Gregorio Jaimovich

Latin America: the next region for haematopoietic transplant progress

Haematopoietic cell transplant activity in the 28 countries comprising Latin America is poorly defined. We conducted a voluntary survey of members of the Latin American Bone Marrow Transplantation Group regarding transplant activity 2009–2012. Collated responses were compared with data of transplant rates from the Worldwide Network for Blood and Marrow Transplantation for other geographic regions. Several socio-economic variables were analysed to determine correlations with transplant rates. In total, 94 teams from 12 countries reported 11 519 transplants including 7033 autotransplants and 4486 allotransplants. Annual activity increased from 2517 transplants in 2009 to 3263 in 2012, a 30% increase. Median transplants rate (transplant per million inhabitants) in 2012 was 64 (autotransplants, median 40; allotransplants, median 24). This rate is substantially lower than that in North America and European regions (482 and 378) but higher than that in the Eastern Mediterranean and Asia Pacific regions (30 and 45). However, the Latin America transplant rate is 5–8-fold lower than that in America and Europe, suggesting a need to increase transplant availability. Transplant team density in Latin America (teams per million population; 1.8) is 3–4-fold lower than that in North America (6.2) or Europe (7.6). Within Latin America, there is substantial diversity in transplant rates by country partially explained by diverse socio-economic variables including per capita gross national income, health expenditure and physician density. These data should help inform future health-care policy in Latin America.

Publications of bone marrow transplants in Latin America. A report of the Latin American Group of Bone Marrow Transplantation

Publications of bone marrow transplants in Latin America. A report of the Latin American Group of Bone Marrow Transplantation

Hematopoietic Cell Transplantation–Specific Comorbidity Index Predicts Morbidity and Mortality in Autologous Stem Cell Transplantation

The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) score is a useful tool to assess the risk for nonrelapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation. Although the HCT-CI has been investigated in autologous stem cell transplantation (ASCT), its use is limited. To improve on the current use of the HCT-CI score on the morbidity and mortality after ASCT, we assessed the 100-day morbidity defined as orotracheal intubation (OTI), dialysis or shock (vasopressors need), 100-day NRM, early composite morbidity-mortality (combined endpoint that included any previous endpoints), and long-term NRM. We retrospectively reviewed a cohort of 1730 records of adult patients who received an ASCT in Argentinean centers between October 2002 and August 2016. Median follow-up was 1.15 years, and median age was 53 years. Diseases were multiple myeloma (48%), non-Hodgkin lymphoma (27%), and Hodgkin lymphoma (17%); 51% were in complete or partial remission; and 13% received ≥ 3 chemotherapy lines before transplant (heavily pretreated). Early NRM (100-day) was 2.7%, 5.4% required OTI, 4.5% required vasopressors, and 2.1% dialysis, with an early composite morbidity-mortality of 6.8%. Long-term (1 and 3 years) NRM was 4% and 5.2% and overall survival 89% and 77%, respectively. High-risk HCT-CI patients had a significant increase in 100-day NRM compared with intermediate and low risk (6.1% versus 3.4% versus 1.8%, respectively; P = .002), OTI (11% versus 6% versus 4%, P = .001), shock (8.7% versus 5.8% versus 3%, P = .001), early composite morbidity-mortality (13% versus 9 % versus 4.7%, P < .001), and long-term NRM (1 year, 7.7% versus 4% versus 3.3%; and 3 years, 10.8% versus 4% versus 4.8%, respectively; P = .002). After multivariate analysis these outcomes remained significant: early composite morbidity-mortality (odds ratio [95% confidence interval] compared with low risk: intermediate risk 2.1 [1.3 to 3.5] and high risk 3.3 [1.9 to 5.9]) and NRM (hazard ratio [95% confidence interval] compared with low risk: intermediate risk .97 [.8 to 2.4] and high risk 3.05 [1.3 to 4.5]). No significant impact was observed in overall survival. Other than comorbidities, significant impact was observed for heavily pretreated patients, age ≥ 55 years, non-Hodgkin lymphoma, and bendamustine-etoposide-citarabine-melphalan conditioning. We confirmed that the HCT-CI had a significant impact on NRM after ASCT, and these findings are mainly due to early toxicity express as 100-day NRM and the 3 main morbidity outcomes as well as the composite endpoint.

Freezing the graft is not necessary for autotransplants for plasma cell myeloma and lymphomas

We studied rates of granulocyte and platelets recovery in 359 consecutive subjects receiving blood cell infusions in the context of autotransplants for plasma cell myeloma (N = 216) and lymphomas (N = 143). Blood cells were mobilised with filgrastim given for 4–5 days and collected after a median of 2 (range, 1–2) apheresis. Apheresis products were stored at 4° C for a median of 3 days (range, 2–6 days). Most subjects received carmustine, etoposide, cytarabine and melphalan (BEAM), cyclophosphamide, carmustine and etoposide (CBV) or high-dose melphalan. Filgrastim was given post transplant to 319 subjects. Median numbers of mononuclear cells collected was 31 × 10E + 6/kg (interquartile range (IQR) 37 × 10E + 6 cells/kg). Median numbers of CD34-positive cells collected was 3.6 × 10E + 6/kg (IQR 3.8 × 10E + 6/Kg). Median viability after collection was 90% (IQR 7%) after storage, 88% (IQR 12%). A total of 255 of 256 evaluable subjects recovered bone marrow function and there was no late bone marrow failure. Median interval to neutrophils >0.5 × E + 9/L was 13 days (range, 9–39 days) and to platelets >20 × 10E + 9/L, 16 days (range, 7–83 days). These rates and ranges seem comparable to those reported after autotransplants of frozen blood cells. There was no correlation between numbers of storage days at 4 °C and viability afte storage (r = −0.018, p = 0.14)) nor rates of recovery of neutrophils (r = −0.054, p = 0.52) or platelets (r = 0.116, p = 0.14). Blood cells collected for autotransplant can be stored at 4 °C for 6 d. This method is simple, inexpensive and widely applicable.

Transforming growth factor-|[beta]|1 functional polymorphisms in myeloablative sibling hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) with sibling donors (s.d.) is a life-saving intervention for patients with hematological malignancies. Numerous genetic factors have a role in transplant outcome. Several functional polymorphisms have been identified in TGF-β1 gene, such as single-nucleotide polymorphism (SNP) at +29C>T within exon 1. Two hundred and forty five patient/donor pairs who underwent a s.d. HSCT in our centers were genotyped for this SNP. In the myeloablative cohort, +29CC donors were associated with an increase in severe chronic GvHD (32% vs 16%, hazard ratio (HR) 9.0, P=0.02). Regarding survival outcomes, +29CC patients developed higher non relapse mortality (NRM) (1–5 years CC 28–32% vs TC/TT 7–10%; HR 5.1, P=0.01). Recipients of +29TT donors experienced a higher relapse rate (1–5 years TT 37–51% vs TC 19–25% vs CC 13%–19%; HR 2.4, P=0.01) with a decreased overall survival (OS) (1–5 years TT 69–50% vs TC/CC 77–69%; HR 1.9, P=0.05). Similar to previous myeloablative unrelated donors HSCT results, we confirmed that +29CC patients had higher NRM. In addition we found that +29TT donors might be associated with a higher relapse rate and lower OS. These results should be confirmed in larger series. Identification of these SNPs will allow personalizing transplant conditioning and immunosuppressant regimens, as well as assisting in the choice of the most appropriate donor.

Narrowing the gap for hematopoietic stem cell transplantation in the East-Mediterranean/African region: comparison with global HSCT indications and trends

Hematopoietic Stem Cell Transplantation (HSCT) activity was evaluated in the African (AFR)/EMRO region and compared to the global activity for the years 2006–2013. Data were obtained from 1570 teams in the 6 WHO continental regions. Of these, 29 (1.85%) of all teams were active in 12 of the 68 AFR/EMRO countries. They reported 2.331 (3.3%) of the worldwide 71.036 HSCT, and a transplant rate of 32.8 (TR; HSCT/10 million inhabitants; worldwide 128.5). This reflects still the lowest regional TR despite an increase of 90% since 2006. HSCT activity in AFR/EMRO countries was characterized by a higher use of allogeneic compared to autologous HSCT, an almost exclusive use of family donors, including haploidentical family donors. These findings contrast with the prevalence of autologous over allogeneic HSCT, and a higher frequency of unrelated HSCT in other parts of the world. Of note, the increase by 200% in HSCT for hemoglobinopathies from 2006 to 2013 (72 per year) in the AFR/EMRO region. This reflects the specific role of HSCT for these disease categories with high prevalence and incidence in the AFR/EMRO region. This report provides information for the competent authorities to foster adequate infrastructure. It urges transplant organization to optimize their cooperation.

Plerixafor, cyclophosphamide and G‐CSF and Blood cell mobilization in a patient with acute promyelocytic leukemia

To the Editor, Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia with distinct morphologic, cytogenetic and molecular features. Therapy of APL has progressed remarkably in the last 30 years with the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) and cures are now achieved in about 90% of patients with APL. High-dose chemotherapy and a transplant of autologous blood cells is widelyused to treat patients who relapse and achieve a 2nd remission. However, it is sometimes difficult to obtain sufficient numbers of blood cells for an autotransplant using chemotherapy and/or G-CSF. In patients with plasma cell myeloma or lympho-proliferative diseases, plerixafor, a molecule which blocks the interaction between CXCR4 and SDF-1, is added to the collection strategy. However, plerixafor is rarely used in the setting of autotransplants for myeloid leukemias because it may also mobilize leukemia cells resulting in leukemia contamination of the autograft. We describe blood cell mobilization with cyclophosphamide, G-CSF and plerixafor in a patient with APL in 2nd complete remission who failed a prior mobilization attempt with G-CSF alone. A 37-year-old woman developed high-risk APL according to PETHEMA risk stratification (WBC 20 3 10E1 9/L and platelets 9 3 10E1 9/L) in July, 2011. She received induction treatment with idarubicin and ATRA achieving a complete hematologic, cytogenetic and molecular remission. She then received 3 courses of consolidation chemotherapy with ATRA, an anthracycline and cytarabine followed by maintenance chemotherapy with 6-mercaptopurine, methotrexate and ATRA over 2 years. But relapsed in June 2014. She achieved a 2nd hematologic, cytogenetic and molecular remission following re-induction therapy with ATO (0.16 mg/kg/d) and ATRA (45 mg/mE1 2) followed by one cycle of consolidation chemotherapy with the same regimen. She was referred to our center for high-dose chemotherapy and an autotransplant. In February 2015, we tried to collect blood cells after giving G-CSF, 10 mg/kg/d for 5 days subcutaneously. An apheresis was not done because the CD34-positive cell concentration in her blood was only 9.4/ml on day 14. In March, 2015 a 2nd mobilization was done with cyclophosphamide 1.5 g/mE1 2 followed by G-CSF, 10 mg/kg/d, the next day. On day 18 the CD34-positive cell concentration was 2.2/ ml (WBC 22,000 3 10E1 9/L). Plerixafor (Revixil Gador Laboratories), 240 mg/kg, was given subcutaneously 11 h before beginning the apheresis. The blood CD34-positive cell concentration increased to 25/ml. We collected 2.41 3 10E1 6 CD34-positive cells/kg on a Spectra Optia (TerumoBCT, Lakewood, CO) processing a blood volume of 22.1 L (198 ml/kg) in one apheresis. The collected cells were frozen and a sample tested for PML/RARa transcripts by nested PCR. No transcripts were detected. Pretransplant conditioning was with intravenous busulfan 3.2 mg/kg/d and fludarabine 40 mg/ mE1 2/d on days 26 to 23 followed by the infusion of the defrosted blood cells. G-CSF, 10 mg/kg/d, was given day 15 until granulocytes were >500 3 10E1 3/L for 2 consecutive days. Granulocytes and platelets recovered on days 116 and 122 and she continues in hematological, cytogenetic and molecular remission 1 year later. Plerixafor facilitates collection of blood cells in patients with plasma cell myeloma and lymphoma who are poor mobilizers. Risk factors for poor mobilization include age 60 years, extensive prior chemotherapy, low platelets, and prior use of alkylating drugs and radiotherapy. As discussed, plerixafor is rarelyused to mobilize blood cells in patients with leukemia because of concern of also mobilizing leukemia cells with resultant contamination of the autograft. Our data and others suggest plerixafor can mobilize blood cells in a patient with APL in 2nd remission without contaminating the graft with leukemia cells. A similar approach is reported in Ph1-positive lymphoblastic leukemia (ALL).

Allogeneic hematopoietic stem cell transplantation in adults with myelodysplastic syndrome: Experience of the Argentinean Group of Bone Marrow Transplantation (GATMO)

Introduction: Allogeneic hematopoietic stem cell transplantation (AHSCT) is a curative approach for patients with myelodysplastic syndrome (MDS). Methods: In this multicenter retrospective study, we analyzed the outcome of adult patients with MDS who underwent AHSCT in Argentina and evaluated the prognostic factors associated with progression-free survival (PFS), overall survival (OS), cumulative incidence (CI) of relapse, and non-relapse mortality (NRM). Results: We analyzed data from 87 adults (median age: 43 years, range 18–66) who underwent SCT after myeloablative (n = 60) or non-myeloablative conditioning (n = 27), and from related (n = 62) or unrelated (n = 25) donors. For all patients, unadjusted 4-year PFS and OS were 37% and 38%, respectively; no significant differences were found between recipients of related or unrelated donors. One-year CI of relapse and NRM were 21% and 20%, respectively. In the multivariate analysis, intermediate disease risk index (DRI) and acute graft versus host disease AGVHD of all grades (I–IV) were independent variables associated with better PFS and lower relapse CI; only intermediate DRI was associated with better OS. Conclusions: AHSCT is a feasible procedure in Argentina, with more than 30% of the patients achieving long-term survival. Recipients with unrelated donors had at least similar outcome than those with related donors. DRI may be useful to identify patients at higher risk of relapse after transplantation.