Cumulative Incidence Of Transplant-related Mortality Research Articles

HLA-haploidentical stem cell transplantation after removal of αβ+ T and B cells in children with nonmalignant disorders

Twenty-three children with nonmalignant disorders received HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) after ex vivo elimination of αβ(+) T cells and CD19(+) B cells. The median number of CD34(+), αβ(+)CD3(+), and B cells infused was 16.8 × 10(6), 40 × 10(3), and 40 × 10(3) cells/kg, respectively. No patient received any posttransplantation pharmacologic prophylaxis for graft-versus-host disease (GVHD). All but 4 patients engrafted, these latter being rescued by a second allograft. Three patients experienced skin-only grade 1 to 2 acute GVHD. No patient developed visceral acute or chronic GVHD. Cumulative incidence of transplantation-related mortality was 9.3%. With a median follow-up of 18 months, 21 of 23 children are alive and disease-free, the 2-year probability of disease-free survival being 91.1%. Recovery of γδ(+) T cells was prompt, but αβ(+) T cells progressively ensued over time. Our data suggest that this novel graft manipulation strategy is safe and effective for haplo-HSCT. This trial was registered at www.clinicaltrials.gov as #NCT01810120.

Engraftment kinetics and graft failure after single umbilical cord blood transplantation using a myeloablative conditioning regimen.

Umbilical cord blood transplant recipients are exposed to an increased risk of graft failure, a complication leading to a higher rate of transplant-related mortality. The decision and timing to offer a second transplant after graft failure is challenging. With the aim of addressing this issue, we analyzed engraftment kinetics and outcomes of 1268 patients (73% children) with acute leukemia (64% acute lymphoblastic leukemia, 36% acute myeloid leukemia) in remission who underwent single-unit umbilical cord blood transplantation after a myeloablative conditioning regimen. The median follow-up was 31 months. The overall survival rate at 3 years was 47%; the 100-day cumulative incidence of transplant-related mortality was 16%. Longer time to engraftment was associated with increased transplant-related mortality and shorter overall survival. The cumulative incidence of neutrophil engraftment at day 60 was 86%, while the median time to achieve engraftment was 24 days. Probability density analysis showed that the likelihood of engraftment after umbilical cord blood transplantation increased after day 10, peaked on day 21 and slowly decreased to 21% by day 31. Beyond day 31, the probability of engraftment dropped rapidly, and the residual probability of engrafting after day 42 was 5%. Graft failure was reported in 166 patients, and 66 of them received a second graft (allogeneic, n=45). Rescue actions, such as the search for another graft, should be considered starting after day 21. A diagnosis of graft failure can be established in patients who have not achieved neutrophil recovery by day 42. Moreover, subsequent transplants should not be postponed after day 42.

HLA-Haploidentical T Cell–Depleted Allogeneic Hematopoietic Stem Cell Transplantation in Children with Fanconi Anemia

We report the outcome of 12 consecutive pediatric patients with Fanconi anemia (FA) who had neither an HLA-identical sibling nor an HLA-matched unrelated donor and who were given T cell–depleted, CD34+ positively selected cells from a haploidentical related donor after a reduced-intensity, fludarabine-based conditioning regimen. Engraftment was achieved in 9 of 12 patients (75%), and the cumulative incidence of graft rejection was 17% (95% confidence interval [CI], 5% to 59%). Cumulative incidences of grades II to IV acute and chronic graft-versus-host disease were 17% (95% CI, 5% to 59%) and 35% (95% CI, 14% to 89%), respectively. The conditioning regimen was well tolerated, with no fatal regimen-related toxicity and 3 cases of grade III regimen-related toxicity. The cumulative incidence of transplant-related mortality was 17% (95% CI, 5% to 59%). The 5-year overall survival, event-free survival, and disease-free survival were 83% (95% CI, 62% to 100%), 67% (95% CI, 40% to 93%), and 83% (95% CI, 62% to 100%), respectively. These data demonstrate that a fludarabine-based conditioning regimen, followed by infusion of high doses of T cell–depleted stem cells, is able to ensure engraftment with good overall survival and disease-free survival, confirming the feasibility of haploidentical hematopoietic stem cell transplantation in FA. To the best of our knowledge, this is the largest series of hematopoietic stem cell transplantation from a haploidentical related donor in FA patients reported to date.

Treosulfan Based Myeloablative Regimen Provides High Rate Of Allogeneic Engraftment and Low Toxicity In Patients With Advanced Myelofibrosis,

AbstractAbstract 5504 BackgroudAllogeneic transplantation (HSCT) is the only potentially curative therapy for myelofibrosis, even in the era of new drugs that only impact on selected manifestations of disease. The time to evolution of myelofibrosis in advanced phases is variable (months to several years). The choice to proceed to allogeneic transplantation is based on several clinical variables; conditioning regimen and time to transplantation may influence the outcome of HSCT. Here we present our experience in a group of patients with myelofibrosis transplanted in Our Center with a myeloablative regimen based on full dose of treosulfan. MethodsWe retrospectively evaluated 20 patients (15 male) with primary myelofibrosis (14) and post-ET (essential thrombocythemia) myelofibrosis (6) who underwent HSCT at our institute from July 2005 to February 2013. In this cohort we included 4 patients in blast phase, 3 of which received a brief course of chemotherapy prior to transplant; 4 patients who underwent a second allogeneic transplantation for disease relapse (2) or graft failure (1); 1 patient referred at our Institute in graft failure 3 months after first HSCT. Only 1 patient had splenectomy before HSCT. ResultsThe median age at diagnosis was 59 years (range 41-76). JAK2 V617F mutation was positive in 7 and unknown in 3 patients. In post-ET MF patients, the median time to transformation in MF was 134 months (60-144). The median time from diagnosis to transplant was 14 months (4-101 months). The median age at transplant was 62 years. DIPSS score at transplant was low in 1, int-1 in 3, int-2 in 13 and high in 3 patients. We adopted myeloablative regimen based on treosulfan 42 gr/ms and fludarabine 150 mg/ms, plus TBI 4 Gy in 7 patients. GvHD prophylaxis was based on ATG, Rituximab and CSA/MTX (8 pts) or rapamycin (11 pts). The graft was PBSCs (19) and BM (1) from related HLA-identical donor (7 pts), matched unrelated donor (5 pts) and haploidentical donor (8 pts). The incidence of graft failure and poor graft function was 5% and 20% respectively. The median time to neutrophils engraftment was 20 days. The incidence of acute and chronic graft versus host disease was 50% and 40% respectively. Cumulative incidence of TRM (transplant related mortality) was 45 %; day 100 OS (overall survival) was 70% while 2 year OS was 40%. In multivariate analysis there was no statistically significant correlation between individual factors (including WBC, hemoglobin, platelets, ferritin, beta2-microglobulin, IgA, IgG, IgM, LDH, psuedocholinesterase levels, age, Sorror comorbidity score, donor match, bone marrow kariotype) and survival. However, we found that a linear composition of level of peripheral blasts (0%, ≥1%, ≥5%), bone marrow CD34+ cells (<5%, ≥5%, ≥20%), spleen size and number of red blood cells units transfused pre-HSCT is able to predict the outcome (p-value 0.03), even if each factor alone is not strongly correlated with survival. There was no statistical significant correlation between the outcome and DIPSS score, Bacicalupo score and Lille score. ConclusionsA myeloablative regimen based on full dose treosulfan provide a 95% rate of primary allogeneic engraftment and 40% overall survival in myelofibrosis at advanced stage, with low extra-hematological toxicity in frail patients. Allogeneic transplantation after myeloablative low-toxicity regimens may be offered in myelofibrosis in early chronic phase of disease and for younger patients, two conditions usually linked with durable engraftment, low toxicities and low rate of relapse. Disclosures:No relevant conflicts of interest to declare.

HLA Haplo-Identical Peripheral Blood Stem Cell Transplantation Using High-Dose Cyclophosphamide Post-Transplantation For Poor Prognosis Or Refractory Acute Leukemia and Myelodysplastic Syndrome: A Prospective Pilot Study At a Single Center

Recently nonmyeloablative, haplo-identical T-cell replete bone marrow transplantation using high-dose cyclophosphamide (CY) post-BMT to control GVHD and prevent graft rejection by inducing bi-directional tolerance was reported. This strategy resulted in promising outcomes with low transplantation-related mortality (TRM) due to a low incidence of GVHD and infectious disease. However, the high relapse rate remained a major problem in high-risk hematological disease. We therefore planned a prospective pilot study of myeloablative or reduced intensity HLA haplo-identical allogeneic hematopoietic cell transplantation (HCT) using reduced doses of CY post-transplantation, followed by administration of peripheral blood stem cells (PBSC) instead of bone marrow, for those with a poor-prognosis or refractory leukemia and MDS.As of 30 June 2013, 17 patients had been enrolled in this prospective pilot study. Patients with a poor prognosis or refractory leukemia and MDS requiring prompt HCT were eligible for this study if they lacked a donor who was serologically HLA-identical or had a single antigen mismatch.The conditioning regimen consisted of fludarabine 15 mg/m2 and cytarabine 2.0 g/ m2 twice a day on days -11 and -10, thymoglobulin 2.0 mg/kg on days -8 and -7, and fludarabine 30 mg/ m2/day with intravenous busulfan 3.2 mg/kg/day on days -6 to -3 (n=11) or melphalan 100 mg (n=6) on day -2. Nine patients received a single dose of 25 mg/kg CY on day 3 and eight patients, double doses of 25 mg/kg CY on days 3 and 4 post-peripheral blood stem cell transplantation (PBSCT). Tacrolimus and oral mycophenolate mofetil was started after the completion of high-dose CY post-HCT.The median age of patients was 42 years (range 18–65). Disease diagnoses included AML (n=14), ALL (n=2) and MDS (n=1). In 12 (71%) of 17 patients, disease status was non-remission, with active disease at the time of PBSCT. Eight (47%) of 17 patients had a history of prior HCT. Donors were partially HLA-mismatched (haplo-identical) first degree relatives of the patients and differed from the patients at a median of 3/8 HLA loci in both the HVG and GVH directions. All patients received G-CSF-mobilized, unmanipulated PBSC containing a median of 3.0 x 106 CD34+cells/kg and 1.4 x 108CD3+T-cells/kg.Non-infectious fever due to PBSC infusion occurred in 14 (82%) patients and persisted until day 2 in most patients. Except for one patient who died soon after PBSCT due to disease progression, full donor T-cell chimerism was achieved at day 30 following PBSCT in all patients. Nine of 17 developed grade II-III acute GVHD. None developed grade IV acute GVHD. Three of nine patients receiving a single dose of CY, but only one of eight patients receiving double doses of CY developed grade III acute GVHD. In 12 of 16 evaluable patients, CMV reactivation was observed by day 100. Three patients developed CMV disease. BK virus cystitis occurred in four of eight patients receiving double doses of CY, however, none receiving a single dose of CY post-PBSCT developed BK virus cystitis. The cumulative incidence of TRM at one year was 13%. At one year, the overall survival of all patients, and the percentages of patients in remission and those with active disease were 43%, 75% and 31%, respectively.The results of our study demonstrated that our HLA haplo-identical transplantation using high-dose CY post-PBSCT resulted in a low incidence of TRM and was feasible even in patients with high-risk acute leukemia and MDS as an alternative stem cell source. Of note, the dose of CY post-PBSCT affected the incidence of both BKV cystitis and severe GVHD. The optimal dose of CY following HLA haplo-identical PBSCT and preparative regimen should be further explored to establish a standard regimen. Disclosures:Nakamae:Otsuka Pharmaceutical Co., Ltd.: Honoraria, Travel/accommodations/meeting expenses, Travel/accommodations/meeting expenses Other; Kyowa Hakko Kirin Pharma, Inc.: Research Funding, Speakers Bureau, Travel/accommodations/meeting expenses Other. Off Label Use: Mycophenolate mofetil was used as one of drugs for acute GVHD prophylaxis. Koh:Kyowa Hakko Kirin Pharma, Inc.: Travel/accommodations/meeting expenses Other. Nishimoto:Otsuka Pharmaceutical Co., Ltd.: Speakers Bureau; Kyowa Hakko Kirin Pharma, Inc.: Travel/accommodations/meeting expenses Other. Nakashima:Kyowa Hakko Kirin Pharma, Inc.: Travel/accommodations/meeting expenses Other. Nagasaki:Kyowa Hakko Kirin Pharma, Inc.: Travel/accommodations/meeting expenses Other. Nakane:Otsuka Pharmaceutical Co., Ltd.: Honoraria, Speakers Bureau; Kyowa Hakko Kirin Pharma, Inc.: Speakers Bureau, Travel/accommodations/meeting expenses Other. Nakamae:Kyowa Hakko Kirin Pharma, Inc.: Research Funding, Travel/accommodations/meeting expenses Other. Hino:Sanofi K.K.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Nippon Shinyaku Co.,Ltd.: Honoraria, Research Funding; Kyowa Hakko Kirin Pharma, Inc.: Honoraria, Research Funding, Travel/accommodations/meeting expenses Other.

Post-Transplant Cyclophosphamide Following a Myeloablative Conditioning For Hematologic Malignancies Receiving An Unmanipulated Haploidentical Bone Marrow Transplant

BackgroundUnmanipulated family haploidentical transplants are becoming increasingly used in patients lacking an HLA identical family donor, or a well matched unrelated donor. Aim of the studyThis is an updated analysis of our program of haploidentical bone marrow transplant (hBMT) , followed by post-transplant high dose cyclophosphamide (PT-CY) in 95 patients with hematoloigic malignancies receiving a myeloablative conditioning. MethodsThe conditioning regimen consisted of thiotepa, busulfan, fludarabine (TBF) (n=47) , thiotepa melphalan fludarabine (n=5) , or 9.9-12 Gy TBI + fludarabine (n=43). The patients' median age was 49 years (17-74); the disease status at the time of transplant, was first complete remission (CR1, n=29) , CR2 (n=23), or active disease (n=38,40%). The diagnosis was AML (35%), ALL (24%), MDS (12%) myeloproliferative disorders (12%), other malignancies (17%). The total nucleated cell dose infused was 3.37 (1.4-9.17). The median follow up for surviving patients is 440 days (90-930). Graft versus host disease (GvHD) prophylaxis consisted in PT-CY on day+3 and +5 , cyclosporine (from day 0) , and mycophenolate (from day +1).▪ ResultsThe cumulative incidence of neutrophil (PMN) engraftment was (90%) and all surviving patients on day +30 had full donor chimerism. The median day for neutrophil engraftment was day +17 (11-32). The cumulative incidence (CI) of grade II-III acute GvHD was 14%, and of moderate chronic GvHD 8%, severe cGvHD 9%. The CI of transplant related mortality (TRM) is respectively 7%, 17%, 26% for patients in CR1, CR2, or with active disease. The CI of relapse is respectively 17%, 30%, 37% for patients in CR1, CR2, or with active disease. The overall actuarial survival is respectively 75%, 44%, 32% for patients in CR1, CR2, or with active disease (p=0.002) (Fig.1). The most frequent cause of death was leukemia (26%) followed by infections (9%). ConclusionsThese data confirm our first report on 50 patients and support the use of myeloablative conditioning regimens, followed by h-BMT with PT-CY. The risk of acute and chronic GvHD seems relatively low , as well as the overall transplant related mortality. We have not seen the excess relapse rate reported when patients are given a non myeloablative regimen, and disease control has been satisfactorily both for patients in remission, as well as for patients with active disease at the time of transplants. Disclosures:No relevant conflicts of interest to declare.

Outcomes After Unrelated Cord Blood Transplantation For Adults With Primary Or Secondary Myelofibrosis: A Retrospective Study On Behalf Of Eurocord and Chronic Malignancy Working Party-EBMT

BackgroundAllogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative option for patients (pts) with myelofibrosis (MF). Patients with MF transformed to Acute Myeloid Leukemia (AML) have a very short life expectancy without transplantation (< 4 months). Umbilical cord blood transplantation (UCBT) from unrelated donor is a valid alternative to conventional allogeneic HSCT for pts with hematologic malignancies who do not have an HLA matched donor. Delayed engraftment and graft failure are the limitations of this procedure and represent a major issue for MF. Patients and MethodsWe analyzed 42 adults (28 males and 14 females) who underwent a single (n=15) or double (n=27) HLA mismatched UCBT between 2005 and 2012 in 26 EBMT centers reported to Eurocord. At diagnosis, 21 had primary MF (PMF), 5 polycythemia vera (PV), and 16 essential thrombocytemia (ET). Twelve patients transformed to acute myeloid leukemia (AML) before UCBT. Among pts with pre-transplant information available, 13/25 had severe marrow fibrosis; 8/16 had a high Lille score at diagnosis and 13/27 had JAK2 V617F mutation; 13/35 underwent splenectomy and 16/30 had an abnormal karyotype. The median time from diagnosis to transplant was 80 months (range 5-316), while in the subgroup of pts with transformation to AML, it was 119 months (range 5-246). Five pts had a prior transplant (1 autologous, 3 allogeneic and 1 had 2 consecutive allogeneic transplants). The median age at UCBT was 54 years (range 28-69). Conditioning regimens were reduced intensity (RIC) (n= 29) or myeloablative (MAC) (n=13). The most common conditioning in both MAC (n=5) and RIC (n=16) was Cyclophosphamide and Fludarabine associated with total body irradiation (TBI). Overall, 27 pts received TBI with a dose of 12-14 Gy in MAC (n=6) and 2-4 Gy in RIC (n=21); 20 pts received anti-thymoglobulin (ATG) in the conditioning regimen. The median infused total nucleated and CD34+ cells were 3,4x107/Kg (range 0,3-6,8) and 1,3x105/Kg (range 0,04-3,8),respectively. ResultsMedian follow-up for survivors was 25 months (range 6 -72). The cumulative incidence (CI) of neutrophil engraftment was 64% (28 pts) with a median time of 29 days, and among the 12 pts transformed to AML, 10 engrafted in a median time of 30 days, while 18 of 30 pts without transformation engrafted in a median time of 28 days. Of the 14 pts who did not reach neutrophil engraftment, 7 had no hematological recovery, 6 of them died after a median of 3 months and 1 pt is alive at 14 months post UCBT. The remaining 7 pts had an autologous reconstitution, and 4 of them are alive with progressive disease at a median time of 42 months. Pts who received RIC conditioning had better engraftment (79% versus 36%, p=0.02).Twelve pts developed acute GvHD of grades II-IV; 7 pts had limited chronic GvHD with a median time of onset of 144 days.Overall, 17 pts relapsed (6 had transformed into AML before transplantation) at a median time of 5 months. The CI of relapse at 2 years was 29%±2%. The CI of transplant-related mortality at 1 year was 33%±2%. Causes of death were relapse (n=9), post-transplant lymphoproliferative disease (n=3), GvHD (n=3), multiorgan failure (n=1), bacterial infection (n=3), acute respiratory distress syndrome (n=2), infection of unknown origin (n=3), cardiac toxicity (n=1) and fungal infection (n=1). OS at 2 years was 44±8%: 80%, 21% and 52% for pts transplanted respectively for MF secondary to PV, ET and PMF (p=0.07). No difference in OS was seen in the subgroup of pts with JAK2 mutation. OS was 51% versus 29% for pts receiving double or single UCBT (p=0.15), and it was 37% for AML-transformed pts. Pts who did not receive ATG, had an OS of 59% versus 24% for those who received ATG (p=0.01). Among pts who underwent RIC (n=29), 13 had a TBI based conditioning without ATG, and 7 are alive. Failure-engraftment free survival at 2 years was 29±7%, better in pts receiving double UCBT as compared with single (40% versus 8% , p=0,01), and in pts receiving TBI (43% versus 7%, p=0,03). ConclusionGraft failure was a major concern for these pts. Despite a limited number of patients, our results indicate that life expectancy can be increased with UCBT particularly for patients with advanced stage MF. Furthermore, the use of RIC TBI based regimen without ATG and double CB might improve outcomes. Disclosures:Gluckman:Cord use: Honoraria; gamida: Honoraria.

Removal Of Alpha/Beta+ T Cells and Of CD19+ B Cells From The Graft Translates Into Rapid Engraftment, Absence Of Visceral Graft-Versus-Host Disease and Low Transplant-Related Mortality In Children With Acute Leukemia Given HLA-Haploidentical Hematopoietic Stem Cell Transplantation

T-cell depleted HLA-haploidentical hematopoietic stem cell transplantation (HSCT) is a suitable option for patients in need of an allograft who lack a HLA-matched donor. Although it offers the advantage of being immediately applicable to virtually all patients, so far, graft manipulation with removal of all T lymphocyte subsets and of natural killer (NK) cells has been associated with an increased risk of life-threatening infections, as well as, in some studies, of leukemia recurrence.We recently developed a new method of graft manipulation based on the physical removal of αβ+ T cells and CD19+ B cells, which permits to leave mature NK cells and γδ+ T cells in the graft. We, thus, started a formal study (NCT01810120) in children with acute leukemia aimed at evaluating the safety and efficacy of this approach. As of April 2013, we enrolled 45 patients (pts; 29 males, 16 females). Median age at HSCT was 10.1 years (range 0.9-17.9). Thirty-five pts had acute lymphoblastic leukemia (ALL) and 10 acute myeloid leukemia (AML); all children were transplanted in morphological complete remission (CR). Fifteen pts were transplanted in first CR, 27 in second CR and 3 in more advanced CR. All pts transplanted in CR1 had either poor cytogenetic/molecular characteristics or high levels of minimal residual disease (MRD) at the end of induction therapy. The donor was either the mother (n=25) or the father (n=20); according to the model of KIR/KIR ligand disparity, 22 pts were transplanted from an NK-alloreactive donor. The median number of CD34+ cells, NK cells, γδ+ T cells, B cells and αβ+ T cells were 14.6, 31.7, 7.8, 0.08 and 0.04x106/kg, respectively. A myeloablative regimen, containing Total Body Irradiation in 34 cases, was given to all children, who also received anti-thymocyte globulin (12 mg/kg over 3 days, from -5 to -3). Rituximab (200 mg/m2) was administered on day -1 to further prevent EBV-related lymphoproliferative disorders. No pharmacological graft-versus-host disease (GVHD) prophylaxis was employed after transplantation.Sustained primary engraftment occurred in 44/45 pts, the remaining child being successfully re-transplanted from the other parent. The median time to reach an absolute neutrophil count >0.5x109/L and a platelet count >50x109/L was 13 days (9-18) and 11 days (8-20). No child developed gut or liver acute GVHD. Thirteen pts experienced skin-only grade I-II GVHD, this leading to a cumulative incidence (CI) of 29% (95% confidence interval, CO. IN., 18-45). Only 2 pts developed skin limited chronic GVHD. Two pts died for causes other than disease relapse (both in the first 60 days after HSCT), the CI of transplantation-related mortality (TRM) being 4% (CO. IN. 1-16). Seven pts relapsed, the CI of disease recurrence being 16% (CO. IN. 6-32). With a median follow-up of 11 months (range 2-30), the 2-year Kaplan Meier estimate of leukemia-free survival (LFS) was equal to 75% (CO. IN. 57-86); this value was 73% (CO. IN. 52-85) for pts with ALL. LFS of pts who did or did not experience skin-only acute GVHD was 83% (CO. IN. 48-96) and 72% (CO. IN. 50-86), p=NS. The probability of LFS of the 39 pts with either negative or low (<1x10-4) MRD at time of HSCT was 81% (CO. IN. 62-91) as compared to 25% (CO. IN. 1-67) of the 6 pts with positive MRD (p<0.01). The CI of cytomegalovirus (CMV) reactivation was 53% (CO. IN. 29-68). In the first 45 days after HSCT, circulating T cells mainly consisted of the γδ+ subset, while αβ+ T lymphocytes predominated thereafter. CMV reactivation promoted the expansion of Vδ1+ T cells. Mature NK cells expressing inhibitory KIRs and negative for NKG2A, including also the alloreactive cells, were detectable at 1 month in peripheral blood after HSCT, showing the persistence of transplanted cells with potential anti-leukemia activity. These percentages increased at later time points, reaching values comparable to those found in the HSCT donor.These data indicate that a selective graft manipulation results into effective prevention of both acute and chronic GVHD, rapid recovery of neutrophil and platelet counts and low TRM. Although the median observation time is still limited, also the CI of disease recurrence is encouraging. Post-transplant add-back of limited numbers of αβ+ T cells transduced with the iCasp9 suicide gene could optimize the recovery of this subset in early weeks after HSCT, maximizing immune-mediated viral and leukemia control, without an unacceptable risk of GVHD. Disclosures:No relevant conflicts of interest to declare.

Bone Marrow Transplantation For Thalassemia Using Related Other Than HLA- Identical Siblings: Improved Transplant Outcomes With a Novel Approach

BackgroundAlthough in some areas of the world a chance of finding a related HLA- matched non sibling donor could be as high as 13% to 18%, and approximately 13% of patients could have a one-antigen mismatched related donor, the role of such alternative donor HSCT in thalassemia is not well established. Our previous study (BMT 2000,25:815) examining alternative related BMT for thalassemia was not successful due to a high graft failure, GVHD, and low disease-free survival rates. In 2005 we adopted a new transplant approach for alternative related donor transplantation in thalassemia and here we report transplant outcomes. Patients and MethodsHere we used a new treatment protocol (Pc 26.1) in 16 thalassemia patients (median age 9.6 years; range 1.4-24 years) to perform BMT using phenotypically HLA-identical or one-antigen mismatched related donors (related donors-RDs). We compared these results with HLA matched sibling donor (matched sibling donors-MSDs) BMT in 66 patients (median age 10 years; range, 1.8-27 years). The two groups were similar in terms of disease and demographic characteristics. Patients in the RD group received pre transplant cytoreduction/immunosuppression with hydroxyurea, azathioprine from day -45 pretransplant, and fludarabine from day -16 through day -12. Their conditioning regimen consisted of weight based targeted i.v. Busulfan (Bu), thiotepa (TT) (10 mg/kg), Cyclophosphamide (CY) (200 mg/kg), and Thymoglobulin 10 mg/kg. The conditioning regimen in the MSD group consisted of BuCY200 ±TT10 for class 2 patients and BuCY90-160 preceded by preconditioning cytoreduction/immunosuppression for class 3 patients. All patients received cyclosporine, methylprednisolone, and methotrexate as GVHD prophylaxis. Most patients in both groups were heavily transfused before transplantation and had moderately severe iron overload and liver fibrosis. In the RD group 11 of 16 donors were HLA-phenotypically identical (parents eight, cousin two, and uncle one), and 5 were one-antigen mismatched (siblings three, mother or aunt one). ResultsIn total, 16 patients in the RD and 58 (88%) in the MSD group had sustained engraftment. The median times to an ANC>0.5 x 109/L or to a platelet count >20 x 109/L were similar in both groups. Graft rejection occurred in 8 MSD group patients but in none of the RD group patients. The cumulative incidence of rejection was 12% (95% CI, 6–21%) in the MSD group and 0% in the RD group, which was not statistically significant (P = 0.15). The cumulative incidence of acute GVHD (grades 2–4) in the RD group (19%; 95% CI, 4–41%) was less than that in the MSD group (36%; 95% CI, 24–48%), but the difference was not statistically significant (P = 0.21). Two patients in the RD group and six in the MSD group had chronic extensive GVHD. At present, all patients are off immunosuppressive medication. The cumulative incidence of transplant-related mortality (TRM) at 100 days and 1 year was 0% and 6% (95%CI 1-26%) in the RD and 8% and 8% (95% CI, 3–16%) in the MSD group, respectively (P = 0.77). At the time of survival analysis, 15 patients (94%) in the RD group and 61 patients in the MSD group (92%) were alive, with median follow-up durations of 72 months (range, 17–93 months) and 80 months (range, 25–107 months), respectively. The probabilities of overall survival were 94% (95% CI, 63–99%) for the RD group and 92% (95% CI, 83–97%) for the MSD group (P = 0.83). The respective probabilities of thalassemia-free survival were 94% (95% CI, 63–99%) and 82% (95% CI, 70–89%), with no statistically significant difference (P = 0.24). Despite the preexisting disease and treatment-related organ damage this intensified preparative regimen was well tolerated as no significant toxicity was observed. The treatment-related toxicities were similar for the two group of patients, and none of the patients experienced grade 4 toxicity. ConclusionThe novel treatment protocol Pc 26.1 effectively and safely prevented graft rejection and ensured a high thalassemia-free survival rate in patients who received BMT from related donors who were not HLA-matched siblings. Our data show that thalassemia patients treated with Pc26.1 and receiving RD transplant have similar outcomes (rates of OS, TFS, GVHD, and TRM) to recipients of MSD transplantation. These findings are significant because they expand the availability of the treatment to more patients. Disclosures:No relevant conflicts of interest to declare.

Comparison of Unrelated Cord Blood Transplantation and HLA-Matched Sibling Hematopoietic Stem Cell Transplantation for Patients with Chronic Myeloid Leukemia in Advanced Stage

This is the first report to present a clinical comparison of unrelated cord blood transplantation (CBT) and HLA-matched sibling allogeneic hematopoietic stem cell transplantation for patients with chronic myeloid leukemia (CML) in advanced stage (accelerated phase or blast crisis). A total of 32 consecutive patients with advanced CML received unrelated CBT (n = 16) or HLA-matched sibling allogeneic peripheral blood stem cell or bone marrow transplantation (allo-PBSCT/BMT) (n = 16) between 2002 and 2011. The median day to neutrophil engraftment and the median day to platelet engraftment were longer in the unrelated CBT group. The cumulative incidence of grades 1 to 2 acute graft-versus-host disease (aGVHD), grades 3 to 4 aGVHD, and chronic graft-versus-host disease did not differ significantly between the 2 cohorts. The cumulative incidence of transplantation-related mortality (TRM) at day +180 was higher in CBT group (37.5% versus 12.5%, P = .013). The risk of relapse was lower in CBT patients compared with that of allo-PBSCT/BMT patients (14.2% versus 42.7%, P = .03). The long-term survival in CBT group patients was slightly better than that of allo-PBSCT/BMT group, although the difference did not reach statistical significance: the 5-year overall survival for CBT patients and allo-PBSCT/BMT patients was 62.5% and 48.6%, respectively (P = .10), whereas the 5-year leukemia-free-survival rate was 50% and 40.5%, respectively (P = .12). Our comparisons suggest that patients with advanced CML receiving unrelated CBT had a lower relapse rate, a slightly better long-term survival, but a higher early TRM than those receiving HLA-matched related allo-PBSCT/BMT.

Multiple infusions of mesenchymal stromal cells induce sustained remission in children with steroid‐refractory, grade III–IV acute graft‐versus‐host disease

Mesenchymal stromal cell (MSC) infusions have been reported to be effective in patients with steroid-refractory, acute graft-versus-host disease (aGvHD) but comprehensive data on paediatric patients are limited. We retrospectively analysed a cohort of 37 children (aged 3 months-17 years) treated with MSCs for steroid-refractory grade III-IV aGvHD. All patients but three received multiple MSC infusions. Complete response (CR) was observed in 24 children (65%), while 13 children had either partial (n = 8) or no response (n = 5). Cumulative incidence of transplantation-related mortality (TRM) in patients who did or did not achieve CR was 17% and 69%, respectively (P = 0.001). After a median follow-up of 2.9 years, overall survival (OS) was 37%; it was 65% vs. 0% in patients who did or did not achieve CR, respectively (P = 0.001). The median time from starting steroids for GvHD treatment to first MSC infusion was 13 d (range 5-85). Children treated between 5 and 12 d after steroid initiation showed a trend for better OS (56%) and lower TRM (17%) as compared with patients receiving MSCs 13-85 d after steroids (25% and 53%, respectively; P = 0.22 and 0.06, respectively). Multiple MSC infusions are safe and effective for children with steroid-refractory aGvHD, especially when employed early in the disease course.

Allogeneic stem cell transplant for adults with myelodysplastic syndromes: relevance of pre-transplant disease status

The aim of the present study was to investigate the outcome of 94 adult patients with myelodysplasia (MDS) who received an allogeneic stem cell transplant between January 1995 and September 2010 in two Italian hematology centers. At the time of transplant, 53 patients (56%) had relapsed/refractory disease. The cumulative incidence of grades II–IV acute graft-versus-host disease (GVHD) and chronic GVHD was 33% (95% confidence interval [CI] 21–45%) and 78% (95% CI 66–90%), respectively. The cumulative incidence of transplant-related mortality (TRM) at 100 days was 13% (95% CI 6–21%). The 2-year progression free survival (PFS) and overall survival (OS) were 41% (95% CI 31–51%) and 49% (95% CI 38–59%), respectively. On multivariate analysis, advanced disease stage at transplant was the major independent variable associated with an inferior 2-year PFS (HR 3.66, 95% CI 1.98–6.76) and OS (HR 3.68, 95% CI 1.95–6.93). Use of an alternative donor was an independent variable associated with TRM (HR 3.18, 95% CI 1.31–7.72). In conclusion, our data suggest that disease status at the time of transplant is the major predictor for improved PFS and OS, and treatments required to reach this goal may have value in leading to an improved outcome.

Combination of low-dose mycophenolate mofetil with cyclosporine and methotrexate as GVHD prophylaxis in unrelated donor allogeneic stem cell transplantation

We report the results of HLA-matched unrelated donor allogeneic stem cell transplantation with new GVHD prophylaxis regimen consisted of cyclosporine, methotrexate and low-dose mycophenolate mofetil in 139 patients with hematologic malignancies. The incidence of grades II-IV and III-IV acute GVHD were 43.0% and 17.3%, respectively. The incidence of chronic GVHD was 42.1%, with 16.5% extensive grade. The cumulative incidence of transplant-related mortality at 100 days and 3 years were 7.9% and 29.7%, respectively. Three-year overall survival, disease-free survival and relapse incidence were 58.7%, 55.3% and 19.6%, respectively. These results suggest the new regime may be effective for the prophylaxis of acute and chronic GVHD in unrelated donor transplantation.

Re‐emerging Philadelphia chromosome‐positive acute leukaemia more than 20 years after allogeneic haematopoietic stem cell transplantation

Re‐emerging <scp>P</scp>hiladelphia chromosome‐positive acute leukaemia more than 20 years after allogeneic haematopoietic stem cell transplantation

A Novel Conditioning Regimen Improves Outcomes in b-Thalassemia Major Patients Using Unrelated Donor Peripheral Blood Stem Cell Transplantation

Abstract 4514We used a novel NF-08-TM transplant protocol in 100 consecutive patients with β-thalassemia major (TM), including 66 with allogeneic peripheral blood stem cell transplantation (PBSCT) from unrelated donors (UD) with well-matched human leukocyte antigens (HLAs) and 34 with hematopoietic stem cell transplantation (HSCT) from matched sibling donors (MSD). The median age at transplantation was 6.5 yo (range: 0.6–15 yo), and the ratio of male to female patients was 68:32. The median follow-up time was 24 months (range: 12–39 months). The 3-year overall survival (OS) and TM-free survival (TFS) were 92.4% and 90.9% in the UD-PBSCT group and 88.2% and 82.4% in the MSD-HSCT group. The cumulative incidences of graft rejection (GR) and grade II–IV acute graft-versus-host disease (aGVHD) were 1.5% and 10.6%, respectively, in the UD-PBSCT group and 6.1% and 5.9%, respectively, in the MSD-HSCT group. The cumulative incidence of transplant-related mortality (TRM) was 7.6% in the UD-PBSCT group and 11.8% in the MSD-HSCT group. In conclusion, UD-PBSCTs using the well-tolerated NF-08-TM protocol show similar results to MSD-HSCTs and can be used to treat b thalassemia patients in the absence of MSD. Disclosures:No relevant conflicts of interest to declare.

Comorbidity and Outcomes for Patients Over Age 65 Years Treated with Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndrome

AbstractAbstract 2032▪▪This icon denotes a clinically relevant abstract Background:Acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) preferentially afflict patients 65 years of age and older. Patients in this age group are likely to have underlying comorbid conditions. These comorbidities affect treatment planning decisions and clinical outcomes. Here we report comorbidity-stratified outcomes of patients older than 64 treated at MD Anderson Cancer Center from 1996 until 2011, inclusive, treated with allogeneic stem cell transplant (ASCT). Methods:182 patients older than 64 received an ASCT for AML (n=143) or MDS (n=39). Patient charts were reviewed and comorbidity data abstracted using a standardized form. Burden of comorbidity was assessed using the Hematopoetic Stem Cell Transplant-Specific Comorbidity Index (HSCT-CI). Low-risk, intermediate-risk, and high-risk patients were categorised at 0, 1–2, and >=3 points as per the HSCT-CI. 157 patients were evaluable for pre-transplant comorbidity. Outcomes of interest were cumulative incidence of transplant-related mortality (TRM), cumulative incidence of relapse-related mortality (RRM), incidence of acute and chronic graft-versus-host disease (GVHD), and overall survival (OS). These were estimated from the date of transplantation. Results:The median age of transplanted patients was 67 (range 65–79), and 37 patients age 70 and older were treated. The majority of patients were intermediate-risk and high-risk patients (table), 9 patients had HSCT-CI scores of >=5. Median follow-up for alive patients was 12.6 months (n=63; range 0–118). Cumulative incidence of TRM was 6% at 100 days, 14% at 1 year, 23% at 2 years, and 36% at 5 years (figure). Cumulative incidence of RRM was 36% at 1 year, 42% at 2 years, and 47% at 5 years. HSCT-CI did not independently predict for either TRM or RRM (log-rank test p=0.95). The incidence of grade III and IV acute GVHD was 10% of all patients. The cumulative incidence of chronic GVHD was 25% at 1 year, 27% at 2 years, and 30% at 5 years, with no association between GVHD and HSCT-CI comorbidity. Conclusion:ASCT is a curative option for selected patients over age 64. HSCT-CI did not predict TRM or survival on this cohort of high-risk patients. Disease relapse was of greater concern than TRM, and so novel approaches to relapse prevention are needed.TablePatient characteristicsCategoryParameterNumber (%)HSCT comorbidity indexLow risk (0)34 (22)Intermediate risk (1)67 (37)High Risk (2)56 (36)Donor typematched related donor87 (48)matched unrelated donor73 (40)mismatched unrelated donor17 (9)Preparative regimensfludarabine/melphalan85 (47)fludarabine/busulfan61 (34)fludarabine/idarubicin13 (7)Immunosuppressiontacrolimus/mini-methotrexate147 (81)tacrolimus/mycophenolate8 (4)post-transplant cyclophosphamide16 (9)Cell sourcePeripheral blood122 (67)Marrow53 (29)Cord7 (4)CytogeneticsGood risk14 (8)Intermediate risk86 (42)Poor risk71 (50)Disease status at ASCTprimary induction failure21 (12)complete remission 138 (21)complete remission 2 or 315 (8)refractory/untreated disease120 (66) [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Prospective Validation of the Predictive Power of the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) for HCT Outcomes At US Transplant Centers: A Center for International Blood and Marrow Transplant Research (CIBMTR) Study

AbstractAbstract 733In 2005, the HCT-CI was introduced by a single institution as a weighted scoring system to predict mortality risk following allogeneic HCT. Since then, not all investigators were able to validate the HCT-CI after testing in their respective institutions. In 2007, a new prospective multi-institutional observational study was initiated at the CIBMTR to collect comorbidities from all transplant centers by their respective evaluators and to validate the predictive power of the HCT-CI in a large sample of patients (pts). The HCT-CI was adapted into the Pre-Transplant Essential Data (pre-TED) collection form #2400. Data managers from all institutions attended an education session on comorbidity coding per the HCT-CI at the 2007 Tandem BMT Meeting in Keystone, Colarodo. This session was then made public to all data managers at the CIBMTR website. <>The study accrued 8115 consecutive pts treated with allogeneic HCT from 12/2007 to 12/2009 from related (47%) or unrelated (53%) donors. Median age was 52 [range 1–78) years. Conditioning regimens were high-dose (67%) or either reduced-intensity (RIC) or nonmyeloablative (NST) regimens (34%). Diagnoses were acute (54%) or chronic (12%) leukemia, myelodysplastic syndromes (16%), lymphomas (16%), and others (2%). GVHD prophylaxis regimens were cyclosporine-based (22%), tacrolimus-based (68%), or others (10%). Stem cell source was marrow (17%) or peripheral blood mononuclear cells (83%). Karnofsky performance status scores were <90% (33%), ≥ 90% (62%), or missing (5%). HCT-CI scores were 0 (47%), 1 (15%), 2 (11%), 3 (12%), 4 (7%), 5 (3%), ≥6 (4%), or missing (1%). About 11% of pts with score 0 had other comorbidities listed.Overall, pts experienced cumulative incidence of transplant-related mortality (TRM) of 28% and a survival rate of 48% at 3-years. Pts with HCT-CI scores of 0 vs. 1–2 vs. ≥3 had 3-year TRM incidences of 24%, 28%, and 35% (p <0.001) and 3-year overall survival (OS) rates of 54%, 47%, and 38%, respectively (p <0.001, Figure). Proportional hazards models were used to estimate the hazard ratio (HR) for TRM and OS associated with HCT-CI scores. The models were adjusted for all previously mentioned covariates in addition to disease status, CMV serology status, gender, and race. Increasing HCT-CI scores (1–2 and ≥3 vs. 0) were associated with increases in the HR [95% confidence interval (CI)] for TRM [1.12 (1.00–1.26) and 1.47 (1.31–1.65), respectively, p<0.0001] and OS [1.12 (1.03–1.22) and 1.36 (1.25–1.48), respectively, p<0.0001] in the overall pt population. No statistically significant difference could be detected between pts with score 0 + other comorbidities vs. score 0 for TRM (HR 0.93, p= 0.385) or OS (HR 0.96, p= 0.474). When the HCT-CI was modeled as scores of 0, 1, 2, 3, 4, and ≥5 the HR for TRM were 1.00 vs. 1.12 vs. 1.13 vs. 1.31 vs. 1.52 vs. 1.77, respectively (, p<0.0001) and for OS were 1.00 vs. 1.13 vs. 1.12 vs. 1.22 vs. 1.39 vs. 1.62 (p<0.0001). Likewise, the HCT-CI could discriminate outcomes well among pts given high-dose or RIC/NST regimens and those diagnosed with lymphoid or myeloid diseases (Table 1).The inter-rater reliability (IRR) rate among data managers versus their respective investigators was assessed in 3 institutions. Weighted kappa statistics were 0.54, 0.81, and 0.47 respectively, indicating fair-moderate agreement rate among evaluators.The HCT-CI is a valid tool to discriminate relative risks for TRM and OS after HCT across different institutions, different conditioning intensities, and different diagnoses. The HCT-CI should be used as a standard-of-care health measure in counseling pts for HCT, in clinical trial design, and in adjusting statistical analyses for HCT outcomes. Future efforts will focus on improving the IRR of the HCT-CI.Table 1:Multivariate analysesTRMOSHCT-CI scoresHRp-valueHRp-valueHigh-dose regimens01.00<0.00011.00<0.000111.191.1421.121.1031.341.1941.531.415+1.881.64RIC/NST regimens01.000.0011.00<0.000110.951.1221.101.1231.271.2741.461.395+1.661.65Lymphoid diseases01.00<0.00011.00<0.000111.161.1521.241.1231.371.3242.131.675+2.151.88Myeloid diseases01.00<0.00011.00<0.000111.121.1321.001.0631.251.1441.291.275+1.631.52 [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Hematopoietic Cell Transplantation for Children with High Risk Acute Lymphoblastic Leukemia in First Complete Remission: A Report From the Italian Association of Pediatric Hematology and Oncology (AIEOP) Registry.

AbstractAbstract 3036Children with acute lymphoblastic leukemia (ALL) in first complete remission (CR1) and high risk (HR) characteristics can benefit from allogeneic hematopoietic stem cell transplantation (HSCT). We carried out a retrospective, multicenter study to analyze the outcome of 211 consecutive ALL pediatric patients who received either related or unrelated (UD) HSCT for ALL in CR1 and were reported to the Italian Association of Pediatric Hematology and Oncology (AIEOP)-HSCT Registry between 1990 and 2008. Sixty-nine patients (33%) were transplanted between 1990 and 1999, 58 (27%) between 2000 and 2005, and 84 (40%) between 2005 and 2008. A matched family donor (MFD) was employed in 138 patients (65%) and an UD in 73 (35%).The 10-year probability of overall survival and disease-free survival (DFS) was 63.4% (95% CI, 57–70) and 61% (95% CI, 54–68), respectively. In univariate analyses, the donor type had an impact on DFS only for patients transplanted between 1990 and 1999 (MFD: 65% [95% CI, 53–77], UD: 33% [95% CI, 3–64], p=0.06). There were no differences between MFD and UD for patients who underwent HSCT after 2000. DFS was better in patients with grade 0-II aGvHD than in those with grade III-IV aGvHD (65% [95% CI, 58–62] and 40% [95% CI, 22–58], p=0.002). In multivariate analyses, the occurrence of grade IV aGvHD (RR=3.8 [95% CI, 1.58–9.20], p=0.002) was an independent factor associated with worse DFS. On the contrary, the occurrence of grade I and II aGvHD (RR=0.54 [95% CI, 0.29–0.99], p=0.05; RR=0.56 [95% CI 0.30–0.98], p=0.07) were independent favorable prognostic variables for DFS.The 10-year cumulative incidence of relapse incidence (RI) was 24% (95% CI, 19–30). In univariate analyses patients who experienced grade 0-I aGvHD (30% [95% CI, 23–40]) had higher RI than patients with grade II-IV aGvHD (15% [95% CI, 9–25) (p=0.013). In multivariate analysis, the occurrence of aGvHD remained an independent prognostic variable for RI.The 10-year cumulative incidence of transplant-related mortality (TRM) was 15% (95% CI, 11–21). In univariate analyses, TRM was lower for children aged 1–9 years at diagnosis as compared with those aged 10–14 years or older than 15 years (8% [95% CI, 4–15], 18% [95% CI, 11–31], and 54% [95% IC, 34–84], respectively, p<0.00001). The impact of donor type on TRM was only observed for patients transplanted between 1990 and 1999 (UD: 44%, [95% IC, 21–92], MFD: 8% [95% IC, 4–19], p=0.0043). Patients with grade III and IV aGvHD had TRM of 32% (95% CI, 16–61) and 82% (95% CI, 62–100), respectively, versus 13% (95% CI, 7–25), 3% (95% CI, 1–14) and 12% (95% CI, 6–26) of patients with grade II, I and 0 aGvHD, respectively (p<0.00001). In multivariate analysis the strongest predictors of TRM were grade IV aGvHD (RR 18.1 [95% IC, 4.37–75.3], p<0.00001) and UD donor for HSCT performed between 1990 and 1999 (RR 4.83 [95% IC, 1.43–16.3], p=0.01).In this study, 27 and 73 out of the 100 patients investigated had minimal residual disease (MRD)-intermediate risk (IR) and MRD-high risk (HR) features, respectively. The 27 with MRD-IR were given the allograft for the presence of other characteristics rendering them classifiable as HR. The probability of DFS and RI of MRD-IR and MRD-HR was comparable. Thus, although the number of patients investigated was limited, our results seem to suggest that HSCT could reduce or, at best, abrogate the effects of MRD on patient outcome. Our results suggest that after 1999 transplant outcomes are remarkably similar in recipients of UD and MFD. No advantage of total body irradiation (TBI) over chemotherapy in the conditioning regimen in terms of DFS, RI and TRM was found. The benefit offered by the occurrence of GvHD in terms of reduction of disease recurrence was, however, offset by a higher incidence of TRM. Indeed, taking patients who did not have aGvHD as the reference group, a better probability of DFS was observed only in patients who developed grade I-II aGvHD, this suggesting that only GvHD of mild/moderate severity can favorably impact on disease outcome.In conclusion, our data support the choice of performing allogeneic HSCT in pediatric and adolescent patients with HR ALL in CR1 from either MFD or UD. Randomized prospective cooperative group studies are desirable to establish the role of TBI-based conditioning in these patients. Disclosures:No relevant conflicts of interest to declare.

A novel conditioning regimen improves outcomes in ॆ-thalassemia major patients using unrelated donor peripheral blood stem cell transplantation

AbstractWe used a novel NF-08-TM transplant protocol based on intravenous busulfan, cyclophosphamide, fludarabine, and thiotepa in 82 consecutive patients with ॆ-thalassemia major (TM), including 52 with allogeneic peripheral blood stem cell transplantation (PBSCT) from unrelated donors (UDs) with well-matched human leukocyte antigens and 30 with hematopoietic stem cell transplantation (HSCT) from matched sibling donors (MSDs). The median age at transplantation was 6.0 years (range, 0.6-15.0 years), and the ratio of male-to-female patients was 56:26. The median follow-up time was 24 months (range, 12-39 months). The estimated 3-year overall survival and TM-free survival were 92.37 and 90.47 in the UD-PBSCT group and 90.07 and 83.37 in the MSD-HSCT group. The cumulative incidences of graft rejection and grades III-IV acute graft-versus-host disease were 1.97 and 9.67, respectively, in the UD-PBSCT group and 6.97 and 3.67, respectively, in the MSD-HSCT group. The cumulative incidence of transplant-related mortality was 7.77 in the UD-PBSCT group and 10.07 in the MSD-HSCT group. In conclusion, UD-PBSCTs using the well-tolerated NF-08-TM protocol show similar results to MSD-HSCTs and can be used to treat ॆ-thalassemia patients in the absence of MSDs.

Unmanipulated Haploidentical Bone Marrow Transplantation and Posttransplantation Cyclophosphamide for Hematologic Malignancies after Myeloablative Conditioning

Fifty patients with high-risk hematologic malignancies, underwent an unmanipulated haploidentical bone marrow transplantation (BMT), followed by posttransplantation high-dose cyclophosphamide (PT-CY): the myeloablative (MA) conditioning consisted of thiotepa, busulfan, fludarabine (n = 35), or total body irradiation (TBI), fludarabine (n = 15). The median age was 42 years (range, 18-66 years); 23 patients were in remission, 27 had active disease, and 10 patients were receiving a second allograft. Graft-versus-host disease (GVHD) prophylaxis consisted in PT-CY on day +3 and +5, cyclosporine (from day 0), and mycophenolate (from day +1). Three patients died before engraftment, and 2 patients had autologous recovery: 45 patients (90%) had full-donor chimerism on day +30. The median day for neutrophil engraftment was day +18 (range, 13-30 days). The cumulative incidence of grade II-III acute GVHD (aGVHD) was 12%, and of moderate chronic GVHD (cGVHD) 10%. With a median follow-up for surviving patients of 333 days (range, 149-623 days), the cumulative incidence of transplantation-related mortality (TRM) was 18%, and the rate of relapse was 26%. The actuarial 22-month disease-free survival (DFS) rate was 68% for patients in remission and 37% for patients with active disease (P < .001). Causes of death were pneumonia (n = 3), hemorrhage (n = 3), sepsis (n = 3), and relapse (n = 7). In conclusion, an MA conditioning regimen followed by haploidentical BMT with PT-CY results in a low risk of aGVHD and cGVHD and encouraging rates of TRM and DFS.