Significant differences in access to tests and treatments for multiple myeloma between public and private systems in Latin America. Results of a Latin American survey. GELAMM (Grupo de Estudio Latino Americano de Mieloma Múltiple).

The incidence of multiple myeloma (MM) has increased in the last 20 years, particularly in middle and low-middle income countries. Access to diagnostic and prognostic tests and the availability of effective care is highly variable globally. Latin America represents 10% of the world population, distributed in countries of varied size, population, and socio-economic development. In the last decade, great improvements have been made in the diagnosis and treatment of MM. Applying these advances in real life is a challenge in our region. Local data regarding MM standards of care and outcomes are limited. A survey was carried out among hematologists from 15 Latin American countries to describe access to MM diagnostic and prognostic tests and the availability of effective care options. This study provides real-world data for MM in our region, highlighting striking differences between public and private access to essential analyses and therapeutic options.

Self-reported changes in the expanded disability status scale score in patients with multiple sclerosis after autologous stem cell transplants: real-world data from a single center.

In order to reset the immune system to baseline function, autologous hematopoietic stem cell transplantation (HSCT) has been performed in patients with multiple sclerosis (MS). After June 2015, 617 new consecutive patients with MS were autografted in our center with non-frozen peripheral blood stem cells. The autografts were performed on an out-patient basis, after conditioning with cyclophosphamide and rituximab. The aim of the study was the assessment of both safety and efficacy of the method. The study's primary co-end-points were recovery of granulocyte and platelet counts and transplant-related mortality. Secondary end-points were overall survival and clinical response (improvement or stabilization of the self-reported expanded disability status scale score). The protocol was registered in ClinicalTrials.gov identifier NCT02674217.0. We included 401 females and 216 males, with a median age of 46 years. A total of 259 patients had relapsing-remitting MS (RRMS), 228 had secondary progressive (SPMS) and 130 had primary progressive (PPMS) multiple sclerosis. All procedures were initially performed on an out-patient basis and only 32 individuals (5%) required hospitalization. One to three aphereses (median 1) were required to harvest at least 1 × 106 /kg viable CD34+ cells. The total number of viable CD34+ infused cells ranged between 1 and 37·83 × 106 /kg (median 5·68). Patients recovered more than 0·5 × 109 /l absolute granulocytes by day 8 (median, range = 2-14), and platelet values were above 20 × 109 /l by day 4 (median, range = 0-11). Eleven individuals required red blood cells and six needed platelet transfusions. To date, there have been no deaths attributable to the transplant, yielding a 30-month overall survival of 100%. Patients have been followed for 3-42 months (median = 12). The overall response rate (decrease or stabilization of the self-reported EDSS score) at 12 months was 78% for all patients (83% in RRMS, 78% in PPMS and 73% in SPMS), while the disability progression-free survival was 82% for all patients (86% in RRMS, 78·5% in SPMS and 78% in SPMS). Changes in the self-reported EDSS score in parallel with neurological improvement were observed in people with all types of MS after HSCT, employing the 'Mexican method'.

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.

The Latin American experience of allografting patients with severe aplastic anaemia: real-world data on the impact of stem cell source and ATG administration in HLA-identical sibling transplants.

We studied 298 patients with severe aplastic anaemia (SAA) allografted in four Latin American countries. The source of cells was bone marrow (BM) in 94 patients and PBSCs in 204 patients. Engraftment failed in 8.1% of recipients with no difference between BM and PBSCs (P=0.08). Incidence of acute GvHD (aGvHD) for BM and PBSCs was 30% vs 32% (P=0.18), and for grades III-IV was 2.6% vs 11.6% (P=0.01). Chronic GvHD (cGvHD) between BM and PBSCs was 37% vs 59% (P=0.002) and extensive 5% vs 23.6% (P=0.01). OS was 74% vs 76% for BM vs PBSCs (P=0.95). Event-free survival was superior in patients conditioned with anti-thymocyte globulin (ATG)-based regimens compared with other regimens (79% vs 61%, P=0.001) as excessive secondary graft failure was seen with other regimens (10% vs 26%, P=0.005) respectively. In multivariate analysis, aGvHD II-IV (hazard ratio (HR) 2.50, confidence interval (CI) 1.1-5.6, P=0.02) and aGvHD III-IV (HR 8.3 CI 3.4-20.2, P<0.001) proved to be independent negative predictors of survival. In conclusion, BM as a source of cells and ATG-based regimens should be standard because of higher GvHD incidence with PBSCs, although the latter combining with ATG in the conditioning regimen could be an option in selected high-risk patients.

A simplified method for stem cell autografting in multiple myeloma: a single institution experience.

In a 14-year period in a single institution 31 autografts were performed in 26 patients with multiple myeloma (MM), using a simplified and affordable autografting procedure: conducting the grafts on an outpatient basis and avoiding stem cell freezing. Autografts were started on an outpatient basis in all instances, but four patients were admitted to the hospital. Median time to achieve more than 0.5 x 10(9)/l granulocytes was 27 days, whereas median time to recover above 20 x 10(9)/l plts was 37 days. CR was achieved in 19 cases and a very good partial response in 6 cases. The 100-day mortality was 9.6%. The overall median post-transplant survival has not been reached, being above 76 months, whereas the 76-month survival is 80%. The median cost of each procedure was US$ 15 000. Survival results were substantially better than those of historical control in a group of patients treated in the same institution with melphalan/prednisone. It is concluded that high-dose therapy rescued with a simplified autologous stem cell graft is a valid, useful and affordable therapeutic option for patients with MM, even with economical restraints.

Therapeutic choices in patients with Ph-positive CML living in Mexico in the tyrosine kinase inhibitor era: SCT or TKIs?

A total of 72 patients with Ph-positive CML in first chronic phase were followed during a 6-year period in two different institutions in México. Among them, 22 were given a reduced-intensity allogeneic SCT, whereas 50 were given a tyrosine kinase inhibitor (TKI), mainly imatinib mesylate. The 6-year overall survival (OS) after the therapeutic intervention for patients allografted or given a TKI was 77 and 84%, respectively (P, NS); the median OS for both groups has not been reached, being above 90 and 71 months, respectively (P, NS). The freedom from progression to blast or accelerated phases was also similar for both groups, as well as the overall OS after diagnosis. Most patients allografted (91%) chose this treatment because they were unable to afford continuing treatment with the TKI, whereas most treated with the TKI (84%) were given the treatment without charge, through institutions able to pay for their treatment. The median cost of each nonmyeloablative allograft was US$18,000, an amount that is enough to cover 180 days of treatment with imatinib (400 mg per day) in México. Cost considerations favor allogeneic SCT as a 'once only' procedure whereas lifelong treatment with an expensive drug represents an excessive burden on resources.

Non-myeloablative stem cell transplantation in patients with relapsed acute lymphoblastic leukemia: results of a multicenter study.

Using non-myeloablative conditioning, allogeneic hematopoietic stem cell transplantation (HSCT) was conducted in 43 ALL patients in a CR2. The median age of the patients was 19 years. Patients received oral busulfan 4 mg/kg/day for 2 days; i.v. cyclophosphamide 350 mg/m(2)/day for 3 days; and i.v. fludarabine 30 mg/m(2)/day for 3 days. Oral cyclosporin A 4 mg/kg was started and methotrexate 5 mg/m(2) was delivered on days 1, 3, 5 and 11. The median CD34+ cell dose received was 5.0 x 10(6)/kg. The medium time to achieve a granulocyte count above 0.5 x 10(9)/l was 14 days. Thirteen patients were alive 30-1050 days after the HSCT. The 3-year overall survival rate was 30%. Ten patients (23%) developed acute GVHD, whereas eight patients (18.6%) developed chronic GVHD. Thirty patients died between days 47 and 1050 after the HSCT, most of them (70%) because of an ALL relapse. One hundred-day mortality was 15%, whereas transplant-related mortality was 21%. These results are inferior to those obtained using the same allografting method in other leukemias, probably as a consequence of poor susceptibility to the graft-versus-leukemia effect of the ALL cells beyond first remission as compared with other hematological malignancies.

Non-myeloablative hematopoietic stem cell transplantation is of limited value in advanced or refractory acute myeloblastic leukemia. The Mexican experience.

Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective strategy for preventing relapse of acute myelogenous leukemia (AML). We analyzed the outcome of 31 primary AML patients who received a reduced-intensity conditioning regimen for allogeneic HSCT in first or second remission. Thirty-one AML patients, 20 in first complete remission (FCR), 8 in second complete remission (SCR) and 3 in a partial remission (SPR) were included. All received busulfan 4 mg/kg/d/2 days, fludarabine 30 mg/m(2)/d/3 days and cyclophosphamide 350 mg/m(2)/d/3 days as conditioning regimen. The median number of CD34+ cells infused was 5.6 x 10(6)/kg and 5.2 x 10(6) in FCR and SCR group, respectively. All patients received cyclosporine-A (CsA) and methotrexate as graft vs. host disease (GvHD) prophylaxis. All patients showed myeloid engraftment (neutrophils >0.5 x 10(9)/l) after a median of 13 days in FCR group and 15 days in SCR group. Platelet recovery >20 x 10(9)/l was achieved after a median of 13 days in both groups. Relapse for 20 patients in FCR was 35% compared to 91% for 11 in SCR/SPR (p < 0.05). Conclusions. Reduced-intensity conditioning followed by allogeneic HSCT can induce stable remission in primary AML patients transplanted in FCR. A high relapse rate was documented in patients with refractory or relapsed AML.

Outpatient allografting using non-myeloablative conditioning: the Mexican experience.

A group of 132 patients with both malignant and nonmalignant conditions was allografted using the 'Mexican' method of non-ablative conditioning. The conditioning was delivered on an outpatient basis and the procedure was planned to be conducted on outpatients in all cases. While 103 patients (78%) were able to complete the procedure totally as outpatients, 29 (22%) were hospitalized because of fever, mucositis or acute graft-versus-host disease. In a multivariate analysis, although differences were not statistically significant, it was found that the patients who were allografted as outpatients had higher levels of hemoglobin (12 versus 11.8 g/dl), higher platelet counts (248 versus 191 x 10(9)/l), lower white blood cell counts (11.7 versus 12.4 x 10(9)/l), higher Karnofsky scale scores (100 versus 90%) and lower creatinine levels (0.9 versus 0.93 mg/dl). A total of 86% of the patients with normal values for these variables could be allografted as outpatients, whereas only 67% of those with abnormal values completed the entire procedure as outpatients. It is concluded that allografting can be accomplished totally on an outpatient basis using the 'Mexican' reduced intensity-conditioning regimen.

Autologous peripheral blood stem cell transplantation in multiple myeloma using oral versus I.V. melphalan.

Autologous peripheral blood stem cell transplantation is the therapy of choice for the treatment of multiple myeloma (MM) patients younger than 70 years old. Between August 1993 and November 2004, 54 patients with MM were autografted after conditioning with high-dose oral melphalan 140 mg/m(2) in combination with etoposide and carmustine (28 patients) or with high-dose melphalan 200 mg/m(2) I.V. (26 patients). The oral and IV melphalan groups were comparable. There were no significant differences in disease-free survival (DFS) and overall survival (OS) between the groups; however, in patients transplanted in remission, OS and DFS were better in the I.V. melphalan group. Four good-prognostic factors were identified: interval between diagnosis and transplant <18 months, number of prior chemotherapy lines < or =2, remission status (complete or partial), and the use of I.V. melphalan. In conclusion, I.V. melphalan is the therapy of choice for conditioning patients with MM who are in remission.

The early referral for reduced-intensity stem cell transplantation in patients with Ph1 (+) chronic myelogenous leukemia in chronic phase in the imatinib era: results of the Latin American Cooperative Oncohematology Group (LACOHG) prospective, multicenter study.

Using a reduced-intensity stem cell transplantation (RIST) schedule, 24 patients with Philadelphia (Ph1) (+) chronic myelogenous leukemia (CML) in first chronic phase (CP) were prospectively allografted in four Latin American countries: México, Brazil, Colombia and Venezuela, using HLA-identical siblings as donors. The median age of the patients was 41 years (range 10-71 years); there were eight females. Patients received a median of 4.4 x 10(6)/kg CD34 cells. The median time to achieve above 0.5 x 10(9)/l granulocytes was 12 days, range 0-41 days, and the median time to achieve above 20 x 10(9)/l platelets was also 12 days, range 0-45 days. In all, 22 patients are alive 81-830 (median 497) days after RIST. The 830-day probability of survival is 92%, and the median survival has not been reached, being beyond 830 days. A total of 11 patients (46%) developed acute graft-versus-host disease (GVHD), and seven of 23 (30%) developed chronic GVHD. Two patients died 43 and 210 days after RIST, one as a result of sepsis and the other of chronic GVHD. The 100-day mortality was 4.4%, and transplant-related mortality was 8%. RIST for patients with CML in CP appears to be an adequate therapeutic option.

Bloodless (transfusion-free) hematopoietic stem cell transplants: the Mexican experience.

We have analyzed the transfusion requirements of a group of 132 peripheral blood stem cell transplants from a single institution (73 allografts and 59 autografts) over a 10-year period. The allografts were conducted using the 'Mexican' nonmyeloablative conditioning regimen, while the autografts were given single-day high-dose melphalan. For the allografts, the median number of transfused packed red blood (PRBC) cell units was 1 (range 0-22), while the median number of platelet transfusion (PLT) sessions was 1 (range 0-9); 45% of allografted individuals did not require PRBC transfusions and 35% did not require PLT. For autografts, the median number of PRBC units was 2 (range 0-21), while the median number of PLT was 2 (range 0-21); 33% of autografted individuals did not require PRBC and 25% did not require PLT. We conclude that, by using certain preparative regimens, both allo and auto hematopoietic stem cell grafts can be conducted without the transfusion of blood products.

Significance of one human leukocyte antigen mismatch on outcome of nonmyeloablative allogeneic stem cell transplantation from related donors using the Mexican schedule.

Using the Mexican approach to conduct nonablative stem cell transplantation (NST), we have prospectively performed 58 allografts in individuals with various malignant and nonmalignant hematological diseases using sibling donors, either HLA identical (6/6) or compatible, with one mismatch (5/6). When comparing allografts obtained from HLA identical (n=40) or compatible (n=18) siblings, respectively, the overall median survival was found to be 33 vs 8 months (P<0.01), the 52-month survival was 47 vs 38% (P>0.2), the prevalence of acute graft-versus-host disease (GVHD) 57 vs 38%, that of chronic GVHD 25 vs 11% and the relapse rate 45 vs 55%. The two patients who failed to engraft were both 5/6 matches. Probably stemming from the low number of patients, and despite a trend toward worse results in patients allografted from HLA compatible (5/6) siblings, most differences in outcome were not significant. It seems that NST can be offered to individuals with either an HLA identical or a compatible sibling donor.

Role of bone marrow examination in staging Hodgkin's disease: experience in México.

We assessed the value of bone marrow biopsy prospectively in a group of 91 individuals with Hodgkin's disease. The median age of our population was 29 years (range 4-87 years); 59 were males. Most patients (45%) had nodular sclerosing disease and most patients (44%) were in pathological stage II at diagnosis. The bone marrow biopsy showed infiltration by Hodgkin's disease in only three individuals (3.3%); two of these patients displayed constitutional symptoms and had been assigned to stage III before the biopsy. In one case, bone marrow biopsy was the diagnostic procedure, which was performed as part of the investigation of fever of unknown origin. Follow-up periods ranged between 1 and 117 months (median 16 months). All patients achieved complete remission, seven patients relapsed and four were given autologous stem cell transplants. The median survival of the whole group was 117 months, while the 3500-day survival was 76%. As bone marrow biopsy was the diagnostic procedure in one case, bone marrow biopsy was a useful staging procedure in only 2.2% of patients (two out of 90 patients). We suggest that bone marrow biopsy should be only be performed as a staging procedure in a selected subset of patients with Hodgkin's disease (clinical stage III, B symptoms, etc.).

Features of the engraftment of allogeneic hematopoietic stem cells using reduced-intensity conditioning regimens.

The features of the engraftment in 26 patients allografted using reduced-intensity conditioning regimen (8 with chronic myelogenous leukemia, 6 with acute myelogenous leukemia, 9 with acute lymphoblastic leukemia, 1 with hybrid acute leukemia, 1 with myelodysplasia and 1 with thalassemia major) were analyzed. Patients received a median of 10 x 10(8)/Kg mononuclear cells (range 1.6 to 22.9), and a median of 4.2 x 10(6)/Kg CD34 cells (range 0.3 to 14). There was a linear correlation between the number of infused mononuclear cells (MNC) and that of CD34 cells (r = 0.78, p = 0.002). Three patients (11%) failed to engraft; in those who engrafted, the median time to achieve > 500 granulocytes was 11 days (range 10 to 22), and the median time to achieve > 10,000 platelets was 12 days (range 10 to 41). The three patients who failed to engraft received less than 5 x 10(8)/Kg MNC (1.6, 4.6 and 4.9) and less than 0.5 x 10(6)/Kg CD34; however, five of eight patients who received less than 5 x 10(8)/Kg MNC still engrafted successfully. On the other hand, all the patients who received less than 0.5 x 10(6)/Kg CD34 cells failed to engraft. Within the group of patients who engrafted, it was found that those who received more than 7 x 10(6)/Kg CD34+ cells tended to earlier recover > 20 x 10(9)/L platelets (p = 0.02), and > 0.5 x 10(9)/L neutrophils (p = 0.06) before day 15, than those who received less than 7 x 10(6)/Kg CD34+ cells. No such association could be established between the number of MNC and the time for recovery. In these patients allografted using reduced-intensity conditioning regimens, the target doses of hematopoietic cell used were similar to those described for conventional allografts: The number of CD34 infused cells was significantly related to the possibility of failure to engraft and to the recovery rate of the hemopoiesis.

Molecular monitoring of the treatment of patients with BCR/ABL (+) chronic myelogenous leukemia.

BACKGROUND: The molecular follow-up of patients with chronic myelogenous leukemia (CML) has been described as useful in other countries, but there are not data reported in Mexico. METHODS: All patients studied at Laboratories Clínicos de Puebla/Centro de Hematología y Medicina Interna de Puebla in which the BCR-ABL hybrid gene was identified by means of polymerase chain reaction were analyzed. In 22 individuals the molecular marker of the disease was studied at diagnosis and in different instances afterwards; these patients were treated with chemotherapy, interferon, autologous or allogeneic bone marrow transplantation. RESULTS: Only the six patients that were allografted from HLA-identical siblings cleared the molecular marker of the disease; the rest of them did not achieve molecular remissions. The median survival (SV) of the whole group has not been reached, whereas the 53-month SV is 68%. One of the allografted patients died as a result of complications of graft versus-host disease. CONCLUSIONS: We have found useful the molecular monitoring of the treatment of patients with CML. Using this approach, we found that molecular remissions can be accomplished only with allografting; however, other therapeutic approaches may also result in long-lasting hematologic remissions.

Heterozygous beta-thalassemia: not infrequent in Mexico.

BACKGROUND: The prevalence of beta-thalassemia in Mexico is not known in detail. METHODS: Data of studies investigating abnormal hemoglobins between September 1987 and November 2000 were analyzed; in addition, data of red-blood-cell indices and clinical features were analyzed in patients identified as carriers of beta-thalassemia. RESULTS: In 1,639 prospective studies looking for abnormal hemoglobins, 429 disclosed some abnormality; of these, 319 cases displayed abnormally high levels of hemoglobin A2, thus consistent with the diagnosis of beta-thalassemia. This hemoglobin abnormality represented 74.2% of all abnormalities, both quantitative and qualitative, of the molecule of hemoglobin. There were 317 heterozygotes and only two homozygotes. We have previously shown that the most frequent cause of anemia as the iatrotropic condition in Mexican mestizos is iron deficiency. We found that iron deficiency is 11.5 times more frequent than beta-thalassemia and that the latter is 1.3 times more frequent than macrocytic/megaloblastic anemia. CONCLUSIONS: beta-thalassemia should not be considered as infrequent in Mexico, and individuals with red blood cell microcytosis and/or hypochromia with or without anemia should be screened for thalassemia.