Purposes of conditioning

• Creation of space: Immature progenitor cells occupying niches must be eradicated so that donor stem cells can get access to niches.
• Immunosuppression: To prevent host vs graft reaction and subsequent rejection. With high disparity in HLA, higher immunosuppression is needed. Risk of rejection increases in recipient who have been pre- sensitized against minor histocompatibility antigens. Ex: Transfusion of multiple blood products. Rejection is also increased with T cell depleted stem cell products.
• Disease eradication. 

Introduction:

• Errors in application can have serious, even immediately fatal consequences. Conditioning has to be based on pre printed orders. Multiple checks are needed prior to drug is administered
• 4 eyes principle – At least two people must witness or approve certain activity.
• So far no single study has shown any conditioning regimen to provide better long term survival than CY/TBI or BU/CY
• TBI/CY Marginally better than BU/CY
• Radiomimetic drugs include cyclophosphamide, busulfan, etoposide, cytosine, carmustine, and melphalan.
• Most of conditioning regimens including RIC were developed as phase I and II trials and then adopted by individual institutions without formal phase III studies 

Conditioning regimens:

Myeloablative regimens

• Produce profound and usually irreversible pancytopenia within 1 to 3 weeks 
• Usually fatal in absence of stem cell rescue.
• They include
  • Total body irradiation ≥5 Gy or ≥8 Gy fractionated
  • Busulfan>8mg/Kg orally or intravenous equivalent (1mg PO is equal to 0.8mg given IV). 

Non-Myeloablative regimens

• Produce minimal cytopenia
• Do not usually require stem cell rescue for hematopoietic recovery 
• Used in older patients, patients with comorbidities and non-malignant bone marrow disorders.
• They include
  • Total body irradiation ≤2 Gy +/- Purine analogue
  • Fludarabine + Cyclophosphamide +/- ATG
  • Fludarabine + Cytarabine +/- Idarubicin
  • Cladribine + Cytarabine
  • Total lymphoid irradiation + ATG

Reduced intensity regimens

• They are defined by following doses of commonly administered agents
  • Melphalan- <150mg/m2
  • Busulfan- <9mg/kg (Oral)
  • Theotepa - <10mg/kg
  • TBI- <500 cGy single fraction or <800 cGy fractionated
• Many recover without stem cell rescue but need prolonged time for the same
• Produce less immunosuppression due to
  • Decreased duration and depth of neutropenia
  • Presence of host derived immunocompetent cells 
  • Faster recovery of more robust and complex T cell repertoire 
• Less organ toxicity 
• Can afford to do as GVL effect takes care of residual tumor
• Better tolerated and useful in older patients and in individuals with comorbid conditions
• Useful if BMT is being done for nonmalignant disease
• Donor neutrophil engraftment occurs in the absence of recipient granulocyte aplasia-This preservation of circulating granulocyte numbers reduces the risks of serious bacterial sepsis.
• Incomplete eradication of host hematopoietic elements is common feature with all RIC transplants. It may persist for months, then convert on its own to full donor chimerism.
• Following measures may help in converting mixed chimerism to full donor chimerism (though such measures can increase the risk of GVHD)
  • Withdrawing post-transplant immunosuppressive drugs
  • CD34+ selected donor cell boost
  • Donor lymphocyte infusion

GVHD prophylaxis

• Cyclosporine with methotrexate is most commonly used protocol
• Cyclosporin – IV- 1.25-2.5 mg/Kg BD- Started from Day –1 (1 day prior to transplant). If giving IV give 50% oral dose.
• Inj. Methotrexate 15 mg/m2 on day 1, then 10 mg/m2 on 3^rd,6^th and 11^thpost transplant days. Monitor MTX levels or give Leucovorin rescue- Inj. Folinic acid- 15mg- start at 24 hrs after each dose and continue 6hrly until 12 hrs before next dose of methotrexate.
• With this regimen though GVHD is reduced , at the same time GVL effect is also lost which may result in higher rate of disease relapse.
• If patient does not have any GVHD at Day +80, start tapering Cyclosporine and discontinue it at 6 months.
• Other GVHD prophylaxis protocols contain following agents:
  • Methyl prednisolone
  • Mycophenolatemofetil- 1.5-3gm/day
  • Sirolimus- 12mg on day –3, then 4mg per day.
  • ATG- 2.5mg/Kg/day for 4 days
  • Cyclophosphamide- 50mg/Kg/day on days +3 and +4. In 500ml D5% over 6 hrs (for 2-4 days). Prehydrate- 1lit- 6 hrs before and 6 hrs after. Mesna 25mg/Kg- IV bolus- at 0,4 and 8 hrs with each dose of cyclophosphamide.
  • Tab. Tacrolimus- 0.02mg/Kg- PO- BD. (Target Tacrolimus levels- 3-7ng/mL)

Regimens for Autologous stem cell transplants

• High dose melphalan
  • Protocol:
  • Pre-hydration- 500ml D5% with 25cc NaHCO3 over 45 minutes x 4 bottles (i.e- 2 Lit over 3 hrs)
  • Inj. Melphalan 200mg/m2 in 500ml NS over 30min- Stat
  • Post-hydration- 500ml D5% with 25cc NaHCO3 over 2 hours x 3 bottles (i.e. 1.5 Lit over 6 hrs). Give SOS Frusemide
  • Dose adjustments:
  • Creatinine clearance- <40ml/min- Give Melphalan at dose- 140mg/m2 
  • Patients having low WHO performance score- Give Melphalan at dose- 140mg/m2 
• BEAM 
  • Protocol:
  • Inj. BCNU (Carmustine)- 300mg/m2 in 500ml NS over 2 hours- On day -6 (Single dose)
  • Inj. Etoposide 200mg/m2 in 1000ml NS over 2hours- Day -5 to day -2 (4 days)
  • Inj. Cytarabine- 200mg/m2 in 100ml NS over 30min- BD- Day -5 to day -2 (4 days)
  • Inj. Melphalan- 140mg/m2 in 500ml NS over 30min- On day -1. (Single dose)
  • Pre-hydration- 500ml D5% with 25cc NaHCO3 over 45 minutes x 4 bottles (i.e- 2 Lit over 3 hrs)
  • Post-hydration- 500ml D5% with 25cc NaHCO3 over 2 hours x 3 bottles (i.e. 1.5 Lit over 6 hrs). Give SOS Frusemide
  • Inj. GCSF- 300mcg- SC- OD from day +7
  • Dose adjustments:
  • Do not use BEAM if creatinine clearance is <40ml/min.

Protocols for allogeneic stem cell transplant

• Bu-Cy
  • Protocol:
  • Inj. Busulfan 0.8mg/Kg in 100ml NS over 2hrs- QID- From day -7 to  day -4 (4 days)
  • Inj. Cyclophosphamide 60mg/Kg in 500ml D5% over 2hrs- On day -3 and day -2 (2 days)
  • Prehydrate 1000ml over 6 hrs and post hydrate 1000ml over 6 hours.
  • Inj. Mesna 25mg/Kg in 500ml D5% over 6 hrs- QID- on day -3 and day -2- (2 days) Start 1^st dose 3 hrs prior to cyclophosphamide)
  • GVHD Prophylaxis:
    • Inj. Methotrexate –IV-Push- 15mg/m2 on day +1 and 10mg/m2 on day +3, day +6 and day +11. (Check LFT prior to methotrexate, Inj. Folinic acid- 15mg- IV- Push, 24 hrs after methotrexate 6rhly- 2 doses after first injections, 6 doses after subsequent injections)
    • Cap. Cyclosporine- 2.5mg/Kg- BD- Start from day -1. (1 day prior to transplant) On empty stomach with plenty of water. (Monitor BP, RFT, CSA levels every week- Start on day +6- Target CSA levels- Adult- 250-350, Children- 150-200. If using IV cyclosporine- give 50% of calculated dose)
  • Start donor G-CSF on day -4.
  • Start recipient G-CSF on Day +5
  • Dose adjustments:
  • Avoid Busulfan if there is significant pre-existing liver dysfunction or pulmonary dysfunction
  • In event of hypertension or elevation of S. Creatinine to >30% of pretreatment levels- reduce the dose of cyclosporine (Give 50-75% of dose)
  • If oral busulfan is given, 1mg oral busulfan is equal to 0.8mg IV busulfan.
• Flu-Cy
  • Protocol: 
  • Inj. Fludarabine- 30mg/m2 in 100ml NS over 2 hrs- From day -7 to day -3 (5 days)
  • Inj. Cyclophosphamide 60mg/Kg in 500ml D5% over 2hrs- On day -3 and day -2 (2 days)
  • Prehydrate 1000ml over 6 hrs and post hydrate 1000ml over 6 hours.
  • Inj. Mesna 25mg/Kg in 500ml D5% over 6 hrs- QID- on day -3 and day -2- (2 days) Start 1^st dose 3 hrs prior to cyclophosphamide
  • GVHD Prophylaxis:
  • Inj. Methotrexate –IV-Push- 15mg/m2 on day +1 and 10mg/m2 on day +3, day +6 and day +11. (Check LFT prior to methotrexate, Inj. Folinic acid- 15mg- IV- Push, 24 hrs after methotrexate 6rhly- 2 doses after first injections, 6 doses after subsequent injections)
  • Cap. Cyclosporine- 2.5mg/Kg- BD- Start from day -1. (1 day prior to transplant) On empty stomach with plenty of water. (Monitor BP, RFT, CSA levels every week- Start on day +6- Target CSA levels- Adult- 250-350, Children- 150-200. If using IV cyclosporine- give 50% of calculated dose)
  • Start donor G-CSF on day -4.
  • Start recipient G-CSF on Day +5
  • Dose adjustments:
  • In event of hypertension or elevation of S. Creatinine to >30% of pretreatment levels- reduce the dose of cyclosporine (Give 50-75% of dose)
• Flu-Mel
  • Protocol: 
  • Inj. Fludarabine- 30mg/m2 in 100ml NS over 2 hrs- From day -7 to day -3 (5 days)
  • Inj. Melphalan 70mg/m2 in 250ml NS over 30min- On day -2 and day -1 (2 days)
  • Prehydrate 1000ml over 6 hrs and post hydrate 1000ml over 6 hours.
  • GVHD Prophylaxis:
  • Inj. Methotrexate –IV-Push- 15mg/m2 on day +1 and 10mg/m2 on day +3, day +6 and day +11. (Check LFT prior to methotrexate, Inj. Folinic acid- 15mg- IV- Push, 24 hrs after methotrexate 6rhly- 2 doses after first injections, 6 doses after subsequent injections)
  • Cap. Cyclosporine- 2.5mg/Kg- BD- Start from day -1. (1 day prior to transplant) On empty stomach with plenty of water. (Monitor BP, RFT, CSA levels every week- Start on day +6- Target CSA levels- Adult- 250-350, Children- 150-200. If using IV cyclosporine- give 50% of calculated dose)
  • Start donor G-CSF on day -4.
  • Start recipient G-CSF on Day +5
  • Dose adjustments:
  • In event of hypertension or elevation of S. Creatinine to >30% of pretreatment levels- reduce the dose of cyclosporine (Give 50-75% of dose)
• Thiotepa-Triosulfan
  • Protocol: 
  • Inj. Theotepa 8mg/Kg in 100ml NS over 1hr- on day -6 (1 day)
  • Inj. Treosulfan 14,000mg/m2 in 200ml NS over 3 hrs- From Day -5 to day -3 (3days)
  • Inj. Fludarabine- 40mg/m2 in 100ml NS over 1hr- From day -5 to day -2 (4 days)
  • GVHD Prophylaxis:
  • Inj. Methotrexate –IV-Push- 15mg/m2 on day +1 and 10mg/m2 on day +3, day +6 and day +11. (Check LFT prior to methotrexate, Inj. Folinic acid- 15mg- IV- Push, 24 hrs after methotrexate 6rhly- 2 doses after first injections, 6 doses after subsequent injections)
  • Cap. Cyclosporine- 2.5mg/Kg- BD- Start from day -1. (1 day prior to transplant) On empty stomach with plenty of water. (Monitor BP, RFT, CSA levels every week- Start on day +6- Target CSA levels- Adult- 250-350, Children- 150-200. If using IV cyclosporine- give 50% of calculated dose)
  • Start donor G-CSF on day -4.
  • Dose adjustments: None

Total body irradiation

• Excellent activity against malignancies that are resistant to chemotherapy 
• Has both immunosuppressive and antileukemia properties
• Sanctuary sites like testicles and CNS are also treated 
• Often TBI is combined with cyclophosphamide.
• 10-16 Gy of TBI is administered in single dose or in fractionation (Toxicity can be can be decreased by fractionation)
• Toxicity- 
  • GIT- Nausea, vomiting, diarrhea, parotitis
  • Veno-occlusive disease of liver
  • Lungs- Pneumonitis
  • Long term- Cataract, Hypothyroidism, Infertility, Growth retardation, Secondary malignancies.
• Delivered using a linear accelerator
• Good results with fractionated TBI + Etoposidein case of ALL.
• Should be done under guidance of specialist radio physicist or radiation oncologist.
• Irradiation is given with horizontal beams using anterior – posterior or lateral – lateral technique 
• Radio immunotherapy- Using antibodies tagged with radio nucleotides- (CD33, CD45, CD20)

Conditioning in pediatric transplants

• Children tolerate side effects better
• Higher total doses can be applied
• Conditioning affects growth and endocrine development 
• Avoid TBI especially in <2 years.

Disease specific aspects in conditioning

• SCID and other disease with profound ID
  • No conditioning is necessary as capacity for graft rejection is extremely Low.
  • Unusual form of lympho- hematopoietic chimerism is seen, which lymphoid system is of donor and myeloid series is of patient
  • If donor is mismatched, conditioning is required (As there is partial graft failure i.e B cell reconstitution does not occur)
  • Regimen used in such situations
    • BU-2mg/kg/day for 4 days
    • Cy-50mg/kg/day for 4 days
    • If there is serious infection prior to transplant, do HSCT without conditioning as even partial immunological reconstitution benefits the child
  • In less severe variants of immunodeficiency, conditioning is required.
• Severe aplastic anemia.
  • Marrow is already empty, hence sole aim of conditioning is to provide immunosuppression
  • Appropriate regimen
    • CY-50mg/kg/day since 4 successive days
    • If patients is sensitized to donor antigens, ATG needs to be added
    • If alternative donor transplant is being attempted (conditioning is not yet defined), add flu and low dose TBI to conditioning
• Fanconianaemia.
  • They are extremely susceptible to chemotherapy and radiation, as there is defect in DNA repair mechanism.
  • Decreased intensity conditioning is needed.
  • CY 5-10mg/kg/day for 4 days. +/- Low dose TB (400 CGY) and ATG are used

ATG in conditioning regimens

• Used when there is high risk of graft failure, to facilitate engraftment
• Examples
  • T cell depleted grafts
  • Cord blood SCT
  • Allo immunization of the recipient due to multiple transfusions
  • RIC HSCT
• Major side effects (Hence not used widely)
  • Anaphylaxis
  • Cytokine release syndrome
  • CMV and EBV reactivation
  • Lymphoproliferative disorders.
  • Increased risk of relapse.

T cell depletion and conditioning

• T cells in graft facilitate engraftment via soluble factors and their direct effects on residual host T cells.
• They are responsible for GVHD and GVL effects
• T cell depletion is done by using
  • Antithymocyte globulin
  • Alemtuzumab (Monoclonal antibody against CD52)
• T cells depletion results in 
  • Decreased chances of GVHD
  • Increased risk of graft rejection
  • Increased risk of disease recurrence
  • Because T cell depletion is so effective in preventing GVHD, no further GVHD prophylaxis are required.

Managing blood group incompatibility in HSCT

• There are 3 subtypes of ABO mismatch between donor and recipient
  • Major mismatch
    • Presence of ABO antibody in recipient plasma against donor RBC antigen
    • It can lead to immediate lysis of RBCs in stem cell product.
    • It can also lead to delayed hemolysis of donor RBCs and pure red cell aplasia
  • Minor mismatch
    • Presence of ABO antibodies in donor plasma against recipient RBC antigens
    • Hemolysis starts between 3 and 15 post-transplant days, lasts for 5-10 days and gradually resolves as the patient’s incompatible RBCs are destroyed.
  • Bidirectional mismatch
    • Presence of both major and minor mismatch
• Passenger lymphocyte syndrome: It is a type of delayed hemolytic reaction, seen in case of minor ABO mismatch. In this condition, memory B cells in graft, produce anamestic reaction when restimulated by recipient ABO antigens. It usually develops 7-14 days post-transplant.
• Management:
  • Major mismatch
    • Immediate hemolysis can be prevented by removing donor RBCs. This can be done using PBSC harvest (slight modifications in machine settings may be needed sometimes). If it is a bone marrow harvest,  bone marrow can be infused without any problem, if Anti A or Anti B titres are <1:16. If titres are >1:16, transfuse FFP of donor blood group every day from start of conditioning till day –1. By this, anti-donor antibodies present in the recipient are mopped off by antigens present in the infused plasma. On the day of transplant of Anti A/B titres are <1:16, proceed with BM infusion without any additional measures. If antibody titres are >1:16, there are 4 options:
      • Higher doses of plasma infusion
      • Plasma exchange – 1.5 times the body volume.
      • Do RBC depletion in the harvest. In such case volume of harvest must be double the usual required volume. This is done by mixing harvest with hydroxy ethyl starch which enhances RBC sedimentation.
      • Do PBSC harvest.
  • Delayed hemolysis
    • Transfusion of “O” RBCs until antidonor antibodies have disappeared.
  • Pure red cell aplasia
    • Rituximab
    • Tapering immunosuppression, so that there is “Graft Vs Plasma cell effect”.

Groups of blood products to be used after ABO mismatched SCT. (Prior to transplant, products of recipients blood group are used)

Procedure of stem cell transplant

• Stem cell products are infused in the same way as other blood products, except that inline blood filters should not be used and they must not be irradiated.
• Damage to RBCs releases hemoglobin which can precipitate acute renal failure, so patient should be adequately hydrated and urine output should be monitored closely.

Engraftment

Neutrophil engraftment

• 1^st day of 3 consecutive days where the absolute neutrophil count is > 500 cells /cmm.
• Median time 
  • Autologous HSCT-11 days
  • Allogeneic HSCT with PBSC- 14 days
  • Allogeneic HSCT with BMSC- 21 days
  • Umbilical cord blood transplant- 28 days.

Platelet engraftment

• Achievement of platelet count of >50,000/cmm which is sustained for 3 consecutive days unsupported by platelet transfusion.
• Median time-
  • Allogeneic HSCT with PBSC-13 days
  • Allogeneic HSCT with BMSC-20 days

Other engraftments:

• NK cell engraftment- 18-12 days
• Monocyte engraftment- 1 month
• B lymphocytes and CD8-T lymphocytes- Over months
• CD4-T lymphocytes-Over years (>5 years)

Factors affecting time of recovery after HSCT

• Use of G-CSF during mobilization and harvest
• Degree of pretreatment chemotherapy
• Source of stem cells
• Presence of infection

Following measures must be taken when patient is on GVHD prophylaxis:

• Fluoroquinolones/ Penicillin V prophylaxis
• Cotrimoxazole prophylaxis for PCP
• Voriconazole/ Posaconazoleprophylxis against moulds/ Fluconazole resistant candida (Interaction with calcineurin inhibitors Ex: Cyclosporine is known, hence appropriate dose adjustments are needed)
• Frequent screening for CMV viremia. Drugs useful in prophylaxis include- Ganciclovir, Valganciclovir, high dose acyclovir, valacyclovir, and letermovir.

Recent advances:

Fludarabine/busulfan versus busulfan/cyclophosphamide as myeloablative conditioning for myelodysplastic syndrome

The effectiveness of Flu/Bu for myelodysplastic syndrome remains poorly understood. A study from Japan, analysed registry data from 2006 to 2018 and compared transplant outcomes of adult MDS patients receiving Flu/Bu and busulfan/cyclophosphamide using propensity score matching. The 3-year OS rates were 52.7% and 49.5% in the Flu/Bu and Bu/Cy group. They concluded Flu/Bu could be an alternative to Bu/Cy for MDS patients prior to allo-HSCT. 

https://doi.org/10.1038/s41409-021-01447-y 

Post-Transplant Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil as the new standard for graft-versus-host disease (GVHD) prophylaxis in reduced intensity conditioning

The most promising GVHD prophylaxis regimen in BMT CTN 1203 was a 3-drug combination of post-transplant cyclophosphamide (PTCy), tacrolimus, and mycophenolate mofetil. Present study reports the results of the randomized phase III study comparing outcomes of alloHCT in those randomized to receive PTCy/Tac/MMF versus standard Tac/MTX. BMT CTN 1703 met its primary endpoint, demonstrating a higher 1-year GVHD/relapse or progression-free survival with PTCy/Tac/MMF compared to Tac/MTX owing to significant improvements in GVHD risk without increased risk of relapse or death. Authors feel PTCy/Tac/MMF should become the standard of care for GVHD prophylaxis from closely-matched donors receiving reduced intensity conditioning.

https://doi.org/10.1182/blood-2022-171463

Second haploidentical stem cell transplantation (HAPLO-SCT2) after relapse from a first HAPLO-SCT in acute leukaemia

This retrospective registry (EBMT) analysis investigated the feasibility and efficacy of second haploidentical stem cell transplantation (HAPLO-SCT2) in adults with acute myeloid and lymphoblastic leukemia (AML/ALL) who experienced hematologic relapse after their first HAPLO-SCT (HAPLO-SCT1). The study involved 82 patients (63 with AML, 19 with ALL) with a median follow-up of 33 months. The engraftment rate was 87%, and at day +180. Two-year overall survival (OS) and leukemia-free survival (LFS) were 34.3% and 25.4%, respectively, with non-relapse mortality (NRM) and relapse incidence (RI) at 17.6% and 57%. The study concludes that HAPLO-SCT2 is a viable option for acute leukemia relapse after HAPLO-SCT1. 

https://doi.org/10.1038/s41409-023-01985-7

Total body irradiation versus busulfan based conditioning for ALL patients >45 years

This retrospective study aimed to assess the role of total body irradiation (TBI) in intermediate intensity conditioning (IIC) for allogeneic hematopoietic cell transplantation in high-risk acute lymphoblastic leukemia (ALL) patients over 45 years old. The study compared TBI-based (FluTBI8) and irradiation-free (FluBu6.4, FluBu9.6) conditioning regimens. At two years, overall survival (OS) was 68.5%, 57%, and 62.2% for FluTBI8, FluBu6.4, and FluBu9.6 respectively. Leukemia-free survival (LFS) was lower with FluBu6.4 and FluBu9.6 compared to FluTBI8. Relapse incidence was higher with FluBu6.4. While the advantage in OS wasn't statistically significant, the study suggests stronger anti-leukemic efficacy of TBI-based IIC.

https://doi.org/10.1038/s41409-023-01966-w

C5a complement inhibitor for acute GVHD with lower GI tract involvement

This phase 2a study evaluated ALXN1007, a monoclonal antibody targeting C5a, in newly diagnosed lower gastrointestinal acute graft-versus-host disease (GVHD) patients receiving corticosteroids. Among 25 enrolled patients, 24 were included in the efficacy analysis. Most patients had acute leukemia and received myeloablative conditioning. Day-28 overall response was 58%, with 63% by Day-56, including complete responses. Responses were observed in high-risk GVHD patients. Non-relapse mortality at 6 months was 24%. The most common treatment-related adverse event was infection. Baseline complement levels did not correlate with GVHD severity or responses. 

https://doi.org/10.1038/s41409-023-01996-4

Survival advantage of treosulfan plus fludarabine compared to busulfan plus fludarabine in active acute myeloid leukemia post allogeneic transplantation 

In a retrospective study comparing conditioning regimens for hematopoietic stem cell transplantation in primary refractory/relapsed acute myeloid leukemia (AML), the researchers compared FT14 (fludarabine and treosulfan) to FB4 (fludarabine and busulfan). The study included 346 patients, with 113 receiving FT14 and 233 receiving FB4. FT14 patients were older and more likely to have unrelated donors but received a lower fludarabine dose. While the incidence of severe graft-versus-host disease was similar, FT14 had a 2-year cumulative relapse rate of 43.4% compared to 53.2% for FB4. Non-relapse mortality was 20.8% for FT14 and 22.6% for FB4. Consequently, FT14 showed better 2-year leukemia-free survival (35.8% vs. 24.2%) and overall survival (44.4% vs. 34%).  

https://doi.org/10.1038/s41409-023-02028-x 

ATG versus PTCy in matched unrelated donor haematopoietic stem cell transplantations with non-myeloablative conditioning

In this retrospective study comparing allogeneic hematopoietic stem cell transplantations (HSCT) with non-myeloablative conditioning (NMC) using anti-thymocyte globulin (ATG, n=95) vs. post-transplant cyclophosphamide (PTCy, n=90) in matched unrelated donors, patients with PTCy had a significantly lower cumulative incidence of acute graft-versus-host disease (GvHD) grade II–IV (21% vs. 48%, p < 0.001). The 3-year moderate/severe chronic GvHD rates were similar. Relapse rates, non-relapse mortality, and overall survival did not significantly differ between the groups. The study suggests that PTCy-based regimens result in a lower incidence of acute GvHD compared to ATG-containing regimens in this context. Prospective studies are needed to determine the impact on overall survival.

https://doi.org/10.1111/bjh.19031

Fludrabine/Busulfan/Cyclophosphamide/rAntiThymocyteGlobulinConditioning for Allogeneic Transplants in Transfusion Dependent Beta-Thalassemia

In a retrospective analysis of 55 consecutive HLA-matched allogeneic stem cell transplants (allo-SCTs) for transfusion-dependent thalassemia (TDT) with Flu/Bu/Cy/rATG conditioning, conducted between October 2018 and April 2022, the median age was 7 years. Bone marrow as the graft source in 96.4% of cases.Neutrophil and platelet engraftment occurred at a median of 16 and 17 days, respectively, and the median follow-up duration was 20.7 months. The study reported no primary rejection, one secondary rejection, a 21.8% incidence of veno-occlusive disease, and low rates of acute and chronic graft-versus-host disease (7.2% each). Overall survival and Thalassemia-Free Survival were 100% and 98%, respectively, emphasizing the safety and efficacy of Flu/Bu/Cy/rATG conditioning in allo-SCT for TDT.

https://doi.org/10.1007/s12288-023-01646-1

Fludarabine melphalan versus fludarabine treosulfan for reduced intensity conditioning regimen in allogeneic hematopoietic stem cell transplantation: a retrospective analysis

This retrospective study compared two reduced-intensity conditioning (RIC) regimens, fludarabine with melphalan (Flu-Mel) and fludarabine with treosulfan (Flu-Treo), over a 10-year period in two donor groups: matched related donor (MRD)/matched unrelated donor (MUD) and haploidentical (Haplo) transplants. Among the MRD/MUD group, patients who received Flu-Mel had a higher incidence of grade 3/4 oral mucositis compared to those who received Flu-Treo (47% vs. 9%, P = 0.02). In the Haplo group, grade 3/4 diarrhea was more frequent with Flu-Mel than Flu-Treo (41% vs. 6%, P = 0.039). Five-year overall survival (OS) in the MRD/MUD group was 62% with Flu-Mel and 53% with Flu-Treo (P = 0.0694), and in the Haplo group, it was 41% with Flu-Mel and 28% with Flu-Treo (P = 0.770). Flu-Treo provided comparable outcomes to Flu-Mel in both donor groups with significantly less severe mucositis and diarrhea.

https://doi.org/10.1007/s12185-023-03674-z

Fecal Microbiota Transplantation Versus Placebo in Allogeneic Hematopoietic Cell Transplantation and AML 

In this randomized, double-blind, placebo-controlled phase II trial involving allogeneic hematopoietic cell transplantation (HCT) recipients and patients with acute myeloid leukemia (AML), standardized oral encapsulated fecal microbiota transplantation (FMT) did not significantly reduce the 4-month all-cause infection rate compared to placebo. While FMT improved postantibiotic recovery of microbiota diversity and restored certain commensals, it did not translate into a significant clinical benefit in terms of infection reduction. 

https://doi.org/10.1200/JCO.22.02366  

Substitution of calcineurin inhibitors with corticosteroids after allogeneic hematopoietic cell transplantation

In a retrospective study evaluating the clinical significance of replacing calcineurin inhibitors (CIs) with corticosteroids after allogeneic hematopoietic cell transplantation (HCT), 42 patients were switched from CIs to corticosteroids within 90 days due to reasons such as renal impairment, fluid overload, and thrombotic microangiopathy. Although creatinine and body weight returned to baseline at 4 weeks after switching, the 100-day non-relapse mortality was high (57.1%). Grade II–IV acute graft-versus-host disease (GVHD) occurred in 24.4% of patients who did not have it before switching treatment. The study suggests that switching from CIs to corticosteroids may be an option in patients with severe clinical conditions, but the short-term mortality rate remains a concern.

https://doi.org/10.1007/s12185-023-03645-4

Post-transplantation cyclophosphamide is associated with increased bacterial infections

Post-transplant cyclophosphamide (PTCy) is commonly used for graft-versus-host disease (GVHD) prophylaxis after hematopoietic cell transplantation (HCT), but it may be associated with a higher risk of infections. This study included patients receiving haploidentical or matched sibling donor HCT for acute leukemias or myelodysplastic syndrome with either PTCy- or calcineurin inhibitor (CNI)-based GVHD prophylaxis. Patients receiving PTCy had a greater incidence of bacterial infections by day 180 compared to those receiving CNI-based prophylaxis. Bacterial infections were associated with increased treatment-related mortality (TRM) and overall mortality across all prophylaxis cohorts. The findings emphasize the need for careful monitoring of bacterial infections in patients undergoing HCT with PTCy.

https://doi.org/10.1038/s41409-023-02131-z

CD24Fc for prevention of graft-versus-host disease

This phase 2a trial investigated the efficacy of a novel human CD24 fusion protein (CD24Fc/MK-7110) in preventing acute graft-versus-host disease (GVHD) in matched unrelated donors (MUD) transplants. The study employed a double-blind, placebo-controlled, dose-escalation phase followed by an open-label expansion phase. The multidose regimen of CD24Fc, when combined with tacrolimus and methotrexate, showed sustained drug exposure and significantly improved grade 3 to 4 acute GVHD–free survival at day 180 compared to matched controls (96.2% vs. 73.6%, respectively). Importantly, no dose-limiting toxicities were observed, indicating that CD24Fc was well tolerated and associated with favorable outcomes in preventing acute GVHD post-transplantation.

https://doi.org/10.1182/blood.2023020250

Eltrombopag improves platelet engraftment after haploidentical bone marrow transplantation

This prospective study investigated the safety and efficacy of eltrombopag in enhancing platelet recovery post-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with bone marrow graft and post-transplant cyclophosphamide (PCy)-based graft-versus-host disease (GVHD) prophylaxis. Patients receiving eltrombopag starting on Day +5 showed a significantly higher rate of platelet engraftment (>50,000/μL by Day 60) compared to the control group. The median time to platelet recovery (>20,000/μL) was shorter in the eltrombopag group, with no eltrombopag-related grade ≥4 adverse events observed. 

https://doi.org/10.1002/ajh.27233

Rituximab added to conditioning regimen significantly improves erythroid engraftment in major incompatible ABO-group HSCT

This retrospective study assessed the impact of pre-transplant rituximab infusion on red blood cell engraftment in 131 patients undergoing ABO-incompatible HSCT. Patients receiving rituximab achieved transfusion independence faster (1 month) compared to those without rituximab (3.2 months, p = 0.02). Rituximab use was linked to accelerated RBC engraftment, while high anti-donor isohemagglutinin titers correlated with delays. These findings suggest that rituximab in conditioning regimens is a safe and effective approach to improve RBC engraftment post-HSCT.

https://doi.org/10.1038/s41409-024-02247-w

High activity of the new myeloablative regimen of gemcitabine/clofarabine/busulfan for allogeneic transplant for aggressive lymphomas

This study evaluated the novel gemcitabine, clofarabine, and busulfan (Gem/Clo/Bu) conditioning regimen in allogeneic stem cell transplantation for refractory aggressive lymphomas. Among 64 patients (median age 46), the regimen demonstrated manageable toxicities, high rates of donor chimerism, and impressive response rates (overall/complete response: 78%/71% in B-NHL, 93%/93% in T-NHL, and 67%/67% in Hodgkin lymphoma). With a median follow-up of 60 months, event-free survival (EFS) and overall survival (OS) rates were 36% and 47%, respectively. Gem/Clo/Bu outperformed Flu/Mel conditioning in matched-pair controls, with superior median EFS (12 vs. 3 months) and OS (25 vs. 7 months). 

https://doi.org/10.1038/s41409-024-02394-0