Comparable Results with Treosulfan Based Conditioning Regimen in Matched Related and Matched Unrelated Donor Transplants for Beta Thalassemia Major and the Challenges from India: A Single Center Experience

Abstract Background: Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for patients with thalassemia major. Majority of the patients undergoing transplants in India belongs to advanced Pesaro risk stratification and 2013 data from India using treosulfan based conditioning for matched related donor transplants (MRD) has showed an event free survival of 78.8 ± 6.0 at 3 years (Mathews et al. Plos One 2013). Advanced age and risk stratification is a deterrent in proceeding with matched unrelated donor (MUD) transplant in India. Since only 25-30 % of patients are likely to get a MRD, MUD transplant is a feasible option in the background of limited life expectancy in patients with thalassemia major. However, there is no data comparing MRD and matched unrelated donor (MUD) transplants from India. Method: This is a retrospective analysis to compare the outcomes between MRD and MUD transplants from a single institution. Events were defined as primary graft failure, graft rejection leading to recurrence of transfusion dependence or death. Results: A total of 123 patients with thalassemia major underwent MUD search in DKMS and DATRI registries. Fifteen (12%) and 13 (10%) patients found 10/10 HLA identical donors respectively and 4 (3%) of them had matches in both the registries. Very few patients underwent NMDP search due to cost constraints. Among the 36 patients who underwent stem cell transplantation, MRD group had 27 patients and MUD group has 9 patients. Base line characteristics of age, sex and Pesaro risk stratification were matched. (Table: 1) Majority of patients belonged to high risk category in both the groups. The conditioning regimens used in both the groups were thiotepa, fludarabine, and treosulfan (TreoFluT). All the MRD non-sibling transplants and MUD transplants also received antithymocyte globulin (ATG) as part of the conditioning regimen. All patients received HLA identical (10/10) grafts. In the MRD group, the stem cell source was 24 (89%), 2 (7%) and 1 (4%) from sibling, parent and 1st cousin respectively. The MUD grafts were procured from 3 different registries DKMS (German) 5 (56%), NMDP (US) 2 (22%) and DATRI (Indian) 2 (22%). Cyclosporine and short course methotrexate were used as Graft versus host disease (GVHD) prophylaxis in all the patients Multiple challenges are involved in the availability and procurement of donor grafts from different registries. A special DCGI (Drug controller General of India) approval needs to be taken for every graft source procured from overseas. The estimated average cost of MRD transplant is 24000 US$ and MUD transplant is 48000 US$ for DKMS and DATRI grafts and 78000 US$ for NMDP grafts. Inspite of lower costs than the western countries, affordability is a major concern even if matched donors are available. Overall survival at 1 year in MRD and MUD groups was 84.3 ± 7.2% and 88.9 ± 10.5% at a median follow up of 20 (0-57) months and 13 (1-31) months respectively (p= 0.799) (Fig:1). The thalassemia free survival at 1 year was 84.3 ± 7.2% and 77.8 ± 13.9% with a median follow up of 20 (0-57) and 12 (1-31) months respectively (p= 0.732). (Fig: 2). Conclusion: Although the incidence of acute GVHD and chronic GVHD incidence are higher in the MUD transplant group, TreoFluT based conditioning for allogeneic stem cell transplantation with both matched related and unrelated donor graft source is a feasible option in beta thalassemia major patients even in high risk category from developing countries. Table 1. Patient demographics and transplant characteristics MRD (n= 27) n(%) Median(range)Mean ± SD MUD n=9 n(%) Median(range)Mean ± SD P-value Age (yrs) 10 (2-18) 9 (2-18) 0.502 Sex: Male 19 (70) 6 (66) 0.835 Class I 1 (4) 2 (22) 0.135 Class II 6 (22) 3 (33) Class III 20 (74) 4 (44) Class III Vellore high risk 11 (55) 3 (75) 0.693 Stem cell source PBSC BM BM + CB BM + PBSC + CB 23 (85) 2 (7) 1 (4) 1 (4) 7 (78) 2 (22) 0 0 0.599 Cell dose MNC/TNC x 108/Kg CD34 x 106/Kg 8.04 (3.49 -14.6) 5.91 (0.23 -27.75) 7.2 (2.83 -10.47) 8.47 (0.49 -21.6) 0.782 0.381 Acute GVHD 6 (22) 6 (66) 0.014 Grades I and II 5 (19) 4 (44) 0.505 Grades III and IV 1 (4) 2 (22) Classic acute GVHD 5 (18) 3 (33) 0.287 Persistent 0 0 Recurrent 0 3 (33) Late onset 1 (4) 0 Chronic GVHD 6 (22) 6 (67) 0.014 Classic Chronic GVH 5 (18) 3 (33) 0.545 Overlap syndrome 1 (4) 3 (33) Disclosures No relevant conflicts of interest to declare.

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Durable Remission after Prophylactic Donor Lymphocyte Transfusion Following Allogeneic Stem Cell Transplantation with Reduced Conditioning for High-Risk AML and MDS.

Blood ◽

10.1182/blood.v104.11.299.299 ◽

2004 ◽

Vol 104 (11) ◽

pp. 299-299

Author(s):

Michael Schleuning ◽

Christoph Schmid ◽

Georg Ledderose ◽

Johanna Tischer ◽

Meike Humann ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Allogeneic Transplantation ◽

Chronic Infections ◽

Term Survival

Abstract Prophylactic transfusion of donor lymphocytes (pDLT) is an attractive form of maintenance therapy after allogeneic stem cell transplantation in patients with high risk of relapse. However, clinical experience is limited, and disease response is often achieved at the expense of severe graft-versus-host disease (GvHD). We here report our data on pDLT in high-risk AML and MDS. Cells were given within a prospective protocol that contained a sequence of chemotherapy, reduced intensity conditioning for allogeneic transplantation, and pDLT (FLAMSA-regimen). For pDLT, patients had to be in CR at least 120 days from transplantation, off immunosuppression for 30 days, and free of GvHD. 22/86 patients alive at day +120 fulfilled the criteria for pDLT. They had been transplanted for refractory or relapsed leukemia (n=9 each) or in CR1 because of unfavorable cytogenetics (n=4). 14 patients had an unfavorable karyotype, 8 with complex aberrations. Reasons for withholding pDLT in 64 patients included cGvHD or prolonged immunosuppression (n=38), refractory or relapsed leukemia (n=15), refusal of patient or donor (n=4 each), a history of grade IV acute GvHD (n=2), and chronic infections (n=3). The median time from transplant to first pDLT was 167 days (range 120–297). Median follow up of transfused patients is 696 days (range 209–1341). Ten patients received 1, 6 patients received 2, and 6 patients received 3 transfusions in escalating doses, containing a median of 1x106, 5x106 and 1x107 CD3+ cells/kg at pDLT 1, 2 and 3, respectively. Reasons for giving less than 3 transfusions were GvHD, relapse or refusal of the patient. Induction of GvHD was the main complication; grade III acute GvHD developed in 1, and chronic GvHD in 7 patients. So far, 5 patients have relapsed despite pDLT. One died of refractory leukemia, whereas 2 achieved secondary CR following adoptive immunotherapy. Two patients are currently under treatment. At present, 18/22 patients are alive and in CR at a median of 423 days post DLT. The current leukemia free survival at two years from first pDLT is 79%. Nineteen patients were complete chimeras at time of pDLT. pDLT converted mixed into complete bone marrow chimerism in 1, but failed in 2 cases. In our experience, pDLT is safe after allogeneic transplantation for high risk AML, when given at low doses and to a selected group of patients. Results are encouraging, and long term survival can be achieved. However, further studies need to define more precisely the contribution of pDLT to the therapeutic effect of the entire procedure.

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Fludarabine, Amsacrine, High-Dose Cytarabine and Total Body Irridation Followed by Allogeneic Stem Cell Transplantation for the Treatment of High Risk or Relapsed Acute Lymphoblastic Leukemia.

Blood ◽

10.1182/blood.v110.11.5086.5086 ◽

2007 ◽

Vol 110 (11) ◽

pp. 5086-5086

Author(s):

Fabian Zohren ◽

Thorsten Graef ◽

Ingmar Bruns ◽

Akos Czibere ◽

Fenk Roland ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Chronic Gvhd ◽

Good Condition ◽

White Blood Count ◽

High Dose ◽

Unrelated Donor ◽

Grade Iii

Abstract In this prospective study we examined the use of an intensified conditioning regimen followed by allogeneic blood-stem-cell transplantation (BSCT) for the treatment of young adults in physically good condition with relapsed or high risk acute lymphoblastic leukaemia (ALL). Eleven patients with ALL received FLAMSA chemotherapy (fludarabine 30mg/m2 - cytarabine 2000mg/m2 -amsacrine 100 mg/m2 on day −10, − 9, − 8and −7), Anti-Thymocyte-Globulin (ATG 20 mg/kg BW on day −6, −5 and −4) and fractionated TBI (2 x 2 Gy on day −3, − 2 and −1) followed by matched unrelated donor (n=10) or matched sibling donor (n=1) SCT. The principle reasons for high risk stratification were refractory disease during first-line induction therapy (6, 55%), relapse (2, 18%), extramedullary disease manifestation (1, 9%), ALL subtype (6, 55%), unfavorable cytogenetics (5, 45%) and white blood count >30000 μL at time of diagnosis (3, 27%). After a median follow-up time of 604 days (range 202 – 1042 days) 8 patients (73%) are alive and 3 patients (27%) died. The median overall survival was not reached. Two patients died after relapse on days +121 and +449, another patient died from treatment related complications (HUS-TTP) on day +87. One patient relapsed on day +200 and is currently alive, the remaining 7 patients are alive and free of desease. Treatment related toxicities were acceptable. With 6 out of 11 patients developing grade III/IV infections during neutropenia, infectious complications remained of major importance. Other non-haematological side effects seen within this group of patients were less frequent and almost exclusively limited to gastrointestinal toxicities. Five patients (45%) had grade III/IV mucositis and 5 patients (45%) had grade III/IV nausea, while 4 patients (36%) showed grade III/IV diarrhoea. There was no case of acute toxicity related to the cardiavascular or central nervous system. The incidence of acute GvHD (aGvHD) was 36% (n = 4) and limited to grades II-III. Eight patients were evaluable for chronic GvHD (cGvHD). Out of those 4 patients (36%) developed cGvHD (3 limited disease, 1 extensive disease). We conclude that allogeneic transplatation after the FLAMSA-ATG-TBI regimen is feasible and provides effective therapy for this group of high-risk patients.

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Chronic graft-versus-host disease after allogeneic blood stem cell transplantation

Blood ◽

10.1182/blood.v98.6.1695 ◽

2001 ◽

Vol 98 (6) ◽

pp. 1695-1700 ◽

Cited By ~ 165

Author(s):

Donna Przepiorka ◽

Paolo Anderlini ◽

Rima Saliba ◽

Karen Cleary ◽

Rakesh Mehra ◽

...

Keyword(s):

Risk Factors ◽

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Blood Stem Cell ◽

Gvhd Prophylaxis ◽

Blood Stem Cell Transplantation

Abstract The incidence, characteristics, risk factors for, and impact of chronic graft-vs-host disease (GVHD) were evaluated in a consecutive series of 116 evaluable HLA-identical blood stem cell transplant recipients. Minimum follow-up was 18 months. Limited chronic GVHD occurred in 6% (95% confidence interval [CI], 0%-13%), and clinical extensive chronic GVHD in 71% (95% CI, 61%-80%). The cumulative incidence was 57% (95% CI, 48%-66%). In univariate analyses, GVHD prophylaxis other than tacrolimus and methotrexate, prior grades 2 to 4 acute GVHD, use of corticosteroids on day 100, and total nucleated cell dose were significant risk factors for clinical extensive chronic GVHD. On multivariate analysis, GVHD prophylaxis with tacrolimus and methotrexate was associated with a reduced risk of chronic GVHD (hazard ratio [HR], 0.35; P = .001), whereas the risk was increased with prior acute GVHD (HR, 1.67;P = .046). When adjusted for disease status at the time of transplantation, high-risk chronic GVHD had an adverse impact on overall mortality (HR, 6.6; P < .001) and treatment failure (HR, 5.2; P < .001) at 18 months. It was concluded that there is a substantial rate of chronic GVHD after HLA-identical allogeneic blood stem cell transplantation, that clinical factors may alter the risk of chronic GVHD, and that high-risk chronic GVHD adversely affects outcome.

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Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell–depleted stem cell transplantation

Blood ◽

10.1182/blood-2014-07-592881 ◽

2015 ◽

Vol 125 (5) ◽

pp. 784-792 ◽

Cited By ~ 122

Author(s):

Nirali N. Shah ◽

Kristin Baird ◽

Cynthia P. Delbrook ◽

Thomas A. Fleisher ◽

Mark E. Kohler ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Acute Gvhd ◽

Peripheral Blood Stem Cell ◽

Unrelated Donor ◽

Matched Unrelated Donor ◽

Key Points ◽

Blood Stem Cell Transplantation

Key Points Acute GVHD occurred in 5 of 9 patients after major histocompatibility–matched, T-cell–depleted peripheral blood stem cell transplantation plus IL-15/4-1BBL aNK-DLI. GVHD was more common in matched unrelated donor transplants and associated with higher CD3 chimerism, suggesting that aNK-DLI may augment T-cell alloreactivity.

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Targeting Mycophenolate Mofetil for Graft-Versus-Host Disease Prophylaxis after Allogeneic Blood Stem Cell Transplantation.

Blood ◽

10.1182/blood.v108.11.756.756 ◽

2006 ◽

Vol 108 (11) ◽

pp. 756-756

Author(s):

Jens Freiberg-Richter ◽

Ingmar Hantzschel ◽

Andreas Jenke ◽

Petra Lorenz ◽

Gerhard Ehninger ◽

...

Keyword(s):

Stem Cell ◽

Mycophenolate Mofetil ◽

High Risk ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Graft Versus Host Disease ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Graft Versus Host ◽

Unrelated Donors

Abstract New immunosuppressive compounds are currently investigated to reduce the rate of lethal Graft-versus-Host disease (GvHD) after allogeneic hematopoietic cell transplantation without adding relevant toxicity. Although positive reports on the efficacy of Mycophenolate Mofetil (MMF) in patients with acute and chronic GvHD are available, there is only limited data on the optimal prophylactic dosing schedule in patients at high risk for GvHD. Since very low trough-levels of MPA are measured in recipients of allogeneic stem cell transplants, we performed a prospective phase I/II trial targeting daily MMF doses according to MPA AUC levels determined at several time-points after transplantation. Twenty-nine patients (18 male, 11 female) with a median age of 53 years were included. The indication for allogeneic transplantation from matched sibling (n=7) and unrelated donors (9/10 alleles matched as minimum requirement; n=22) was high-risk AML/MDS (n=19) or relapsed lymphoma/multiple myeloma (n=10). Conditioning therapy included 30 mg/m2 Fludarabine on days −9 to −6 (4 x 20 mg/m2) combined with intravenous Busulfan 3.45 mg/kg from day −5 to day −2 (4 x 3.45 mg/kg i.v.). Tacrolimus was given orally starting on day −1 at 0.03 mg/kg in order to achieve trough blood levels of 5–10 ng/ml. MMF was started on day 1 at 1500 mg intravenously every 12 hours. AUC measurements of mycophenolic acid (MPA) and its metabolite MPAG by HPLC were scheduled on day 3, 8, 14, 21 and 28 after transplantation. The MMF dose was modified in order to achieve an AUC of 35–60 μg/m*h. MMF was tapered from day 56 on, if possible The dose of MMF had to be increased in 15/29 (52%) patients to 1750–2500 mg every 12 hours on day 4. No patient required a reduction of dosing on day 4. With the respective dose adjustments 52% and 80% of patients reached the AUC target on day 8 and 14, respectively. There was no direct association between dose level and extramedullary toxicity. Early grade 3–4 gastrointestinal toxicity occurred in 4 patients and lead to a reduction of MMF back to 1000 mg every 12 hours. Trilineage engraftment and complete donor chimerism was observed in all patients included. Only one out seven patients with a matched related donor experienced acute GvHD > grade II. The respective proportion of grade III–IV acute GvHD in the unrelated setting was 7/20 (33%). The rate of viral (CMV) and fungal infections was not increased compared to historical controls using standard antimicrobial prophylaxis. With a median follow-up of 18 months 15 (52%) patients are alive and 14 are in complete remission. Reasons for death were relapse (n=5; 17%), pneumonia/sepsis (n=2; 7%), GvHD (n=5; 17%) and organ failure (n=2; 7%). So far, 8 out of 24 evaluable patients (33%) suffer from limited (n=3) or extensive (n=5) chronic GvHD. A retrospective analysis revealed a significant correlation between Cmax levels and the AUC for MPA. The respective target Cmax was shown to be 16 μg/ml. Given the high-risk patient population and the high proportion of unrelated donors (70%) the clinical results observed with the combination of tacrolimus and MMF as prophylactic regimen are encouraging. The regimen has to be optimised for recipients of unrelated transplants. MMF doses of up to 2500 mg every 12 hours can be infused early after stem cell transplantation without an increased risk of toxicity. A simplified MMF targeting strategy based on MPA Cmax levels seems to be warranted in future trials.

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Analysis of a New graft–versus-host Disease (GvHD) Prophylaxis Regimen with Additional Enteric-coated Mycophenolate Sodium (EC-MPS) Starting 10 Days after Unrelated Allogeneic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v112.11.2202.2202 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2202-2202

Author(s):

Herbert G. Sayer ◽

Lars-Olof Mügge ◽

Sebastian Scholl ◽

Anne Klink ◽

Kristina Schilling ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Gvhd Prophylaxis ◽

Grade Ii ◽

Grade Iii

Abstract Introduction: Acute GvHD has, despite established immunosuppressive prophylaxis regimens, significant impact on acute morbidity and mortality following allogeneic stem cell transplantation (SCT). In the unrelated or even non-matched unrelated situation new GvHD-prophylaxis regimens balancing GvHD and graft-versus-leukaemia effect are needed. EC-MPS and mycophenolate mofetil [MMF] are effective immunosuppressants by inhibition of T- and B-cell proliferation. Primary study aims in this ethical board approved, prospective, single-centre, open phase II trial were (1) feasibility of prolongatedly started oral EC-MPS and (2) reduction in the rate of GvHD in unrelated allogeneic SCT. Patients and Methods: EC-MPS [Myfortic ®] 720 mg twice a day orally starting at day +10 after SCT in addition to standard GvHD prophylaxis, consisting of cyclosporine (CSA) 3 mg/kg continuous intravenous infusion with or without methotrexate (MTX) 15 mg/m2 day +1 and 10 mg/m2 day +3,+6,+11 intravenous push, was evaluated. According to the protocol, EC-MPS was tapered from day +40, if no acute GvHD-signs were present. 54 patients, including 8 patients from a previous pilot trial, with advanced haematological malignancies (n=28) or in first remission of acute leukaemia (n=26) between 8/03 and 12/07 were evaluated. The patients had either a 10/10 HLA-matched (n=32) or a 8-9/10 HLA mismatched unrelated donor (n=22). 32 (59%) patients received 40 mg/kg antithymocyte globulin (ATG), with 8 Gray total body irradiation (TBI) and cyclophosphamide (CY), or with fludarabine 120mg/m2, busulfan 8mg/kg or treosulfan 8–12 mg/kg. 12 or 8 Gray TBI and 120 mg/kg CY followed by MTX i.v. were administered to 22 (41%) patients. Results: A median of 5.7 (range: 0.9–9.9) unmanipulated G-CSF-mobilized CD-34 positive stem cells per kg were given on day 0. All of the 23 women and 31 men (median age 48 years (range: 20–65)), except one patient, showed a leukocyte engraftment on median day +14 (range: 9–35). Platelet engraftment was observed on median day +17 (range: 9–132). In 12 patients (22%) initially i.v. MMF (1g twice a day) instead of oral study medication was given temporarily, mostly due to severe mucositis. In six patients (11%) EC-MPS (on day +14, 17, 22, 32, 37, 76) had to be discontinued, due to severe nausea (n=2), neurological toxicity (n=2), graft failure (n=1) and protocol violation (n=1). Acute GvHD grade II-IV was observed in 27 (52%) patients, including 8 (15%) with grade III and 4 (7.5%) with grade IV. The incidence of chronic GvHD was 63 % (n=29) [limited chronic GvHD: 54 % (n=15), extended chronic GvHD: 14% (n=4)] of the 46 patients surviving >100 days after SCT. With 10/10 HLA-matched donors GvHD grade II-IV was seen in 44% (n= 14) [grade III and IV n=5 (16%)], whereas with non fully-matched donors the incidence was 59 % (n=13) [grade III and IV n=7 (32%)]. Chronic GvHD incidence was 50% (14/28) in the fully matched donor situation in contrast to 83% (15/18) in the non-fully matched situation. The conditioning regimen with ATG resulted in a GvHD grade II-IV incidence of 39% (n=12) [GvHD grade III/IV: 19% (n=6)], compared to 68% (n=15) [GvHD grade III/IV: 27% (n=6)] without ATG. With a median follow-up of 16 months (range: 1–56) 28 patients (52%) are alive, 18 fully HLA-matched stem cell recipients (56%) and 10 mismatched HLA recipients (45%). Survival with or without ATG was 50% (n=16) and 55% (n=12), respectively. Twenty-six (48%) patients have died; 12 (22%) due to relapse, 10 (19%) due to acute/chronic GvHD, and 4 (7%) due to infection/secondary cancer without GvHD. Conclusions: EC-MPS with a 10 day prolongated start after transplantation combined with initial standard GvHD prophylaxis in the unrelated stem cell transplantation setting seems to be feasible. Mucositis was the main course for oral intake problems. The toxicity drop-out rate of 7 % should be considered. The analysis of all evaluable patients in the pilot and the prospective trial yielded effectiveness in reducing severe GvHD Grade III/IV, especially in combination with ATG. The MPS application regimen failed to show less incidence of chronic GvHD in the non-fully matched unrelated donor setting. GvHD prevention trials in the future should incorporate new drugs with a different pathway of T-cell inhibition or tolerance induction, respectively.

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