EBMT NEWSLETTER | March 2017 | Volume 56 - Issue 2

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Summary of four EBMT recent studies published in peer-reviewed journals

Use of hematopoietic cell transplantation for patients with myelodysplastic syndrome and chronic myelomonocytic leukemia.
de Witte T, Bowen D, Robin M, Malcovati L, Niederwieser D, Yakoub-Agha I, Mufti GJ, Fenaux P, Sanz G, Martino R, Alessandrino EP, Onida F, Symeonidis A, Passweg J, Kobbe G, Ganser A, Platzbecker U, Finke J, van Gelder M, van de Loosdrecht AA, Ljungman P, Stauder R, Volin L, Deeg HJ, Cutler C, Saber W, Champlin R, Giralt S, Anasetti C, Kröger N.
Blood. 2017 Jan 17. pii: blood-2016-06-724500. doi: 10.1182/blood-2016-06-724500. [Epub ahead of print] No abstract available

In this consensus paper about allogeneic stem cell transplantation  for MDS initiated by the CMWP of EBMT including members of ELN , CIBMTR and other leading experts in the field clear recommendation were given to all aspects in allogeneic stem cell transplantation for MDS.
 
Allogeneic hematopoietic cell transplantation for primary refractory acute lymphoblastic leukemia: A report from the Acute Leukemia Working Party of the EBMT.
Pavlu J, Labopin M, Zoellner AK, Sakellari I, Stelljes M, Finke J, Fanin R, Stuhler G, Afanasyev BV, Bloor AJ, Anagnostopoulos A, Mohty M, Giebel S, Nagler A.
Cancer. 2017 Feb 17. doi: 10.1002/cncr.30604. [Epub ahead of print]

Patients with primary refractory acute lymphoblastic leukemia (PREF ALL) who fail to achieve a complete remission (CR) after ≥2 courses of chemotherapy have a dismal prognosis without undergoing allogeneic hematopoietic cell transplantation (HCT). Data regarding 86 adult patients were analyzed. With a median follow-up of 106 months, the probability of survival was 36% at 2 years and 23% at 5 years. The probability of leukemia-free survival was 28% and 17%, respectively, and the probability of nonrecurrence mortality was 20% and 29%, respectively, at 2 years and 5 years. For 66 patients who achieved a CR (77%), the survival at 2 years and 5 years was 36% and 29%, respectively. In multivariate analysis, use of total body irradiation was found to be associated with improved survival. Total body irradiation and infusion of female hematopoietic cells into male recipients was associated with improved leukemia-free survival. These findings were incorporated into a scoring system that identified 3 groups (those with 2, 1, or no prognostic factors) with survival rates of 57%, 22%, and 8%, respectively.Although overall these patients would clearly benefit from the introduction of novel antileukemic therapies, the data from the current study support the use of allogeneic HCT in selected patients with PREF ALL.
 
Risk factors for treatment failure after allogeneic transplantation of patients with CLL: a report from the European Society for Blood and Marrow Transplantation.
Schetelig J, de Wreede LC, van Gelder M, Andersen NS, Moreno C, Vitek A, Karas M, Michallet M, Machaczka M, Gramatzki M, Beelen D, Finke J, Delgado J, Volin L, Passweg J, Dreger P, Henseler A, van Biezen A, Bornhäuser M, Schönland SO, Kröger N.
Bone Marrow Transplant. 2017 Jan 23. doi: 10.1038/bmt.2016.329. [Epub ahead of print]

For young patients with high-risk CLL, BTK-/PI3K-inhibitors or allogeneic stem cell transplantation (alloHCT) are considered. Patients with a low risk of non-relapse mortality (NRM) but a high risk of failure of targeted therapy may benefit most from alloHCT. We performed Cox regression analyses to identify risk factors for 2-year NRM and 5-year event-free survival (using EFS as a surrogate for long-term disease control) in a large, updated EBMT registry cohort (n= 694). For the whole cohort, 2-year NRM was 28% and 5-year EFS 37%. Higher age, lower performance status, unrelated donor type and unfavorable sex-mismatch had a significant adverse impact on 2-year NRM. Two-year NRM was calculated for good- and poor-risk reference patients. Predicted 2-year-NRM was 11 and 12% for male and female good-risk patients compared with 42 and 33% for male and female poor-risk patients. For 5-year EFS, age, performance status, prior autologous HCT, remission status and sex-mismatch had a significant impact, whereas del(17p) did not. The model-based prediction of 5-year EFS was 55% and 64%, respectively, for male and female good-risk patients. Good-risk transplant candidates with high-risk CLL and limited prognosis either on or after failure of targeted therapy should still be considered for allo. 
 
A comparison between allogeneic stem cell transplantation from unmanipulated haploidentical and unrelated donors in acute leukemia.
Piemontese S, Ciceri F, Labopin M, Arcese W, Kyrcz-Krzemien S, Santarone S, Huang H, Beelen D, Gorin NC, Craddock C, Gulbas Z, Bacigalupo A, Mohty M, Nagler A; Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).
J Hematol Oncol. 2017 Jan 19;10(1):24.
In the absence of a HLA-matched related or matched unrelated donor, allogeneic stem cell transplantation (allo-SCT) from mismatched unrelated donors or haploidentical donors are potential alternatives for patients with acute leukemia with an indication to allo-SCT. The objective of this study was to compare the outcome of allo-SCT from T cell-replete haploidentical (Haplo) versus matched (MUD 10/10) or mismatched unrelated donor at a single HLA-locus (MMUD 9/10) for patients with acute leukemia in remission.Two hundred sixty-five adult patients with de novo acute leukemia in first or second remission that received a Haplo-SCT between January 2007 and December 2013 were compared with 2490 patients receiving a MUD 10/10 and 813 receiving a MMUD 9/10. Propensity score weighted analysis was conducted in order to control for disease risk imbalances between the groups.The weighted 3-year non-relapse mortality and relapse incidence were 29 and 30% for Haplo, 21 and 29% for MUD 10/10, and 29 and 25% for MMUD 9/10, respectively. The weighted 3-year leukemia-free survival (LFS) and overall survival (OS) were 41 and 46% for Haplo, 50 and 56% for MUD 10/10, and 46 and 48% for MMUD 9/10, respectively. Using weighted Cox model, both LFS and OS were significantly higher in transplants from MUD 10/10 compared from those in Haplo but not different between transplants from MMUD 9/10 and Haplo. The type of donor was not significantly associated with neither acute nor chronic graft-versus-host disease.Patients with acute leukemia in remission have better outcomes if transplanted from a MUD 10/10. We did not find any significant difference in outcome between transplants from MMUD 9/10 and Haplo, suggesting that both can be equally used in the absence of a 10/10 MUD.

View all the EBMT publications on the website.



The EBMT Young Ambassadors comment on recent publications published in peer-reviewed journal. Read below:

Yuqian Sun - Physician in the Hematology Department at Peking University Institute of Hematology, Beijing, China - @yuqian_sun_2017
Atorvastatin enhances endothelial cell function in posttransplant poor graft function.
Shi MM, et al. Blood. 2016 Dec 22;128(25):2988-2999. doi: 10.1182/blood-2016-03-702803. Epub 2016 Oct 21.
A new promising therapy emerges for poor graft function after allogeneic stem cell transplantation
Poor graft function (PGF) is a situation of suboptimal hematopoietic reconstitution after hematopoietic stem cell transplantation, defined as incomplete peripheral blood cell count recovery while complete donor chimerism. Due to long-lasting neutropenia and thrombocytopenia, patients with PGF has very poor prognosis. The incidence and risk factors varied in different study group partly due to the different definitions. PGF is thought to be related with graft versus host disease, myelosuppressive drugs, virus reactivation (such as CMV and HHV-6, etc) and some unknown factors. Obviously, it is an emerging complications after allogeneic stem cell transplantation since the increasing use of alternative donor, especially haploidentical related donor. The pathogenesis is not well elucidated. Researchers in Peking University Institute of Hematology (China) found that impaired bone marrow (BM) microenvironment was associated with PGF in their serial work, mainly reduced number of endothelial progenitor cells (EPCs). To further elucidate the pathogenesis and explore a potential therapeutic target, Dr. Kong and colleagues in the recent further study found that dysfunctional BM EPCs (characterized by impaired proliferation, migration, angiogenesis, and higher levels of reactive oxygen species and apoptosis) and activation of p38 and its downstream transcription factor cyclic adenosine monophosphate-responsive element-binding protein in BM EPCs were revealed in subjects with PGF. What is more important, they found that Atorvastatin, a lipid-lowering drug, could reverse this pathway in vitro. These data might provide a new promise to manage the tough complication of PGF after stem cell transplantation.


Eleni Gavriilaki - Hematology fellow in the Hematology Department and BMT Unit at G. Papanicolaou Hospital, Thessaloniki, Greece - @elenicelli
Survival Advantage and Comparable Toxicity in Reduced-Toxicity Treosulfan-Based versus Reduced-Intensity Busulfan-Based Conditioning Regimen in Myelodysplastic Syndrome and Acute Myeloid Leukemia Patients after Allogeneic Hematopoietic Cell Transplantation.
Sakellari I, et al. A. Biol Blood Marrow Transplant. 2017 Mar;23(3):445-451.
 
In this prospective single-centre study we aimed to analyze the safety and efficacy of a treosulfan-based reduced toxicity regimen (FluTreo) conditioning regimen in medically infirm patients who underwent allogeneic hematopoietic cell transplantation. FluTreo (fludarabine 150 mg/m2 and treosulfan 42 g/m2) was administered in 31 consecutive patients with acute myeloid leukemia (AML; n = 21), myelodysplastic syndrome (MDS; n = 6), or treatment-related AML (n= 4). In the FluTreo group, engraftment was prompt in all patients and 74% achieved >99% donor chimerism by day +30. No grades III or IV organ toxicities were noted.
Outcomes were compared to a historical group that received a reduced intensity busulfan-based conditioning (fludarabine 150 mg/m2 to 180 mg/m2, busulfan 6.4 mg/kg and antithymocyte globulin 5 mg/kg to 7.5 mg/kg, FluBuATG). With 20 (range, 2 to 36) months follow-up for FluTreo and 14 (range, 2 to 136) for FluBuATG, the 1-year cumulative overall survival (OS) probability was 76% versus 57%, respectively (P = .026); 1-year disease-free survival (DFS) was 79% versus 38% (P < .001). The CI of relapse mortality was markedly decreased in FluTreo versus FluBuATG (7.4% versus 42.3%, P < .001). FluTreo conditioning was the only independent factor associated with favorable survival rates.
In conclusion, the FluTreo group achieved higher survival rates with low relapse mortality, similar toxicity and treatment-related mortality (TRM).


Inés Oliveira Amat and Paula Cotino Argente - Medical Students at Rovira i Virgili University (URV) Tarragona, Spain - @inesoli_veira; @paulacotino
Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component.
Richards DB, et al. N Engl J Med. 2015 Sep 17;373(12):1106-14. doi: 10.1056/NEJMoa1504942. Epub 2015 Jul 15.
 
The term “amyloidosis” includes a heterogeneous group of diseases, caused by the extracellular deposition of fibrillary proteins which would be soluble in normal circumstances. These proteins, called amyloid fibrils, settle in different tissues and damage the normal function of the affected organ.
 
Currently, with the treatment we support or replace wounded organs; and we try to reduce amyloid fibril precursor protein. Still, that is not enough; at the moment there are no effective therapies for most hereditary forms of systemic amyloidosis. The deposits, by interfering with physiological functions, replace normal tissues components; then death can overcome within six months after diagnosis, and before we could see some real chemotherapy benefit.
 
We differentiate several types of systemic amyloidosis; classified recently by their amyloidogenic protein nature. Furthermore, at least the 65% of amyloidosis in developed countries are of Amyloid Light-Chain Amyloidosis Type (AL), or just primary amyloidosis. In AL, the substitution of certain amino acids in specific positions of the variable domain of the antibody potentially destabilize their light chains; and increases the risk of turning amyloidotic. The specific cause is unknown so far. However, we do know it is related to an abnormal production of antibodies by plasma cells, what is called plasma cells diyscrasia.
 
This clinical trial, which aims to find an effective therapy for hereditary systemic amyloidosis, was designed to increase normal phagocytic clearance mechanisms. Published in the New English Journal of Medicine in September 2015, their results are remarkable and inspiring.
 
As we know, amyloid deposits have something in common: they all contain SAP, regardless of the precursor protein. SAP is a non-fibrillary normal protein; and it is widely believed that acts as a “basic framework”, on which fibrillary proteins are deposited.
 
That is the key to understand the procedure: in this trial, which involved 15 patients, they used a drug (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl] pyrrolidine-2-carboxylic acid (CPHPC) that was able to eliminate most part of SAP from plasma (and some from amyloid deposits)
 
To remove the rest of SAP in tissues, the following administrations of fully humanized IgG1 (monoclonal antibodies) anti-Sap seeked for the activation of macrophage action on SAP-containing amyloid deposits.
 
And certainly, there was a remarkable clinical profit. Without serious adverse events observed and after a six-week treatment, liver stiffness had decreased (measured by transient elastography) and liver function improved, associated with a considerable reduction in hepatic amyloid load. Therefore, we can affirm treatment with CPHPC followed by an anti-SAP antibody categorically reduces amyloid deposits from different tissues.


Zinaida Peric - Postdoctoral research assistant at the School of Medicine, University of Zagreb, Croatia - @zina_peric
Post-transplant cyclophosphamide versus anti-thymocyte globulin as graft- versus-host disease prophylaxis in haploidentical transplant.
Ruggeri A , et al. Haematologica. 2017 Feb;102(2):401-410. doi: 10.3324/haematol.2016.151779. Epub 2016 Oct 6.
 
In recent years, unmanipulated haploidentical stem cell transplantation (haplo-SCT) with no ex vivo T cell depletion emerged as a viable option and has been performed with increasing frequency and success. Among the several methods for graft-versus-host disease (GVHD) prevention, anti-thymocyte globulin (ATG) and post-transplant high-dose cyclophosphamide (PTCY) are the most effective prophylaxis strategies. These two regimens were compared in a retrospective, multicentre, EBMT registry-based study, which included adult patients with acute myeloid leukemia (AML) in first complete remission who underwent haplo-SCT between January 2007 and July 2014. Data were obtained for 193 patients who had received PTCY and 115 patients who had received ATG. Patients receiving PTCY were more likely to receive bone marrow as graft source (60% vs 40%; P=0.01) and had shorter follow up (18 vs. 36 months; P<0.001). Patients in the PTCY group had significantly less grade 3-4 acute GVHD than those in the ATG group (5% vs 12%, respectively; P=0.01), while there was no difference in the cumulative incidence of chronic GVHD or relapse between the groups. In the multivariate analysis, the use of ATG was the only factor associated with occurence of grade 3-4 acute GVHD (HR 2.42; 95%CI: 1.20-5.75; P=0.04). Furthermore, ATG was an independent factor for higher non-relapse mortality (NRM; HR 1.77; 95% CI:1.09-2.86; P=0.02) together with the center experience defined as increase in number of haplo-SCT per year (HR 0.96; 95%CI:0.94-0.98; P<0.001). Finally, the use of ATG was an independent predictor of worse GVHD-free and relapse-free survival (GFRS; HR 1.45; (95%CI: 1.04-2.02; P=0.03) and leukemia-free survival (LFS; HR 1.48; 95%CI: 1.03-2.12; P=0.03) as well as the center experience (GFRS; HR 0.99 (95% CI: 0.97-1.00); p<0.04), LFS; HR 0.97; 95% CI 0.96-0.99; P<0.001). The authors concluded that haplo-SCT using PTCY-based regimen can achieve better LFS, GFRS, lower incidence of GVHD and NRM as compared to the ATG-based regimen for GVHD prophylaxis in patients with AML.


Jana Gummel - 6th year medical student at the Iuliu Hatieganu University of Medicine and Pharmacy in Cluj-Napoca, Romania - @jana123456789
One or two umbilical cord blood cell units? Caveat emptor
Sanz J and Gale RP, Bone Marrow Transplant 52: 341-343; advance online publication, January 9, 2017; doi:10.1038/bmt.2016.277
 
In this interesting perspective J. Sanz and R.P. Gale are discussing the best approach for allotransplantation with umbilical cord blood (UCB) and future research that needs to be conducted in this field.
Due to the lower amount of stem and progenitor cells in UCB units and the presumed risk of less effective bone marrow recovery compared to other transplant methods, often two units are combined. This practice they trace especially back to a typescript report published in 2005, where in 21 adults the engraftment rate was higher for two units than for one, yet also the risk of GvHD was higher.
However no randomized double blinded study in adults has ever been performed to support this assumption. On the contrary they are citing two randomized trials in younger than 24 year olds that could not show any benefit for two and a higher risk of GvHD after two units UCB.
They question the concept of “adequately dosed” in relation with weight, the correlation of TNC and CD34-positive cell dose based on body weight with a better outcome and the assumed correlation of TNC dose with almost all relevant variables, since they are doubting that one value can mirror this amount of diverse biological activities.
Another problem they see is the definition of transplant endpoint as there are many different possibilities of outcomes.
Many approaches to the problem of graft size in adults have been recently reviewed but still need validating randomized trials.
Even though from their point of view it is clear that until now not much benefits and a higher risk have been proven for two instead of one UCB unit, they are not very optimistic that the current attitude will change any time soon. 


Khaled Ghanem - Pediatrics hematology-oncology fellow at the American University of Beirut (AUB), Lebanon - @khaledghanem 
Prospective study of nonmyeloablative, HLA-mismatched unrelated BMT with high-dose posttransplantation cyclophosphamide
Yvette L. Kasamon, et al. Blood Advances 2017 1:288-292; doi: https://doi.org/10.1182/bloodadvances.2016002766
 
One of the major challenges in the process of bone marrow transplantation (BMT) is to find suitable donors for the corresponding patients who lack HLA-matched, related haploidentical, and unrelated umbilical cord options. Main barriers for the mismatched unrelated donor (mMUD) BMT include graft-versus-host disease (GvHD), graft rejection and death. The use of T-cell depletion with reduced-intensity regimens in the setting of mMUD BMT has led to impaired disease-free survival and major infectious complications. Promising outcome has been reported with 1 to 2 locus mismatched unrelated BMT using  bortezomib or alemtuzumab-based GvHD prophylaxis regimens.
A recent prospective study from Johns Hopkins has been released few weeks ago in Blood Advances Journal for the use of high-dose post-transplant cyclophosphamide and nonmyeloablative conditioning regimen (buslfan/fludarabine or fludarabine/cyclophosphamide/TBI) in the setting of mMUD BMT with relatively good results. The limitations of the study include the small number (N=23) and the heterogeneity of the patients. Five patients had > 2 HLA locus mismatch. All patients achieved sustainable engraftment. No grade 3-4 acute GVHD occurred. The estimated incidence of grade 2 aGVHD was 25% at day 180. The cumulative incidence of chronic GvHD was 16% at 1-year. The cumulative incidence of nonrelapse mortality was 0% at 1 year and 6% at 2 years. The estimated overall survival was 75% at 1 year, 69% at 2 years and 62% at 3 years.
The authors have concluded that the relatively good survival rate and low toxicity profile should be confirmed by larger studies, as in the just-opened phase 2 NMDP trial (15-MMUD)
The promising results of this study might open the doors for a huge surge in the field of mMUD transplant which might make BMT available for every eligible patient. However, we should take the results with caution considering the previously mentioned limitations.

Bone Marrow Transplantation journal featured articles

Bone Marrow Transplantation publishes high quality, peer reviewed original research and reviews that address all aspects of basic biology and clinical use of haemopoietic cell transplantation.
The journal also covers all aspects of the research and treatment of transplant-related complications and consequences including quality of life and psychological issues. Basic research studies on topics of relevance are also covered.

Celebrating 30 years of publication - read our collection of some of the best BMT articles of all time
 
Impact Factor 3.636*
Average time to first decision without external review = 7 days
Average time to first decision following external review = 34 days
Average time to online publication  = 24 days
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Read our pick of the latest articles …
 
One or two umbilical cord blood cell units? Caveat emptor
J Sanz & R P Gale
 
The EBMT–ELN working group recommendations on the prophylaxis and treatment of GvHD: a change-control analysis
T Ruutu, A Gratwohl et al
 
Evolving paradigms in the treatment of relapsed/refractory multiple myeloma: increased options and increased complexity
R F Cornell & A A Kassim
 
Impact of drug development on the use of stem cell transplantation: a report by the European Society for Blood and Marrow Transplantation (EBMT)
J R Passweg, H Baldomero et al
 
Pre-existing invasive fungal infection is not a contraindication for allogeneic HSCT for patients with hematologic malignancies: a CIBMTR study
R T Maziarz, R Brazauskas et al
 
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*2015 Journal Citation Reports® Science Edition (Thomson Reuters, 2016)

 
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