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Haplo HSCT
- 1. Haploidentical Stem celltransplantation Arjun Mandade Coordinator- Rasmi P
- 2. • History anddevelopment • Principles • Role of RT • Role of ATG • Role of various conditioning regimens and their outcome • To understand and manage complications of Haplo BMT
- 3. Father of bonemarrow transplantation DR. E. DONNALL THOMAS(DON)
- 4. Introduction H S CT h a s e v o l v e d … . . D E A D … … 1 9 6 0 s From the laboratory to clinical reality.
- 5. Early Enthusiasm and Disappointment •Research efforts on how to repair radiation effects – atomic bomb- JAPAN. • In 1949, Jacobson and colleagues- protection of mice from TBI----2 y r s l a t e r … • Lorenz - protection of mice and guinea pigs by infusing marrow cells. • Initially many investigators- some humoral factor(s) in spleen or marrow. • M i d 1 9 5 0 s – REJEC TED.
- 6. • In 1967,van Bekkum and de Vries stated- –clinical applications were undertaken too soon –most of them before even the minimum basic knowledge – Clinical HSCT was declared a total failure. History continues….
- 7. Resuming Clinical Transplantation: 1968–1980s •Second half of the 1960s- HI conditioning regimens • TBI and maximally tolerated doses of CY or BU. • By 1968 -stage was set . • First successful transplants- –Primary immune deficiency disorders. –A 5-month-old boy with “thymic alymphoplasia and agammaglobulinemia –Marrow and peripheral blood cells were infused intraperitoneally without conditioning.
- 8. • During thefirst 7 or 8 years- advanced hematological malignancies and SAA. • Longest survivors - aplastic anemia who are approaching their 47th anniversary from HSCT. • Failure- graft rejection. • Finally- irradiation of blood products with 2000 cGy . • Graft rejection in transplantation for AA- EXCEPTION- with HLA-identical sibling , HLA- matched unrelated grafts range from 90% to 100%.
- 9. Moving Ahead: The1990s and Beyond • Conventional HSCT – High-intensity – Risky and – Requires specialized intensive care wards. • Toxicities restrict - younger, medically fit • Older, medically infirm or very young – Less intensive. • Reduced-intensity regimens- tolerated, BUT relapse and GVHD.
- 10. PRINCIPLE OF HSCT •Simple: “High-dose radiation/chemotherapy would both destroy the diseased marrow and suppress the patient’s immune cells for a donor graft to be accepted.”
- 11.
- 12. • Major breakthroughin the history of successful haplo-hsct: – Efficient T cell-depletion. – Prevented both acute and chronic gvhd. • Importance of t cell-depleted haplo-hsct: – First shown in children SCID. • However- – BM cells obtained from an hla-haploidentical – Associated with a high engraftment- SCID – Unacceptably high incidence of graft failure- acute leukemias
- 13. • In thesecases, due to the extensive T cell-depletion- BALANCE. • Possible solution to this obstacle: – “Megadoses” of G-CSF -to overcome the barrier of HLA incompatibility . • This approach into the clinical setting was first reported- pilot study : – Transplanted “megadoses” of T cell-depleted HSC - without any subsequent pharmacological GvHD prophylaxis.
- 14. • Engraftment ratewas above 90%. • Cumulative incidence of both grade II–IV acute and chronic GvHD below 10%. • U s i n g p u r i f i e d C D 3 4 + c e l l s h a v e c o n f i r m e d : – sustained engraftment – without the occurrence of GvHD – become long-term survivors
- 15. • Underlining forthe first time - not only adaptive immunity, but also innate immunity- crucial element • INDEED - therapeutic effect of haplo-HSCT is largely dependent on the GvL effect. • It is now evident that - GvL effect can be mediated by donor-derived alloreactive NK cells.
- 16. ROLE OF RT •1956 by Dr. Donnall. • Rationale for use of TBI not changed. • Tremendous change in – Delivery of TBI – Radiation sources used – Co^60 / LINAC – Dose measure techniques- more reliable and accurate rather than erythema dose for determination of dose delivered
- 17. TBI • One ofmain component in interdisciplinary treatment. • Enables myeloablative high dose therapy (HDT) & immunoablative conditioning therapy • TA S K S : • Eradicating diseased marrow • Reducing tumor burden • Immunosuppression • Deplete the BM • Eradication of cells with genetic disorders-
- 18. Targeted TBI –TMI and TMLI • Total marrow irradiation - skeletal bone. Conditioning regimen for multiple myeloma • Total marrow and lymphoid irradiation (TMLI) - bone,major lymph node chains, liver, spleen, and sanctuary sites, such as brain. - - Conditioning regimen for myeloid and lymphoid leukemia
- 19. Current Indications • HighRisk AML/CML In First Remission. • Second Remission AML • Second Remission ALL If There Is HLA Compatible Sibling Donor • First Remission ALL With CNS Involvement / Ph Chromosome Postivity • Low Grade Lymphoma After Chemo Failure • Childhood AML/ ALL In Second / Subsequent Remissions
- 20. ADVANTAGES • No sparingof sanctuary sites (testis, brain) • Dose homogeneity regardless of blood supply • Independent of hepatic & renal functions • No problems with excretion or detoxification • Ability to tailor the dose distribution by shielding specific organs or by boosting sites
- 21. DISADVANTAGES • Potential lateside effects Sterility Cataract Growth retardation Neurological toxicity • Patient body contour irregularities causes adding of compensators
- 22. TECHNIQUES OF TBI IMPORTANTCRITERIAS: • Patient comfort and Reproducibility • Position of patient and stability • The common factor in the different techniques of TBI is to deliver the prescribed dose of radiation to the entire body in uniformity of +/-10% of the prescription dose. +/-5% considered as the best.
- 24. BILATERAL TBI • Designedby Khan et al • Patient sitting or lying down on a couch • Good Patient comfort • Less homogeneous dose distribution due to variable body thickness, needs compensating blocks.
- 25. TARGET VOLUME • All malignantcells including those circulating • whole cellular immune system • The Whole Body, including Skin
- 26. DOSE PRESCRIPTION • HighDose TBI – 13.2 Gy in 6 fractions over 3 days • Standard dose TBI – 12 Gy in 6 fractions over 3 days • Low dose TBI – 2 Gy in single fraction • Lung is the dose-limiting organ (maximum 10 Gy).
- 27. ACUTE COMPLICATIONS • Nausea&Vomiting • Headache • Fatigue • Ocular dryness • Esophagitis • Loss of apetite • Erythema/hyperpigmentation • Mucositis • Diarrhea • Fever
- 28. CHRONIC COMPLICATIONS • Ocular– Cataract, dryness, keratitis • Salivary glands – Xerostomia, dental caries, tooth abnormalities • Pneumonitis or pulmonary fibrosis • Hepatotoxicity • Radiation nephropathy • Growth abnomalities in children • Sterility and endocrine abnormalities • Secondary mets
- 29.
- 30. Mobilization • A techniqueused to increase the number of circulating hematopoietic stem cells from the bone marrow into the bloodstream. • Only used for patients undergoing a peripheral blood stem cell transplant (not bone marrow transplant)
- 31. • Progenitor cellsbegin rapid reproduction when depletion is recognized. • Depletion occurs by natural processes (aging/illness) and by artificial means (cell depletion by chemotherapy). • Artificially causing depletion will result in an increase in progenitor cell counts. • Excess progenitor cells in the bone marrow will be forced into the peripheral blood. The premise of mobilization is based on the following…
- 32. Mobilization: Growth FactorAlone • Standard : 300-480mcg daily until after chemotherapynadir • Mobilization dosing: 10-32mcg/kgQD until apheresiscomplete. • Basically 2-4x dose.
- 33. Side Effects • BonePain (reported at 86%) *Spine, hips, pelvis, ribs and sternum • Headache (reported at ~40%) • Injection-site irritation • Flu-like symptoms • Extremely Rare-Splenic rupture • Long-term sequelae are unknown but following healthy donors for more than 20 years has shown no greater health complications than healthy siblings
- 34. UCB transplant inthe Indian context • UCB, the most recently identified source of stem cells, appears to be as effective as bone marrow when an HLA-matched adult donor is not available. • 26 million births per year. • Would be poised to be the largest collector of UCB in the world. • Three & ten private banks - international companies. • Cryo Stemcell, Banglore, Karnataka Pvt Ltd is India's first family cord blood bank
- 36. Success of UCBtransplantation in the world • BM and PBS - proven track record of success. • 13 million registered volunteer donors- accessible worldwide. • In a report of 623 consecutive patients - that ALL. • 8.3 years of follow up, – five year overall survival- 29% – leukemia free survival (LFS) – 26 % – relapse were- 43% • Five year LFS – RD(31%), URD(17%), UCB(27%)
- 37. • UCB haspotential applications in non-malignant and metabolic disorders- thalassemia. • Fanconi anemia - significantly improved engraftment (89 vs 69%) and survival (52 vs. 13%) in those received fludarabine versus no fludarabine. • Major problem faced in India- to high cost and comparatively less functional public banks. • Need more public banks- affordable/ non affordable people.
- 38. Different modalities ofhaplo-HSCT.
- 39. Anti-thymocyte Globulin (ATG) Based •In 2006 the Chinese—158-HLA-identical V/S 135 Haplo after a MAC regimen • R e s u l t s w e r e s u r p r i s i n g : OS and DFS identical for both groups – Ara-C (4 g/m2/day, on days −10 to −9), – BU (4 mg/ kg/day, orally on days −8 to −6 before January 2008 and 3.2 mg/kg/day, IV on days −8 to −6 after January 2008) – CY (1.8 g/m2/day, on days −5 to−4), – Me-CCNU (250 mg/m2, once on day −3), – ATG (2.5 mg/kg/day, rabbit; Sanofi Genzyme, France, days −5 to −2)
- 40. • All patientsreceived CSA, MTX, and MMF. • Graft source was a combination of G-BM and G- PB. • Mismatch group had a higher risk of acute GvHD and of TRM but OS was comparable (P = 0.6). • F I R S T R E P O R T on a large number of family mismatched grafts- showing survival identical to sibling HLA-matched grafts.
- 41. • ATG-based programwith unmanipulated G-BM alone. • INTENSIVE GVHD prophylaxis - ATG, CSA, MTX, and MMF with the addition of basiliximab, an anti- CD25 antibody. • ACUTE GvHD grade II–IV and III–IV was, respectively, 24% and 5% - extremely low for family HLA-haplotype mismatch, T-cell-replete transplants. • 3 yr OS- 54% for SR and 33% fro HR.
- 42. • Use ofPT-CY on day +3 and +4 pioneered by the Baltimore group. • BASED ON THE IDEA THAT : - High-dose CY (50 mg/kg) will kill alloreactive T-cells proliferating on day +3 and +4 after the transplant. - Whereas stem cells would be protected because they are not proliferating and with a high concentration of aldehyde dehydrogenase. Post transplant Cyclophosphamide (PT-CY)
- 43. • In 2001,the Baltimore group- first clinical study: – PT-CY was able to protect patients from GvHD after haplo-HSCT. • Again, this was not picked up immediately: - Not until 2008- haplo-HSCT in HL produces DFS superior to sibling or unrelated transplants. - Not only GvHD could be prevented, but GvL superior, at least in with HL.
- 44. • A totalof 30 studies including 22,974 participants. • PT-CY increased all-cause mortality compared with • MRDs (matched related donors). • Similar with MUDs(matched unrelated donors) • Reduced with MMUDs(mismatched unrelated donors) • Nonrelapse mortality - WORSE outcomes compared with MRDs but BETTER outcomes compared with MUDs. • Relapse- PT-CY was a/w similar outcome compared with MRDs and MMUDs but showed increased relapse compared with MUDs.
- 45. Baltimore protocols • Numerousvariations of the Baltimore protocol • G-PB instead of BM, rapamycin and MMF instead of a CNI • MAC regimen instead of the NMA.
- 46.
- 47. ATG + PT-CY •Baltimore group is using- sickle cell disease. • Saint-Antoine, Paris: – combination of ATG 2.5 mg/kg and PT-CY, CSA, and MMF – acute leukemia undergoing a MAC haplo-HSCT
- 48.
- 49. • Anti CD52- T, B and some dendritic and NK cells. • Combined use of alemtuzumab (100 mg), fludarabine, and cyclophosphamide : – in low cumulative incidence of acute GVHD. – low TRM acceptable incidence of primary graft failure (GF).
- 50. • MYELOID DISEASE: – Fludarabine (40 mg/m2 /day) - on days −5 through −2 – Busulfan (130 mg/m2 /day) - on days −3 through −2 – Alemtuzumab (20 mg/day) - on days −4 through −1 • LYMPHOID DISEASE: – Fludarabine (40 mg/m2 /day) - on days −5 through −2 – Melphalan (140 mg/m2 /day) - on day −2 – Alemtuzumab (20 mg/day) - on days −4 through −1
- 51. • NEUTROPHIL ENGRAFTMENT: –After MRD, MUD, or HAPLO transplantation was 19, 19 and 16.5 (P = .06), respectively. • CHRONIC GVHD: – 2 years after transplantation from MRD, MUD, or HAPLO donors was 22%, 35% and 39% respectively. • 2-year : – DFS rate after SCT from MRD, MUD, and HAPLO donors was 47% ,23%, and 16% respectively. – PFS rate was 43% , 22%, and 15% respectively. – OS rate was 51%, 22%, and 23% respectively – MUD or HAPLO donors in comparison to MRD was the only adverse factor - OS
- 52. CONCLUSION: Reduced-intensity regimen thatincluded fludarabine, busulfan or melphalan, and alemtuzumab (80 mg), using only mycophenolate mofetil as the GVHD prophylaxis, conferred favorable outcomes in the MRD group but lower survival rates in the MUD and HAPLO groups.
- 53. • Alemtuzumab- 0.25mg/kg for 2 days on days −4, and −3. • Primary out‐ come measure - Survival rate with the engraftment of donor cells and without grade III‐IV aGVHD at 60 days
- 54. • The primaryoutcome measure was achieved in 86%. • Six – Relapsed. • Three- Non relapsed death • Overall survival and progression free survival rates at 1 year were 51% and 43%, respectively. • No deaths due to viral infection. • slower recovery of CD8+ T‐cells and lower incidences of GVHD and EB virus reactivation
- 55. Other Relevant Aspectsof Haplo-HSCT 1. Choice of the Best Haploidentical Donor:
- 56. 2. Comparison ofATG-Based Versus PT-CY-Based Platforms: - EBMT Acute Leukemia Working Party . - ATG-based haplo grafts grafts had a higher risk of failure – - LFS (RR 1.48, p = 0.03), - GvHD relapse-free survival (RR 1.45, p = 0.03), and - OS (HR 1.43, p = 0.06) learning curve is required for optimal results in haplo-HSCT
- 57. 3. Bone Marrowor Peripheral Blood: -Now two studies comparing BM versus PB for unmanipulated haplo-HSCT • EBMT study : – Increased GVHD II–IV and III–IV with PB, – Same chronic GVHD, same relapse, and same 2-year OS (55% and 56%). • Cibmtr study: – Increased GVHD II–IV, BUT not III–IV with PB grafts, – Increased chronic GVHD, and reduced relapse, – Survival at 2 years also in this study is quite similar, 54% vs 57%.
- 58. Advantages and Limitationsof Haploidentical Donors • MAJOR ADVANTAGES: – Increased availability of highly motivated donors. – Immediate availability. – Adequate doses of hematopoietic stem cells. – Lower cost of graft acquisition. – Immediate availability of the donor for repeated donations of HSCs or lymphocytes to treat relapse.
- 59. • MAJOR DISADVANTAGES: –Higher rate of fatal graft rejection. – Severe or fatal GVHD in the absence of effective prophylactic measures. – Increased non relapse mortality (NRM) due to infectious complications.
- 60.
- 61. GRAFT VS TUMOREFFECT (GVT) • Most potent form of tumor immunotherapy currently in clinical use. • Contribute towards curative aspect of allogenic HSCT • Poorly understood • Allogeneic T cells clearly play a fundamental role in the initiation and maintenance of the effect on neoplastic cells mainly CD8, CD4 and NK cells (Tumour specific CTLs)
- 62. FORMS OF GvHD (Glucksberg-Seattleclassification) ACUTE (OCCURING WITHIN 100 DAYS ) CHRONIC (OCCURING AFTER 100 DAYS ) clinical manifestation and histologic findings are now the sole factors used in defining these distinct entities
- 63. GRADING OF ACUTEGvHD
- 64. ACUTE GvHD • Incidenceis about 20-70% • Depends upon • Conditioning regimen intensity • HLA disparity between donor and recipient • Age of the recipient • Stage of primary disease • Clinical staging is established which takes into account the primary organ involvement (Skin,Liver,GIT)
- 65.
- 66. PROPHYLAXIS • Steroids • MTX •Mycophenolate mofetil • Cyclosporin/Tacrolimus (Calcineurin A Inhibitor) • ATG • Post transplant Cyclophosphamide • T Cell Depletion Esp Cd45ra + T Cells • α & β T CellDepletion
- 67. CHRONIC GvHD • Reportedin 60 to 70% of allogenic recipients • Limited information available • More extensive involvement but most people recover • Involve practically all the organs • Shares common features with many autoimmune diseases like Scleroderma, Sicca syndrome etc
- 68. CHRONIC GvHD PATHOPHYSIOLOOGY Decreasednumber of regulatory T cells B cell dysregulation and production of autoantibodies Decreased negative selection of T cells Th2 type response Th2 Cytokines Increase THYMIC DYSFUNCTION Acute GvHD Conditionin g
- 71. GRAFT-VS-LEUKEMIC EFFECT • NKcell alloreactivity – plays IMP role. • Described by Moretta et al.(1990) over 20 years ago: –Associated with defined NK cell subsets –Or lack thereof of novel surface molecules –Identified as HLA class i-specific receptors • Emergence of the concept - revolution in the field of haplo-HSCT.
- 72. GVHD Prophylaxis -How much? Aggressive Prophylaxis •LESS GVHD •MORE infection •MORE relapse Minimal Prophylaxi •MORE GVHD •LESS infection •LESS relapse SURVIV AL
- 73. SUMMARY • Despite advancesin procedure and post- transplantation prophylaxis more than half of Allogenic HSCT patients develop GvHD • Major cause of morbidity and mortality • Still poorly understood • Elimination of alloreactive T cells and preserving tumor and pathogen-specific
- 74. KEY POINTS Following thepioneering work of the Perugia group, HLA-haplotype mismatch family transplants- • Rapidly increasing in numbers • With encouraging results in most centers • True with different stem cell sources • Different conditioning regimens, and • Different GVHD prophylaxes IN ONE WORD, THERE IS MORE THAN ONE WAY TO PERFORM HAPLO-HSCT.
- 75. • One importantquestion is how haplo- HSCT compare with unrelated donor grafts: – answer this question, randomized trials have been designed and are about to start.
- 76.
Editor's Notes
- #4 a hematologist who earned a Nobel Prize in 1990 for establishing bone marrow transplantation as a successful treatment for leukemia and other blood conditions, died Oct. 2012 at the age of 92.
- #5 HSCT has evolved from a field that was declared dead in the 1960s to the amazing clinical results obtained today in the treatment of otherwise fatal blood disorders. We will see how HSCT has progressed from the laboratory to clinical reality.
- #6 Research efforts on how to repair radiation effects resulted from observations on radiation damage among survivors of the atomic bomb explosions in Japan. In 1949, Jacobson and colleagues discovered protection of mice from TBI by shielding their spleens with lead. Two years later, Lorenz and colleagues reported radiation protection of mice and guinea pigs by infusing marrow cells. Initially many investigators, including Jacobson, thought that the radiation protection was from some humoral factor(s) in spleen or marrow. However, by the mid-1950s, this “humoral hypothesis” was firmly rejected, and several laboratories convincingly demonstrated that the radiation protection was due to seeding of the marrow by donor cells.
- #7 In 1967, van Bekkum and de Vries stated, “These failures have occurred mainly because the clinical applications were undertaken too soon, most of them before even the minimum basic knowledge required to bridge the gap between mouse and patient had been obtained.” Clinical HSCT was declared a total failure and prominent immunologists pronounced that the barrier between individuals could never be crossed.
- #8 The second half of the 1960s saw the refinement of high-intensity conditioning regimens, including fractionated TBI and maximally tolerated doses of CY or BU. By 1968, the stage was set to resume clinical trials. The first successful transplants were for patients with primary immune deficiency disorders. A 5-month-old boy with “thymic alymphoplasia and agammaglobulinemia” was not perfectly matched with his sister. Marrow and peripheral blood cells were infused intraperitoneally without conditioning. After a booster infusion several months later, the patient fully recovered with donor hematopoiesis and is well.
- #9 During the first 7 or 8 years, most clinical studies were for patients with advanced hematological malignancies and SAA, who were in poor condition and presented tremendous challenges in supportive care. The longest survivors from that era are patients with aplastic anemia who are approaching their 47th anniversary from HSCT with fully recovered donor-derived hematopoiesis and leading normal lives. Chronic GVHD emerged as a new problem among long-term survivors. The major cause of failure was graft rejection as expected from canine studies on transfusion-induced sensitization to minor antigens. Finally, irradiation of blood products with 2000 cGy in vitro almost completely averted sensitization to minor antigens. Consequently, graft rejection in transplantation for AA has become the exception, and current survivals with HLA-identical sibling and HLA-matched unrelated grafts range from 90% to 100%.
- #10 Conventional HSCT following high-intensity conditioning is risky and requires specialized intensive care wards. The associated toxicities restrict the therapy to younger, medically fit patients. To allow the inclusion of older (highest prevalence of hematological malignancies), medically infirm or very young immunodeficiency patients, less intensive conditioning programs have been developed. While reduced-intensity regimens have been well tolerated, but risk of relapse and GVHD is there, which needs improvement.
- #11 The principle of HSCT was simple: high-dose radiation/chemotherapy would both destroy the diseased marrow and suppress the patient’s immune cells for a donor graft to be accepted.
- #12 In this protocol, HSC-enriched cell populations are obtained by negative selection upon removal of T cell receptor α/β+ T cells and CD19+ B cells. Notably, in addition to CD34+ cells, these cell suspensions contain mature NK cells and TCR γ/δ+ T cells. Using this strategy, two sources of alloreactive NK cells will come into play: (1) those generated from CD34+ cells after 6–8 weeks from transplantation and (2) those present in the fresh cell suspension infused into patients. It is evident that the prompt availability of alloreactive effector cells may greatly improve the anti-leukemia effect and the removal of residual patient’s DCs and T lymphocytes, thus ensuring a more efficient prevention of leukemic relapses, GvHD and graft-rejection. In addition, transplanted NK and γ/δ T cells may provide a first line of defense against different infectious agents.
- #13 A major breakthrough in the history of successful haplo-HSCT was the demonstration that an efficient T cell-depletion of the graft prevented both acute and chronic graft-vs-host disease (GvHD), even when the donor was a relative differing for an entire HLA-haplotype from the recipient. The importance of T cell-depleted haplo-HSCT was first shown in children with severe combined immunodeficiency and it can now be estimated that hundreds of SCID patients have been transplanted worldwide using an HLA-haploidentical related donor, with a high rate of long-term, either partial or complete, immune reconstitution. However, while the infusion of bone marrow (BM) cells obtained from an HLA-haploidentical relative was associated with a high engraftment rate in children with SCID, it was associated with an unacceptably high incidence of graft failure in patients with acute leukemia
- #14 In these cases, due to the extensive T cell-depletion of the graft, the balance between competing host and donor T cells shifts in favor of the unopposed host-vs-graft rejection. As a possible solution to this obstacle, the use of “megadoses” of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood-derived HSC was shown, in animal models, to overcome the barrier of HLA incompatibility and to elude the residual anti-donor T lymphocyte reactivity of the recipient. An effective translation of this approach into the clinical setting was first reported in a pilot study performed in adults with acute leukemia (Aversa et al., 1994). In this study, Aversa et al. (1994) transplanted “megadoses” of T cell-depleted HSC from BM or G-CSF-mobilized peripheral blood without any subsequent pharmacological GvHD prophylaxis.
- #15 The reported engraftment rate was above 90% with a cumulative incidence of both grade II–IV acute and chronic GvHD below 10%. Clinical trials performed using purified CD34+ cells have confirmed that sustained engraftment of donor hematopoiesis, without the occurrence of GvHD, can be obtained in the majority of adult patients and that a substantial proportion of them, especially when affected by acute myeloid leukemia (AML) or myelodysplastic syndromes, become long-term survivors
- #16 underlining for the first time that not only adaptive immunity, but also innate immunity is a crucial element for guaranteeing a successful clinical outcome. Indeed, it became evident that the therapeutic effect of haplo-HSCT is largely dependent on the GvL effect exerted by NK cells which originate from donor HSC and largely contribute to eradicate leukemia cells surviving the preparative regimen. it is now evident that, in haplo-HSCT, an efficient GvL effect can be mediated by donor-derived alloreactive NK cells which compensate for the lack of T cell intervention.
- #17 TBI started using in 1956 by Dr. Donnall Thomas to treat patients with end stage leukemia. Rationale for use of TBI not changed Tremendous change in Delivery of TBI Radiation sources used – Co^60 / LINAC Dose measure techniques- more reliable and accurate rather than erythema dose for determination of dose delivered
- #18 One of main component in interdisciplinary treatment of hematological malignancies- leukemia, lymphoma, rarely solid tumors Enables myeloablative high dose therapy (HDT) & immunoablative conditioning therapy prior to stem cell transplantation TASKS: Eradicating diseased marrow Reducing tumor burden Immunosuppression- lymphocyte elimination to allow grafting of donor bone marrow Deplete the BM to allow physical space for engraftment of healthy donor marrow Eradication of cells with genetic disorders- Fanconi’s anemia, thalassemia major, Wiskott- Aldrich syndrome
- #33 Standard (those who JUST need recovery after chemo): 300-480mcg daily until after chemotherapy nadir Mobilization dosing: 10-32mcg/kg QD (or divided and administered BID) until apheresis complete Basically 2-4x dose, which means more significant s/e
- #35 UCB, the most recently identified source of stem cells, appears to be as effective as bone marrow when an HLA-matched adult donor is not available With India's booming birth rate of 26 million births per year30 and genetic diversity; the country would be poised to be the largest collector of UCB in the world. Three public banks are established in India – Relicord, Jeevan Cord and Stemcyte, collectively having 5,000 units. Similarly, ten private banks have been established to date. Most of these are affiliated with or are subsidiaries of international companies. Cryo Stemcell, Banglore, Karnataka Pvt Ltd is India's first family cord blood bank, established in May 2003.
- #37 While bone marrow and peripheral blood stem cell transplants have a proven track record of success, the search process can take several months. Despite almost 13 million registered volunteer donors are presently accessible worldwide, many patients do not get HLA matched grafts. In a report of 623 consecutive patients undergoing myeloablative transplant at the University of Minnesota, Tomblyn and colleagues14 have shown that ALL. After a median of 8.3 years of follow up, five year overall survival, leukemia free survival (LFS) and relapse were 29, 26 and 43 per cent respectively. Five year LFS was 40, 42 and 49 per cent with related donors (RD), well matched unrelated donors (URD) and UCB sources, respectively, while relapse was 31, 17 and 27 per cent in the same group.
- #38 In addition to paediatric and adult haematological malignancies, UCB has potential applications in non-malignant and metabolic disorders17. . In cases of Fanconi anemia, Gluckman et al20 have demonstrated significantly improved engraftment (89 vs 69%) and survival (52 vs. 13%) in those received fludarabine versus no fludarabine. The major problem faced in India is collection of UCB due to high cost and comparatively less functional public banks. In addition, considering a large population with deliveries in public hospital due to low cost, UCB storage in India needs increased public-private partnership model where UCB can be stored by affordable and non-affordable people as well.
- #39 Fig. 65.1 Different modalities of haplo-HSCT. details abbreviations: ATG anti-thymocytenglobulin, GBMnG-CSF-mobilized bone marrow, MTX methotrexate, PT-CY post transplant cyclophosphamide, CNI calcineurin inhibitor, MMF mycophenolate, Rapa rapamycin
- #40 In 2006 the Chinese group led by Dao-Pei Lu compared the outcome of 158 leukemia patients grafted from HLA-identical siblings with 135 leukemia patients grafted from HLA-haplotype mismatch family members, after a MAC regimen. ATG-based; (GBM + G PB +CSA + MMF + MTX). results were surprising, with the OS and DFS identical for both groups. The conditioning therapy consisted of Ara-C (4 g/m2/day, on days −10 to −9), BU (4 mg/ kg/day, orally on days −8 to −6 before January 2008 and 3.2 mg/kg/day, IV on days −8 to −6 after January 2008), CY (1.8 g/m2/day, on days −5 to −4), 1-(2-chloroethyl)-3-(4-methylcyclohexyl)- 1-nitrosourea (Me-CCNU) (250 mg/m2, once on day −3), and ATG (2.5 mg/kg/day, rabbit; Sanofi Genzyme, France, days −5 to −2).
- #41 All patients received CSA, MTX, and MMF; the c(Lu et al. 2006). The graft source was a combination of G-CSF (G)-mobilized bone marrow (G-BM) and G-mobilized PB. The cohort in HLA-haplotype mismatch group had a higher risk of acute GvHD (P = 0.02) and of TRM (P = 0.05), but OS was comparable (P = 0.6). This was the first report on a large number of family mismatched grafts, showing survival identical to sibling HLA-matched grafts, and this led to the emergence of other programs.
- #42 Another group of Chinese investigators developed an ATG-based program with unmanipulated G-BM alone (G-BM + CSA + MMF + MTX + basiliximab). They included intensive GvHD prophylaxis with ATG, CSA, MTX, and MMF with the addition of basiliximab, an anti-CD25 antibody. The same GvHD prophylaxis has been reported by an Italian consortium: acute GvHD grade II–IV and III–IV was, respectively, 24% and 5%, which is extremely low for family HLA-haplotype mismatch, T-cell-replete transplants. Overall 3-year survival was 54% for standard and 33% for high-risk patients.
- #43 The use of PT-CY on day +3 and +4 after an unmanipulated haplo-HSCT has been pioneered by the Baltimore group. It is based on the idea that high-dose CY (50 mg/kg) will kill alloreactive T-cells proliferating on day +3 and +4 after the transplant, whereas stem cells would be protected because they are not proliferating and with a high concentration of aldehyde dehydrogenase.
- #44 In 2001, the Baltimore group published their first clinical study and showed that PT-CY was able to protect patients from GvHD after haplo-HSCT. Again, this was not picked up immediately, not until 2008 when a joint Baltimore Seattle study showed that haplo-HSCT in Hodgkin’s lymphoma (HL) produces DFS superior to sibling or unrelated transplants, not only GvHD could be prevented, but GvL superior, at least in with HL.
- #45 A total of 30 studies including 22 974 participants were analyzed. HAPLO stem cell transplantation with posttransplant cyclophosphamide therapy was associated with increased all-cause mortality compared with MRDs (OR, 1.17; 95%CI, 1.05-1.30), similar all-cause mortality compared with MUDs (OR, 1.06; 95%CI, 0.96-1.18), and reduced all-cause mortality compared with MMUDs (OR, 0.75; 95%CI, 0.61-0.92). Regarding nonrelapse mortality, HAPLO stem cell transplantation with posttransplant cyclophosphamide was associated with worse outcomes compared with MRDs (OR, 1.20; 95%CI, 1.04-1.40) but better outcomes compared with MUDs (OR, 0.75; 95%CI, 0.61-0.92) and MMUDs (OR, 0.51; 95%CI, 0.25-1.02). In terms of relapse, HAPLO stem cell transplantation with posttransplant cyclophosphamide was associated with similar outcome compared with MRDs (OR, 1.01; 95% CI, 0.86-1.17) and MMUDs (OR, 1.06; 95%CI, 0.77-1.47) but showed increased relapse compared with MUDs (OR, 1.20; 95%CI, 1.03-1.40).
- #46 There have been numerous variations of the Baltimore protocol (Fig. 65.1) with use of G-PB instead of BM, rapamycin, and MMF, instead of a CNI the use of a MAC regimen instead of the NMA regimen of Baltimore. The original Baltimore protocol consisting of CY 14.5 mg/kg × 2, fludarabine 30 mg/m2 × 5, and total body irradiation (TBI) 2 Gy day −1. CY 50 mg/kg days +3 and +4 and CSA, MMF starting day +5. GCSF starts on day +6. (Figs. 65.2 and 65.3), the use of a MAC regimen instead of the NMA regimen of Baltimore.
- #47 A modified PT-CY regimen has recently been reported in patients with AML. in this multicenter retrospective study on 150 patients, Thiotepa (T), busulfan (B), and fludarabine (F) followed by unmanipulated haploidentical BM. Cyclosporin on day 0, mycophenolate on day +1, and CY 50 mg/ kg on days +3 and +5. The MA regimen consisted mainly of TBF: the rate of leukemia relapse was extremely low in remission patients The major difference here lies in the CSA given before PT-CY and in the two doses of PT-CY spaced on days +3 and +5. It should be noted that this regimen is safe when using BM as a stem cell source, with acute GvHD III–IV rates of 3%; however, it is not known what the outcome would be with PB as a stem cell source, since CSA will protect some T-cells from PT-CY purging, and these may produce a beneficial GvL effect but also cause detrimental GvHD.
- #48 The Baltimore group is using this combination for patients with sickle cell disease, in the attempt of avoiding GvHD completely. Also, the group in Saint-Antoine, Paris, is using a combination of ATG 2.5 mg/kg and PT-CY, CSA, and MMF for patients with acute leukemia undergoing a MAC haplo-HSCT
- #50 a humanized monoclenal antibody directed against human CD52 that is expressed on many T and B cells and some dendritic and NK cells. The combined use of alemtuzumab (100 mg), fludarabine, and cyclophosphamide as a conditioning of haploidentical transplantation resulted in low cumulative incidence of acute GVHD, low TRM, and an acceptable incidence of primary graft failure (GF). However, the high incidences of infection and relapse due to slow immune reconstitution have been significant obstacles to these strategies
- #51 myeloid disease consisted of fludarabine (40 mg/m2 /day) infused over a period of 30 minutes on days −5 through −2; busulfan (130 mg/m2 /day) infused over a period of 3 hours on days −3 through −2; and alemtuzumab (20 mg/day) infused over a period of 3 hours on days −4 through −1. The conditioning regimen used for lymphoid diseases consisted of fludarabine (40 mg/m2 /day) infused over a period of 30 minutes on days −5 through −2; melphalan (140 mg/m2 /day) infused over a period of 15 minutes on day −2; and alemtuzumab (20 mg/day) infused over a period of 3 hours on days −4 through −1.
- #52 revealed that SCT from MUD or HAPLO donors in comparison to MRD was the only adverse factor that affected the OS rate (hazard ratio [HR] for MUD However, the OS rate after SCT from HAPLO donors did not differ significantly from the OS rate after SCT from MUD.
- #54 Alemtuzumab was added at 0.25 mg/kg for 2 days. The primary out‐ come measure was the survival rate with the engraftment of donor cells and without grade III‐IV acute graft‐vs‐host disease (GVHD) at 60 days after t Patients aged 55 years or less without a previous history of allogeneic HSCT received a myeloablative regimen that consisted of cyclophos‐ phamide (60 mg/kg for 2 days) and total body irradiation (TBI; 2 Gy twice daily for 3 days). Patients who had a previous history of allogeneic HSCT or were aged more than 55 years received reduced‐intensity regimens that consisted of fludarabine (25 mg/m2 for 5 days), melphalan (40 mg/m2 for 2 days), and TBI (2 Gy twice daily for a day), or fludarabine (30 mg/m2 for 6 days), busulfan (3.2 mg/kg once daily for 2‐4 days), and TBI (2 Gy twice daily for a day). Alemtuzumab was added to each regimen at 0.25 mg/kg for 2 days (days −4, and −3), with a capping dose of 30 mg/body in total. To prevent acute infusion‐related reactions to alemtuzumab, patients were pretreated with 1 mg/kg of methylprednisolone and 5 mg/body of chlorpheniramine maleate intravenously, and 500 mg/body of acetaminophen orally. On the first day of alemtuzumab infusion, 3.0 mg of alemtuzumab was infused over 2 hours. After confirming that there were no severe infusion‐related toxicities, we infused the remaining alemtuzumab over the next 4 hours. On the second day, all 0.25 mg/kg of alemtuzumab was infused over 4 hours
- #55 The primary outcome measure was achieved in 86% of the patients. Six patients experienced relapse/progression. Non‐relapse death was observed in three patients, and all of them had a history of previous allogeneic HSCT. Overall survival and progression free survival rates at 1 year were 51% and 43%, respectively. There were no deaths due to viral infection. Compared to those who underwent haploidentical HSCT using thymoglobulin, patients with alemtuzumab showed a slower recovery of CD8+ T‐cells and lower inci‐ dences of GVHD and EB virus reactivation. Conclusion: using alemtuzumab at a total dose of 0.5 mg/kg was safely performed in patients who underwent their first HSCT, but we should improve the conditioning regimens or GVHD prophylaxis to overcome the high RR in non‐ CR patients.
- #56 age, CMV status, and ABO matching are general rules which should always be considered: a CMV+ patient should be grafted with a CMV+ donor, if available, and a CMV- patient with a CMV− donor.
- #57 The EBMT Acute Leukemia Working Party has compared these two platforms in a recent study (Ruggeri et al. 2017). In a Cox analysis, ATG-based haplo grafts had a higher risk of failure, in terms of LFS (RR 1.48, p = 0.03), GvHD relapse-free survival (RR 1.45, p = 0.03), and OS (HR 1.43, p = 0.06): there was for all end points a very strong center effect (p < 0.001), suggesting that a learning curve is required for optimal results in haplo-HSCT.
- #58 There are now two studies comparing BM versus PB for unmanipulated haplo-HSCT: the EBMT study (Ruggeri et al. 2018) shows increased GvHD II–IV and III–IV with PB, same chronic GvHD, same relapse, and same 2-year OS (55% and 56%). CIBMTR shows increased GvH II–IV, but not III–IV with PB grafts, increased chronic GvHD, and reduced relapse (Bashey et al. 2017): survival at 2 years also in this study is quite similar, 54% vs 57%.
- #59 Immediate: an HLA-haploidentical donor can be identified and mobilized in two weeks to one month while the time to identify and mobilize an adult unrelated donor can be longer than three months for up to 25 percent of patients. HLA-haploidentical grafts have sufficient doses of HSCs for transplantation and of memory T cells for immune reconstitution. the costs of acquiring grafts for adult unrelated donors and umbilical cord blood are substantially higher than those of related donors. for patients with highrisk acute leukemia, HLA-haploidentical HSCT may be associated with a stronger graft-versus-leukemia effect compared with HLA-matched sibling HSCT, resulting in a lower cumulative incidence of relapse and an improved overall survival
- #60 Increased non relapse mortality (NRM) due to infectious complications secondary to slow immune reconstitution, mostly seen in T cell depleted strategies.
- #72 IT was originally described by Moretta et al. (1990a) over 20 years ago when killing of allogeneic lymphoblasts was observed in vitro and associated with defined NK cell subsets identified by the expression or lack thereof of novel surface molecules, subsequently identified as HLA class I-specific receptors. The emergence of the concept of the efficacy of NK cell alloreactivity in this transplantation setting has represented a sort of revolution in the field of haplo-HSCT,
- #75 Following the pioneering work of the Perugia group, HLA-haplotype mismatch family transplants are rapidly increasing in numbers, due to improved platforms in both TCD, as well as unmanipulated grafts, with encouraging results in most centers. This is true with different stem cell sources, different conditioning regimens, and different GvHD prophylaxes- in one word, there is more than one way to perform haplo-HSCT.
- #76 One important question is how haplo-HSCT compare with unrelated donor grafts, and to answer this question, randomized trials have been designed and are about to start.