High-dose melphalan (HD-Mel) has been successfully employed in autografting patients with multiple myeloma. An advantage of this regimen is that the total dose of Mel can be delivered in a single ...day, being particularly useful when non-frozen hematopoietic stem cells are employed in the autograft.
All consecutive patients with R/R lymphomas, both HL and NHL studied and treated at two different centers were prospectively included in a study of ASCT employing a single dose of HD-Mel (200 mg/m
2
). A group of R/R HL or NHL autografted employing BEAM-like preparative regimens was constructed matched by diagnosis and age. The primary endpoint of the study was overall survival (OS), the secondary endpoint was event-free survival (EFS).
Twenty-five R/R HL/NHL patients were prospectively accrued in the study. There were 8 (32%) females, 13 (52%) patients had at least 1 adverse effect: 7 (28%) developed mucositis, 5 (20%) neutropenic fever, and 6 (24%) grade IV nausea. In the HD-Mel group, median overall survival (OS) was not achieved and OS at 36 months was 71%, the transplant-related mortality being 0%. In the control group, median OS was not achieved and the 36-month OS was 76%, results not statistically significant (p 0.5). The EFS was also similar in both groups (p 0.5).
HD-Mel alone is non-inferior to a BEAM-like regimen as a preparative regimen for autografting patients with R/R HL and NHL. The regimen is adequate to graft persons with non-frozen stem cells.
Natural Killer (NK) cells are innate immune cells that mediate antiviral and antitumor responses. NK cell activation and induction of effector functions are tightly regulated by the integration of ...activating and inhibitory receptors such as killer immunoglobulin-like receptors (KIR). KIR genes are characterized by a high degree of diversity due to presence or absence, gene copy number and allelic polymorphism. The aim of this study was to establish the distribution of KIR genes and genotypes, to infer the most common haplotypes in an admixed Colombian population and to compare these KIR gene frequencies with some Central and South American populations and worldwide. A total of 161 individuals from Medellin, Colombia were included in the study. Genomic DNA was used for KIR and HLA genotyping. We analyzed only KIR gene-content (presence or absence) based on PCR-SSO. The KIR genotype, most common haplotypes and combinations of KIR and HLA ligands frequencies were estimated according to the presence or absence of KIR and HLA genes. Dendrograms, principal component (PC) analysis and Heatmap analysis based on genetic distance were constructed to compare KIR gene frequencies among Central and South American, worldwide and Amerindian populations. The 16 KIR genes analyzed were distributed in 37 different genotypes and the 7 most frequent KIR inferred haplotypes. Importantly, we found three new genotypes not previously reported in any other ethnic group. Our genetic distance, PC and Heatmap analysis revealed marked differences in the distribution of KIR gene frequencies in the Medellin population compared to worldwide populations. These differences occurred mainly in the activating KIR isoforms, which are more frequent in our population, particularly KIR3DS1. Finally, we observed unique structural patterns of genotypes, which evidences the potential diversity and variability of this gene family in our population, and the need for exhaustive genetic studies to expand our understanding of the KIR gene complex in Colombian populations.
Fludarabine 120-160 mgs/m2 plus melphalan 140 mgs/m2 (Flu- Mel) is a well known reduced intensity conditioning protocol used in allogeneic transplantation, however it can be no enough intense to ...treat high risk acute leukemia, specially in the relapse setting. On the other hand, 400 cGy of total-body irradiation (TBI 400) has been successfully added to myeloablative dose of fludarabine busulfan without excessive toxicity. We designed a regimen adding TBI 400 to usual dose of Flu-Mel with the idea to increase its anti-leukemic activity. Below we present our experience
Methods and patients
Peripheral blood stem cells were mobilized with figrastim for 5 days, later, 1 or 2 apheresis were done to achieve a minimum of 3 million of CD34 + cells/kg. The conditioning consisted of fludarabine 30-40 mgs/m2 for four days, melphalan 140 mgs/m2 one dose, on day - 1, TBI 400 was administered split in 2 fractions. The prophylaxis against graft versus host disease (GVHD) was done with cyclosporine and methotrexate, all patients were given pegfilgrastim
22 patients were transplanted, median age 26.5 years (range 8-49), the diagnosis were; acute lymphoblastic leukemia (13), acute myeloid leukemia (6), chronic myeloid leukemia (1), high risk myelodisplasia(1), mixed acute leukemia(1). 32% were in first remission, 41% in second, 27% were in third or they had active disease. The discrimination according CIBMTR disease risk index (CIBMTR-DRI) was: 54% high risk, 41% intermediate and 5% low
Results
All donors were matched siblings, a median of 10 millions/kg of CD34+ cells were infused; all patients engrafted, the neutrophil and platelet recovery occurred on days +11 and + 14 respectively. The grade III toxicity was; mucositis, 45% and one case of encephalopathy, there were not any case of sinusoidal obstruction syndrome. The incidence of GVHD acute (GII-IV) and chronic extensive was 10 and 25%. With a median follow up of 11 months (range 6-30) the overall survival (OS)(Kaplan-Meier) at 24 and 36 months is 69 and 55% . Six patients have died, one due to sepsis and five secondary to relapse. The OS according to CIBMTR-DRI at 36 month was 75 and 46% for intermediate and high risk groups
Conclusion:
The addition of TBI 400 to Flu- Mel regimen is feasibly, the main toxicity is mucositis, the non- relapse mortality is very low and the incidence of GVHD, acute a chronic, is not higher than expected
This combination shows an encouraging anti leukemic effect, as it is demonstrated by an OS of 75 and 46% in patients classified in intermediate and high risk CIBMTR DRI groups.
This preparative protocol can be a low toxicity alternative to more conventional myeloablative regimen. It warrants further studies
No relevant conflicts of interest to declare.
Introduction
The use of Haploidentical Transplantation (haploSCT) with pos-transplantation cyclophosphamide (PTCy) has become in a very good alternative for patients with acute leukemia who need a ...transplant but without a well matched donor, however, it is not clear what is the "best" conditioning regimen in this setting; on the other hand, fludarabine + melphalan (flu-mel) is a well-known preparative protocol, it has a good balance between toxicity and anti-leukemic activity. We explored the use of it plus the addition of 200-400cGy of total body irradiation (TBI) in a group of 34 patients with acute leukemia who were allografted with haplo peripheral blood stem cells (PBSC) and PTCy.
Methods and Patients
Donors were mobilized with filgrastim 5 mg/kg/BID for five days, the PBSC were collected with one or two large volume apheresis procedure. The conditioning consisted of melphalan 100-120 mgs/m2 administered on day -6, fludarabine 150 mgs/m2 split in 5 days, and 200-400 cGy of TBI added on day - 1 (Flu Mel TBI). All patients were given PTCy 50 mg/kg/day on D+3 and D+4, followed by ciclosporin and mycophenolate starting on day + 5. In all cases filgrastim was administered after transplant beginning on d + 6.
After a signed informed consent, 34 patients underwent to transplant; median age was 22 years (range 5-53), the diagnosis were: acute myeloid leukemia 11 patients, acute lymphoid leukemia 22 and 1 had myelodysplasia. 26.5% were in first remission (CR1), 47 % in second (CR2), and 26.5% in third or with more than 5% of blast in bone marrow (CR3). 5 out of 30 cases in remission had MRD positivity
Results
50% of patients received flu-mel +TBI 400 cGy, while the other half were given flu-mel + TBI 300 or 200 cGy. A mean of 12 million of PBSC/kg was infused. The neutrophil engraftment rate was 97%, median time to achieve 500 or more was 15 days (range 11-20), 3 patient died before d+ 100 without platelet recovery, the remaining had a self- sustained platelet count of 20.000 or more at an average of 15 days (range 12-48). Chimerism was available in all cases that survived beyond day + 100; all of them had full donor hematopoiesis.
The main toxicities were gastro intestinal; mucositis G II-III 35%, and two cases of hemorrhage, and bacteremia (30%). With a median follow-up for surviving patients of 11 months, the incidence of GVHD acute (GII-IV) and chronic extensive was 29.4 and 25% respectively. The transplantation related mortality was 17.4% while the rate of relapse was 14%. Causes of death were relapse: 4, sepsis: 4 fusariosis: 1, intestinal GVHD: 1.
Event was defined as death for any cause or relapse, the event free survival (Kaplan Meier) at 12 and 24 months was; 63% for the whole group, 73% for CR1+CR2 and 31% for patients in CR3 or with active disease (figure 1)
Conclusion
The use of fludarabine - melphalan plus 200-400 cGy of TBI as a preparative regimen previous to transplant of haplo PBSC with PTCy was associated to a fast and almost universal engraftment, acceptable toxicity and encouraging disease free survival showing a very good balance between tolerance and anti leukemic activity. It deserve more studies
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No relevant conflicts of interest to declare.
Introduction: T cell replete haploidentical stem cell transplantation with post-transplantation cyclophosphamide (PTCy) has shown encouraging results for the treatment of hematologic malignancies, ...its main advantage is that almost every patient will have a donor in a timely manner. However this technique has been explored mainly in adults and using bone marrow as a cellular source. Here we present our experience using T cell replete haploidentical peripheral blood stem cell transplantation (TCR-Haplo-PBSCT) with PTCy in 21 pediatric patients whit high-risk acute leukemia
Methods and Patients: Donors were mobilized with filgrastim 5 mg/kg/BID for five days, the PBSC were collected with one large volume apheresis procedure. The conditioning consisted of fludarabine 30 mg/m2/day for 5 days, oral busulfan 4-8 mg/kg/split in 1-2 days and, one day before transplant, total body irradiation 400 cGy divided in two fractions (Flu Bu TBI) or fludarabine 150 mgs/m2 split in 5 days, melphalan 100-140 mgs/m2, one day and TBI 200-400 cGy on day - 1 (Flu Mel TBI). All patients were given PTCy 50 mg/kg/day on D+3 and D+4, followed by ciclosporin and mycophenolate starting on day + 5. In all cases filgrastim was administered after transplant beginning on d + 6.
After a signed informed consent, 21 patients who needed an urgent transplant, were allografted; median age was 11 years (range 1-16), 10 were girls, the diagnosis were: acute lymphoblastic leukemia 11 patients, acute myeloid leukemia 9, and blastic phase of chronic myeloid leukemia one. 19% were in first remission (CR1), 43% in second (CR2), and 39% in third or with refractory disease(CR3).
Results:
17 patients were given Flu Bu TBI conditioning while 4 received Flu Mel TBI combination
All the donors shared 4 out of 8 alleles with the recipient; in 62% of the cases the donor was the Mother in 19% the Father and in other 19% one sibling. A median of 16 million of CD34+ cells/kg was infused. The engraftment rate was 100%, median time to achieve 500 neutrophil or more was 15 days (range 14-20), 1 patient out of 21 died without platelet recovery, the remaining had a self- sustained platelet count of 20.000 or more at a median of 14 days (range 10-21). Chimerism at day + 100 was available in 19 cases; all of them had full donor hematopoiesis.
The median follow-up is 11 months (range 3-28), the cumulative incidence of graft versus host disease (GVHD) acute grade II-IV and chronic extensive was 23.8% and 25% respectively. Six patients have died, the causes were; pneumonia (n:1) and relapse of leukemia(n:5).
In table 1 is presented the overall survival (OS) and event free survival (EFS) for the whole group and discriminated according remission Table 1Whole groupCR1CR2CR3OS month 1277.4% ± 10100%100%47.3% ± 18.8EFS month 1271.5% ± 10.9100%100%43.8% ± 18.8OS month 2469.6% ± 11.6100%80% ± 17.947.3% ± 18.8EFS month 2463.6% ± 12.3100%83% *22 months21.9% ±18.1
Conclusion: The use of TCR-Haplo-PBSCT with PTCy and a medium intensity conditioning for treating pediatric high risk acute leukemia is promising; it is associated with very good engraftment rate, low transplantation related mortality and an acceptable incidence of GVHD despite the use of peripheral blood.
This protocol produces a remarkable leukemia free survival rate, especially in patients in CR1 and CR2. This approach could be a good alternative for children with high-risk leukemia and without suitable matched donors. It deserve further studies
No relevant conflicts of interest to declare.
Storage of peripheral blood stem cells (PBSC) at 4ºC is a simple and inexpensive alternative to cryopreservation for preserving the clonogenic capacity of progenitors cells in the autologous ...transplant setting, however it has been perceived as unsafe and has deserved little attention. We present the experience of two Latin-American centers using refrigerated, non-cryopreserved stem cells after conditioning with high dose melphalan, CBV or BEAM in a large group of lymphoma and myeloma patients
Materials and Methods
PBSC were mobilized with filgrastim 5 mg/kg/BID for three to six days.One to three apheresis procedure were employed; the cells were stored at 4ºC for 5 to 6 days in patients who received BEAM or CBV and for 3 days in those given melphalan. All of the conditioning regimens were administered preserving the full intensity of dose (Table 1). After the autograft all patients received filgrastim or pegfilgrastim
Table 1BEAMD-5D-4D-3D-2D-1BiCNU 300 mgs/m2XEtoposide 200-400 mgs/m2XXXXCitarabine 300-400 mgs/m2XXXMelphalan 140 mgs/m2XCBVBiCNU 300 mgs/m2 13 patients received carboplatin 900 mgs/m2 instead BiCNUXEtoposide 300 mgs/m2XXXCiclophosphamide 2.000 mgs/m2XXXMelphalanMelphalan 200 mgs/m2XMelphalan 100 mgs/m2XX
Results
102 lymphoma patients: 48 Hodgkin's lymphoma (HL) and 54 non-Hodgkin´s lymphoma (NHL) received BEAM (71) or CBV (31). A median of 3.3 millions/kg of CD34 was infused; the median viability of the cells after 5-6 days of refrigeration (trypan blue exclusion) was 82%. 101 out of 102 patients engrafted, median time to achieve 500/ul neutrophil or more was 12 days, 100 were evaluable for thrombopoiesis, 99 of them had a self- sustained platelet count of 20.000 or more at a median of 17 days. The OS at 5 years was 59% and 42% for patients with Hodgkin and lymphoma respectively
151 patients with multiple myeloma received melphalan 200 mgs/m2. After 72 hours of refrigeration, a median of 2.6 millions/kg of CD34 cells were infused, the viability in all cases being > 90%. Three patients were not evaluable because early death. Median time to achieve 500 neutrophil or more and 20.000 platelets was 12 (9-50) and 15 (7-50) days. The OS at 5 years was 50%
21 patients with NHL and HL received as conditioning regimen melphalan 200 mgs/m2. After 72 hours of storage, a median of 1.75 millions/kg of CD34 cells were transplanted, 100% of them engrafted, median time to 500 neutrophils and 20.000 platelets was 11.9 and 15 days respectively
There were no cases of secondary engraftment failure in any of the three groups
Conclusion
In this series of 268 patients, we have shown that autologous PBSC can be kept at 4ºC in a conventional blood bank refrigerator for up to six days and use them to rescue high-dose chemotherapy in both multiple myeloma and lymphoma patients.
Avoiding freezing procedures results in substantial cost savings. The availability of freezing devices for hematopoietic stem cells is not anymore an obstacle to start a an autologous transplantation program This observation is critical in areas of underprivileged economic circumstances, where more than 50% of the inhabitants of the world live.
No relevant conflicts of interest to declare.
We compared outcomes of 1461 adult patients with acute lymphoblastic leukemia (ALL) receiving hematopoietic cell transplantation (HCT) from a haploidentical (n = 487) or matched unrelated donor (MUD; ...n = 974) between January 2005 and June 2018. Graft-versus-host disease (GVHD) prophylaxis was posttransplant cyclophosphamide (PTCy), calcineurin inhibitor (CNI), and mycophenolate mofetil (MMF) for haploidentical, and CNI with MMF or methotrexate with/without antithymoglobulin for MUDs. Haploidentical recipients were matched (1:2 ratio) with MUD controls for sex, conditioning intensity, disease stage, Philadelphia-chromosome status, and cytogenetic risk. In the myeloablative setting, day +28 neutrophil recovery was similar between haploidentical (87%) and MUD (88%) (P = .11). Corresponding rates after reduced-intensity conditioning (RIC) were 84% and 88% (P = .47). The 3-month incidence of grade II-IV acute GVHD (aGVHD) and 3-year chronic GVHD (cGVHD) was similar after haploidentical compared with MUD: myeloablative conditioning, 33% vs 34% (P = .46) for aGVHD and 29% vs 31% for cGVHD (P = .58); RIC, 31% vs 30% (P = .06) for aGVHD and 24% vs 29% for cGVHD (P = .86). Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 44% and 51% with haploidentical and MUD (P = .56). Corresponding rates after RIC were 43% and 42% (P = .6). In this large multicenter case-matched retrospective analysis, despite the limitations of a registry-based study (ie, unavailability of key elements such as minimal residual disease testing), our analysis indicated that outcomes of patients with ALL undergoing HCT from a haploidentical donor were comparable with 8 of 8 MUD transplantations.
•HCT outcomes were retrospectively compared between patients with ALL who underwent haploidentical (n = 487) or MUD (n = 974) transplant.•HaploHCT with PTCy patients and those undergoing MUD HCT with conventional GVHD prophylaxis (plus or minus ATG) had comparable outcomes.
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More than a million HCT have been performed worldwide to date, but transplant rates and indications vary widely across regions. The Latin American Bone Marrow Transplantation Group (LABMT) was ...created under the auspices of the Worldwide Network for Blood and Marrow Transplantation (WBMT) in 2011 to assist in diffusing the practice, to integrate centers from multiple countries and to improve access to transplantation in the region. To evaluate the actual HCT activity, trends and contemporary practices in Latin America (LA), the LABMT surveyed centers for the annual activity from 2009 to 2012. Methods: The WBMT Global Activity Survey was used as a template and sent to all Hematology and HCT Societies in the region. This survey includes information of annual HCT numbers by center, indications, stem cell source and donor type. Results: A total of 11,116 HCT were performed between 2009 and 2012 with an increase in annual numbers from 2,517 in 2009 to 3,072 in 2012 (22%). The majority of the HCT were autologous (62%) with a 32% increase in activity over the period analyzed. In contrast, the increase in allogeneic HCT (6%) was relatively small. The majority of allogeneic HCT used related donors (n=3210), mostly HLA-identical peripheral blood (n=1812), bone marrow (n=1128) and non-identical related peripheral blood (n=156). Unrelated donor HCT (n=982) were performed mostly using cord blood (n=427), followed by bone marrow (n=332) and peripheral blood (n=223). In 2012, 91 teams from 12 countries reported 3,072 patients. Transplant rates (TR; HCT/10 million population) were 21 for allogeneic (ranging from 6 in Venezuela to 85 in Uruguay) and 60 for autologous HCT (ranging from 8 in Mexico to 215 in Uruguay). Unrelated donor TR was 5, ranging from 0 (Costa Rica, Panama, Peru, Paraguay and Venezuela) to 18 (Chile). Transplant center team density (team/10 million inhabitants) was 1.8 in 2012, with the highest in Uruguay (15), followed by Panama (8), Costa Rica (4), and Argentina (4). In comparison to other regions, transplant center density in LA was identical to the Asian Pacific region and lower than in Europe (7) or US/Canada (6). TR in LA compared to Asia/Pacific were higher for autologous (39 vs. 14) and lower for allogeneic (21 vs. 24, respectively, Table 1). Most transplant indications for autologous HCT (65% of all HCT) were plasma cell disorders (48%) and lymphomas (41%). Most allogeneic transplants (35% of all HCT) were performed for acute leukemias (58%, equally myeloid and lymphoid leukemias) and 18% for non-malignant disorders. Conclusion: While transplant indications are comparable to HCT performed in Europe and North America, transplant rates, transplant center and transplant team densities in LA are markedly lower. More autologous than allogeneic HCT are performed and autologous HCT increased considerably between 2009 and 2012. Unrelated donor TR is lower than in other regions. Initiatives are currently being taken to increase transplant activity, especially using alternative donor transplants within the region.
Table 1Transplant Rates and Team Density WorldwideTransplant rates (HCT/10 million population)Team densityRegionPOPTOTALAUTOALLOFAMILYSIBLINGUNRELATEDLA511.760.039.220.916.014.34.91.8SEAR/WPR3078.038.614.224.412.58.211.91.8EUROPE846.4379.3222.5156.868.257.088.67.6USA/Canada348.0482.5264.9217.591.275.8126.36.2EMR/AFR690.929.812.717.215.715.01.40.4HCT, hematopoietic cell transplantation; POP, population; AUTO, autologous; ALLO, allogeneic; SEAR/WPR, South East Asia/Western Pacific Region; LA, Latin America; EMR/AFR; Eastern Mediterranean/African Region
No relevant conflicts of interest to declare.
Haploidentical transplantation performed with post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis has been associated with favorable outcomes for patients ...with acute myeloid leukemia and lymphomas. However, it remains unclear if such approach is effective for patients with acute lymphoblastic leukemia (ALL). We analyzed outcomes of 109 consecutively treated ALL patients 18 years of age and older at 5 institutions. The median age was 32 years and the median follow-up for survivors was 13 months. Thirty-two patients were in first complete remission (CR1), while the rest were beyond CR1. Neutrophil engraftment occurred in 95% of the patients. The cumulative incidence (CI) of grades II–IV and III–IV acute GVHD at day 100 post-transplant was 32% and 11%, while chronic GVHD, non-relapse mortality, relapse rate and disease-free survival (DFS) at 1 year post-transplant were 32%, 21%, 27% and 51%, respectively. Patients in CR1 had 52% DFS at 3 years. These results suggest that haploidentical transplants performed with PTCy-based GVHD prophylaxis provide an excellent alternative to HLA matched transplants for patients with ALL.
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