underwent allogeneic bone marrow transplant on 15 June, 2009.
Post-transplant period was unremarkable with slight delay in engraftment and grade I skin GvHD. STR for donor chimerism remained more than 90% and lymphocyte subset analysis demonstrated good immune reconstitution. Once off immunosuppression, the patient was treated for HCV with interferon and ribavirin. He was vaccinated after treatment for hepatitis C.
Mateen is currently doing his BBA from a prestigious university in Pakistan and enjoys good quality of life with his family.
Contributed By: Dr. imtenan Sharif
Amina, resident of Sahiwal was noted to have pallor since infancy. She, however, received no blood transfusion till she was 7 years old. She received her first RCC transfusion in Jun 2013. A bone marrow biopsy was done to find out the cause of anemia which demonstrated ringed sideroblasts; findings were consistent with Sideroblastic Anemia. The patient was referred to our hospital for prospects of bone marrow transplant.
As blood transfusion requirement grew, she was put on oral iron chelation therapy. Amina’s was matched with her elder sister Javeria. The family was counseled regarding allogeneic bone marrow transplant and the patient was put on waiting list. Pre-transplant workup of the patient and the donor was started in Feb 2015. By then Amina had received 22 RCC. On examination liver was palpable 3 cm below costal margin. Serum ferritin was 440 ng/ml. There e was no ABO mismatch.
For transplant, Amina was given 150 modified long protocol of Flu 16 160 Bu and Cy. She tolerated conditioning well. Bone marrow was harvested from her donor (sister) on 24 Apr 2015 and transfused through central venous line the same day. Cyclosporine and short methotrexate were given as prophylaxis for graft versus host disease.
Post-transplant period was unremarkable. Neutrophil engraftment was achieved on D+14 and platelet engraftment on D+26. The patient was discharged to home after her neutrophil recovery and was advised weekly follow up in OPD.
In Oct 2015, Amina reported with 2-day history of pain abdomen along with 3 episodes of vomiting and constipation. She had tense abdomen with generalized tenderness. S. Amylase and S. Lipase were raised to 1370 u/l and 1127, respectively. A diagnosis of Acute Pancreatitis secondary to cyclosporine was made and patient was managed conservatively. The patient recovered, her pain subsided and laboratory findings returned to normal and she was discharged after 2 weeks in hospital.
Amina is now off immunosuppression, her STR for donor chimerism was more than 90% and lymphocyte subset analysis demonstrated good immune reconstitution. She has received her post-transplant vaccination as per protocol.
Amina has rejoined her school in class 6 and is living a normal life free from blood transfusions. She is a BMT survivor
Contributed By: Dr. Imtenan Sharif
Fazal was 15 months old when he first presented at AFBMTC in July 2017 with transfusion dependent anemia for last 7 months. He was born to a consanguineous marriage and had 3 elder healthy siblings. Examination revealed marked hepatosplenomegaly. He had noisy breathing and according to parents he had nasal obstruction since early infancy. Hearing and vision were intact. CBC showed anemia and thrombocytopenia. His X-ray chest and X-rays of long bones revealed markedly increased bone density with no intramedullary spaces. Bone marrow examination showed thick bony trabeculae and scarce hemopoietic tissue. He was diagnosed with osteopetrosis, the “Marble Bone Disease”. He had received 10 RCC and 16 units of platelets.
The patient was HLA matched with his elder sister Areesha and, at the age of 19 months, underwent Allogeneic bone marrow transplantation on 15 Nov 2017. Pre-transplant conditioning was 2 done with Fludarabine (150mg/m) and Busulfan (18mg/kg iv).
Bone marrow transplant course was largely uneventful, he achieved engraftment on day+16. However, discharged was delayed till day+43 due to fever caused by very resistant Stenotrophomonas maltophilia. After that, post-transplant course was smooth, tapering of immunosuppression was started at 9 months and stopped by 11 months post-transplant.
This November his 12 months post-transplant milestone has been achieved. He has good immune reconstitution and post-transplant chest x-ray showed normal bone density.
Contributed By: Dr Muhammad Farhan, FCPS (Clinical Haem)
Hamna from Multan was 5 months old when, in March 2010, she was diagnosed with β-thalassemia major and given first blood transfusion. She required blood transfusion every month and developed iron overload. Iron chelation therapy was started at the age of 2 years.
Fahad, Hamna’s younger brother, was HLA matched with his sister. The family reported at AFBMTC in February 2013 for transplant. As Hamna was in Pesro Class-III, modified long protocol with thiotepa was given for pre-transplant conditioning. Hamna underwent bone marrow transplant on 14
March 2014 at the age of 4 years. Her donor was just 2¼ years of age. Almost 3 years after her transplant, Hamna is off all medications. She is 7 years old now and studies in class 2. She visits AFBMTC at 6 monthly intervals for checkup. Fahad, Hamna’s bone marrow donor is now 5 years of age and enjoys his sister’s company.
Contributed By: Dr Imtenan Sharif
Mrs. Saima Mehdi, was 35 years of age when, in Oct 2013, she was transferred to AFBMTC with Acute Leukemia. Bone marrow examination demonstrated findings of AML M5a. Immunophenotyping was consistent with AML M2 and cytogenetics revealed 45XX with monosomy 8. She achieved remission after 2 courses of induction with D3A7. Being a high-risk case, upfront allogeneic HSCT from HLA matched brother was offered. Patient proceeded to USA for second opinion and reported back after 2 months without any treatment. Her bone marrow was still in remission. Consolidation was given with high dose Cytarabine. Pretransplant conditioning was with Bu16/ Cy200. Allogeneic HSCT was done on 9/5/2014. Engraftment was prompt and patient was discharged on Day+15. Patient was readmitted on Day+19 with complaints of vomiting and diarrhea. Upper GI endoscopy was normal. Positive PCR confirmed CMV reactivation which was treated with ganciclovir. Soon afterwards transplant associated microangiopathy (TMA) developed; cyclosporine was replaced with mycophenolate. There were multiple episodes of melena. A repeat endoscopy revealed erosive gastritis requiring intensive treatment. On Day+68 Mrs. Mehdi developed respiratory failure requiring mechanical ventilation. She was weaned off ventilator after 76 hours. CMV reactivated in Jul 2014 & responded to ganciclovir. In Nov 2014 the patient was admitted with shock and respiratory distress. Clinical and radiological findings were consistent with Invasive Aspergillosis which was treated with Amphotericin B. Immunosuppression was stopped at 6 months post-transplant. At 8½ months post BMT, PCR for HCV RNA came up positive. At the same time Herpes Zoster Opthalmicus developed. Treatment for HCV was postponed and patient was treated for HZ and post-herpetic neuralgia for months. Later Sofosbuvir and Ribavirin were started and PCR for HCV RNA became negative. Despite this turbulent course, donor chimerism remained more than 90% and lymphocyte subset analysis demonstrated good immune reconstitution. Mrs. Mehdi is now almost 3 years post-transplant. There is no sign of leukemia. She is off all medications and enjoying good quality of life with her family.
Contributed By: Dr Imtenan Sharif
Nk Ali Bux, a 33 year old, soldier serving in Pakistan Army was referred to AFBMTC on 10th Sep, 2012 with pancytopenia. The patient gave history of gum bleeding off & on for last 2 years. Couple of weeks before admission he sustained injury while cutting wood and reported to CMH Sialkot. He was found to have pancytopenia; bone marrow examination was consistent with aplastic anemia. The patient was then shifted to our center for further workup and management.
Initial work up confirmed diagnosis of Aplastic Anemia. Cytogenetics showed normal karyotype. Flowcytometry revealed 2% red blood cells deficient in CD55 and CD59. The patient was 8/8 HLA matched with his younger brother. There were no comorbidities and HCT-CI score was zero.
The patient underwent allogeneic hematopoietic stem cell transplant on 7th Dec, 2012. Pre-transplant conditioning consisted of Flu120Cy160ATG20. Source of stem cells was combined bone marrow and PBSC harvest with a total cell dose of 6.1 x108/kg. Post-transplant period was uneventful and patient continued his immunosuppressive medications for a year which were then tapered off. STRs for donor chimerism remained more than 90% and lymphocyte subset analysis reported good immune reconstitution.
Nk Ali Bux is now off all medicines and has completed his vaccination. He is feeling fit and enjoying normal life. After transplant Ali Bux has been blessed with a daughter and a son in 2014 and 2015, respectively.
Contributed By: Dr. Imtenan Sharif
Mrs. Saifullah, a 37-year-old school teacher, resident of Mianwali, was referred in Jan 2011 to AFBMTC with pancytopenia. Bone marrow examination was consistent with aplastic anemia. She underwent hematopoietic stem cell transplant from HLA matched brother on 4th Feb, 2011. Pre-transplant work up revealed normal cytogenetics and no comorbidities. Conditioning was done with Flu120Cy120ATG14. Stem cell source was bone marrow harvest. The patient had an uneventful posttransplant period. There was minimal GvHD and no major infections. Immunosuppressive medications were tapered off after one year and then stopped. STRs for donor chimerism remained more than 90% donor and lymphocyte subset analysis showed good immune reconstitution. She is now 6 years post-transplant and enjoys good quality of life with her family. She re-joined her job as a school teacher last year in Mar 2016.
Contributed By: Dr. Imtenan Sharif
Five-year-old Kashaf, daughter of a soldier of Pak Army developed complaints of progressive pallor, fatigue and easy bruising in Oct 2014. She had an episode of epistaxis in Feb 2015 for which she was taken to Multan CMH where she was found to have pancytopenia and a hypocellular marrow. In Apr 2015, the patient was referred to AFBMTC for further workup and management. A repeat BM examination revealed 5-10% cellularity, consistent with Very Severe Aplastic Anemia. HLA typing of siblings, parents and first cousins did not reveal a match. Cytogenetics and flowcytometry were negative for Fanconi’s anemia and PNH, respectively. Kashaf was put on Ciclosporin to which there was no response. Considering the disease severity and low probability of response to immunosuppressive therapy, it was decided to take the patient to haplo-identical transplantation. As this was the first patient who was being considered for haploidentical transplant at our center, a new conditioning protocol for aplastic anemia was made. Her donor was 7 years old sister with 75% HLA compatibility. Patient’s and donor’s pre-transplant workup were satisfactory. Pre-transplant conditioning consisted of Flu150Cy100TG10Thiotepa5 with post-transplant Cy100. Kashaf underwent haplo-identical stem cell transplant on 28th Aug 2015. Total nucleated cell dose achieved from primed bone marrow was 16 x108/kg with a CD34 count of 9.12 x106/kg. Neutrophil recovery was on D+14. In addition to post-transplant cyclophosphamide, Ciclosporin and MMF were given for GVHD prophylaxis. Post-transplant, the patient developed hemorrhagic cystitis which she was managed accordingly. She also had CMV reactivation with PCR revealing 11,333 copies/ml and was treated with IV ganciclovir. Her STR for donor chimerism remained more than 90% and lymphocyte subset analysis reported good immune reconstitution at 3, 6 and 12 months respectively. Her immunosuppression was tapered off and stopped after 1 ½ years of transplant. Now, almost 2 years after her transplant, Kashaf has no sign of GVHD and enjoys good quality of life with her family.
Contributed By: Dr. Imtenan Sharif
Hadia is daughter of an officer serving in the Pakistan Army. She was diagnosed as case of β-thalassemia major at the age of 6 months. The patient was 4 years old when she first reported at our center. She was 8/8 HLA matched with her younger sister Anoosha. At the time of transplant, Hadia was 4 years and 2 months old while her donor Anoosha was 9 months of age.
Hadia underwent transplant on 25 Jan 2008. Her pre-transplant conditioning consisted of short protocol consisting of Busulfan and Cyclophosphamide. Stem cells were collected by bone marrow harvest. Cyclosporine was given for graft versus host disease (GVHD) prophylaxis. The patient had prompt engraftment with neutrophil recovery on day+15. There were no significant transplant related complications. Post-transplant, STRs for donor chimerism remained more than
90% and lymphocyte subset analysis showed good immune reconstitution. Immunosuppression was tapered off and stopped after 1 year of transplant and vaccination was done as per protocol.
The patient required a few sessions of phlebotomies for high serum ferritin levels (3619 ng/ml). There is no sign of GVHD with normal growth pattern. Hadia is now 13 years old and is in 7th class while her donor Anoosha is of 10 years of age studying in class 4. Anoosha is the youngest bone marrow donor for a sibling at our center.
Contributed By: Dr. Imtenan Sharif
Mr. Zaheer, 41 years of age, presented with short history of easy fatigability and weight loss in Dec 2014 at another hospital. Physical examination revealed a palpable spleen tip. Blood picture and bone marrow exam were consistent with Chronic Myeloid Leukemia in accelerated phase. PCR for bcr-abl1 was positive. The patient was put on nilotinib in Jan 2015 which was stopped due to severe pancytopenia in April 2015. The patient was then referred to AFBMTC in May 2015.
Bone marrow examination done at our center showed iatrogenic hypoplasia with focal collections of blasts and grade ll fibrosis. Cytogenetics were positive for Philadelphia chromosome in all metaphases of 46XY. On recovery of blood counts, the patient was given a trial of imatinib but once again the drug had to be stopped due to low platelets. On recovery of blood counts, the patient was given a trial of imatinib but once again the drug had to be stopped due to low platelets. 2016. Source of stem cell was bone marrow. Total nucleated cell dose was 4.28 x108/kg. GVHD prophylaxis was with ciclosporin and short methotrexate. Neutrophil engraftment was on 13th post-transplant day.
Mr. Zaheer was troubled by grade III mucositis but otherwise there was no major complication. He improved gradually and was discharged. Subsequently, mild chronic GvHD involving skin, eyes and liver developed due to which Immunosuppression was continued till 6 months after which tapering was started. Test for donor chimerism showed complete donor chimerism.
Mr. Zaheer is now on nilotinib (150mg twice daily) which he is planned to take for 2 years posttransplant. His latest FISH for BCR ABL is negative. There is no GvHD, he enjoys good quality of life with his family and has rejoined full time job.
Contributed By: Dr. Imtenan Sharif
Sahir Fatima from Multan was diagnosed with β-thalassemia major on 25th Feb, 2001. She received her first blood transfusion at the age of 3.5 years. Since then, she was transfused blood on monthly basis. She reported at AFBMTC on 12th April, 2014 with 8/8 HLA matched sibling.
Sahir was 15 years of age and had approximately received 150 RCC transfusions when she reported at AFBMTC. On examination liver was palpable 3 cm below right costal margin with rest of the examination being unremarkable.
Her liver biopsy was performed which revealed a Knodell Score as follows: Hepatic Activity Index 2/18 and Fibrosis 1/6. During pretransplant assessment, Sahir’s anti HBc antibody and anti HCV antibody came up positive. However, PCR for HCV RNA and HBV DNA were negative. There was no ABO mismatch.
Conditioning for transplant was given with long protocol of Flu150 BuIV Cy160 Thiotepa10 and ATG10. She tolerated conditioning well. Bone marrow was harvested for her donor sister) on 4th Sep, 2015 and the harvest yielded a Total Nucleated Cell dose of 5.13 x108/kg and a CD34 count of 8.19 x106/kg.
The patient received cyclosporine and methotrexate for graft versus host disease prophylaxis. She developed mild hematuria on D+10 which was managed conservatively and settled by D+14. Neutrophil engraftment was achieved on D+15 and platelet engraftment a little later on D+27.
Sahir’s immunosuppression was tapered off and stopped after 1 year of transplant and she was revaccinated as per protocol. Her donor chimerism remained more 90% and lymphocyte subset analysis demonstrated good immune reconstitution. Sahir is a Survivor. She is now studying in college and enjoys good quality of life with her family and friends.
Contributed By: Dr. Imtenan Sharif
Husnain was just one year old when, in March 2013, he presented with history of recurrent fever and rash. He had gross hepatosplenomegaly 9 and WBC count of 40 x 10 /l with absolute monocyte count of 11.2 x 9 10 /l. There were 4% blasts on peripheral film and 8% on bone marrow examination, consistent with diagnosis of Juvenile Myelomonocytic Leukemia. PCR for BCR-ABL, Hb electrophoresis and cytogenetics were unremarkable.
Husnain reported at AFBMTC in Jun 2013. On examination liver and spleen were palpable 5 cm and 4 cm below costal margin, respectively. He was put on hydroxyurea and folic acid. The patient had HLA matched sister and was scheduled to undergo allogeneic stem cell transplant in Feb 2014.
However, the patient continued to have low grade intermittent fever. A repeat bone marrow examination demonstrated no progression of disease. Work up for infectious disease etiology also came up negative. Fever did not respond to antibiotics and antifungal therapy and was considered due to disease burden.
Therefore, before transplant, 2 courses of low dose cytarabine (100mg x 5 days) were given to which the patient responded quite well and his fever subsided. However, hepatosplenomegaly persisted (Liver 9 cm; Spleen 10 cm).
During transplant conditioning was 16 160 140 given with Bu Cy Mel (recommended by EBMT/EWOG- MDS group for children). Husnain tolerated conditioning well. Bone marrow was harvested from his 8/8 HLA matched sister on 16 May 2014. As there was an ABO mismatch, bone marrow harvest was processed which yielded a dose 8 (MNC) of 5.0 x10 /kg. The bone marrow was transfused the same day through central venous line.
Graft versus host disease (GvHD) prophylaxis was given with cyclosporin (CSA) short methotrexate (MTX). Neutrophil engraftment was achieved on D+14 and platelet engraftment later on D+87. Liver at the start of conditioning was 9 cm BCM which regressed to 5 cm at the time of discharge on D+20.
Husnain’s donor chimerism was more than 90% at 1 and 3 months. However, he was not maintaining Hb and was on regular RCC transfusions. His bone marrow examination on D+138 was consistent with post-transplant pure red cell aplasia.
The patient was given 2 doses of 2 Rituximab at 375mg/m after which his Hb came up and he became transfusion free. The donor chimerism remained more than 90% and lymphocyte subset analysis demonstrated good immune reconstitution. Immunosuppression was stopped at 6 months post-transplant. By this time there was no visceromegaly. Vaccination was carried out as per protocol.
Husnain is now 5 ½ years old and enjoys good quality of life with his family.
Contributed By: Dr. Imtenan Sharif