P. Di Bartolomeo

Second allogeneic bone marrow transplantation in acute leukemia : a multicenter study from the Gruppo Italiano Trapianto Di Midollo Osseo (GITMO)

Thirty-eight second allogeneic bone marrow transplants (BMT) for acute leukemia relapsed after first BMT were performed in 13 Italian centers between 1987 and 1994. Twenty-one patients had acute myelogenous leukemia (AML), 17 acute lymphoblastic leukemia (ALL); at second BMT 24 patients were in complete remission (CR) and 14 in relapse. The median time to relapse after first BMT was 10 months (range 1–70). Grade II or greater acute graft-versus-host disease (GVHD) after second transplant occurred in 34.2% of patients and a chronic GVHD in 31.5% of patients. Twenty-four patients died: seven from early transplant-related mortality (TRM), 13 from relapse and four from late toxicity. As of 31 July 1996, at a median follow-up of 47 months (range 22–85), there are 14 survivors. The three-year probability of TRM, relapse and event-free survival (EFS) is 28%, 40% and 42% respectively. In 20 of 27 evaluable patients, remission duration after second BMT was longer than after the first BMT. A diagnosis of AML was correlated with a better outcome. These data support the usefulness of second allograft in selected patients with AML relapsing after a first BMT.

Efficacy of caspofungin as secondary prophylaxis in patients undergoing allogeneic stem cell transplantation with prior pulmonary and/or systemic fungal infection

Transplanted patients with a history of invasive fungal infection (IFI) are at high risk of developing relapse and fatal complications. Eighteen patients affected by hematological malignancies and a previous IFI were submitted to allogeneic stem cell transplantation, using Caspofungin as a secondary prophylaxis. Patients had a probable or proven fungal infection and 16 had a pulmonary localization. No side effects were recorded during treatment with Caspofungin. Compared to pre-transplant evaluation, stability or improvement of the previous IFI was observed in 16 of the 18 patients at day 30, in 13 of the 15 evaluable patients at day 180 and in 11 of the 11 evaluable patients at day 360 post transplant. In particular, all the six patients with a proven fungal infection were alive, with a stable or improved IFI after 1 year from transplant. At a maximum follow-up of 31 months, eight patients died for disease progression or transplant-related complications, but only two had evidence of fungal progression. Secondary prophylaxis with Caspofungin may represent a suitable approach to limit IFI relapse or progression, allowing patients with hematological malignancies to adhere to the planned therapeutic program.

Impact of marrow unrelated donor search duration on outcome of children with acute lymphoblastic leukemia in second remission

Summary:We analyzed the outcome of 167 consecutive children with second CR acute lymphoblastic leukemia (ALL), for whom an unrelated donor (UD) search was activated between 1989 and 1998 at a median time of 2 months after relapse. A suitable donor was identified for 70 patients at 1 year and 6.5 months before and after 1995 from search activation, respectively; a further leukemia relapse occurred during the search in 94 children at a median of 4 months after search activation, 36 of whom underwent UD (14) or other types of transplant (22), beyond second CR, while 58 died of progressive disease. Of 73 patients not experiencing a second relapse, 64 underwent UD (46) or other types of transplant (18), while nine proceeded with chemotherapy, and only four of them survived. The 3-year disease-free survival (DFS) from second CR for the 167 patients is 15.1%, whereas 3-year DFS after transplant for the 60 UD and 40 alternative donor transplanted children is 31.6 and 25.4%, respectively. In conclusion, a further relapse is the main factor adversely affecting outcome of children with second CR ALL. Thus, for these patients, the search should be activated early after relapse and either a UD or an alternative transplant should be performed as early as possible.

Fotemustine plus etoposide, cytarabine and melphalan (FEAM) as a new conditioning regimen for lymphoma patients undergoing auto-SCT: a multicenter feasibility study.

BEAM is a widely used conditioning regimen for relapsed/refractory lymphoma patients undergoing auto-SCT. We conducted a multicenter study with an alternative regimen (fotemustine plus etoposide, cytarabine and melphalan (FEAM)) in which BCNU was substituted by the chloroethylnitrosourea fotemustine (FTM). Eighty-four patients with relapsed/refractory Hodgkins (n=20) and non-Hodgkins lymphoma (n=64) were conditioned with a FEAM regimen (FTM 150 mg/m2 on days –7, –6, etoposide 200 mg/m2 and cytarabine 400 mg/m2 on days –5, –4, –3, –2 and melphalan 140 mg/m2 on day –1). Patients were evaluated for toxicity and engraftment parameters. Median times to neutrophil (>500 × 109/l) and plt (>20 000 × 109/l) engraftment were 11 and 13 days, respectively. Grade 3 mucositis occurred in 19 patients (23%), while G3 nausea/vomiting and G3 diarrhea were observed in 13 (15%) and 6 (7%) patients, respectively. No severe hepatic, renal or pulmonary toxicity was detected. Seven patients (7%) experienced G4 mucositis, while no other G4 toxicities or unexpected adverse events of any grade were recorded. Transplant-related mortality was 2.4%. We conclude that a FEAM regimen is feasible and safe. Although toxicity and engraftment times compared favorably with BEAM, longer follow-up is needed to evaluate fully its efficacy and long-term safety.

Retrospective survival analysis and cost-effectiveness evaluation of second allogeneic bone marrow transplantation in patients with acute leukemia

The therapeutic options for patients with acute leukemia who relapse after the initial transplant include second bone marrow transplantation (2BMT) and conventional chemotherapy (CC). In this work, we conducted an analysis of published survival data and we evaluated the cost-effectiveness of 2BMT in comparison with CC. We retrieved survival information on 167 patients treated with 2BMT and 299 patients treated with CC. Survival figures were derived from individual patient data and were compared between 2BMT and CC. The mean lifetime survival (MLS) was estimated for each of the two patient cohorts using standard techniques of survival-curve extrapolation. The cost data of patients given 2BMT or CC were estimated from published data. Our analysis of individual survival data showed that 2BMT improved survival at levels of statistical significance (survival gain = 19.6 months per patient). Using an incremental cost of

Final height of thalassemic patients who underwent bone marrow transplantation during childhood.

90 000 per patient, the cost-effectiveness ratio of 2BMT in comparison with CC was calculated as

Haploidentical, G-CSF-primed, unmanipulated bone marrow transplantation for patients with high-risk hematological malignancies: an update

52 215 discounted dollars per discounted life year gained. Our results indicate that, in patients with acute leukemia who relapse after their first transplant, 2BMT significantly prolongs survival in comparison with CC and seems to have an acceptable cost-effectiveness profile.

Growth after recombinant human growth hormone (rhGH) treatment in transplanted thalassemic patients.

We evaluated the final height achieved by 47 patients who had bone marrow transplantation (BMT) for thalassemia major. Subjects were separated into two groups: patients who received BMT before 7 years of age and patients who received BMT after 7 years of age. Parental height and genetic target height (TH) were calculated. Our data indicated a strict correlation between age at time of transplant and final adult height. The patients whose age at transplant was <7 years had a less impaired growth rate than did patients who were >7 years. Moreover, greatest loss in height was observed in subjects who had higher serum levels of transaminase and ferritin and these biochemical parameters were strictly correlated to the final adult height. Mean final adult height, however, did not differ from the genetic target height in subjects who received BMT before 7 years of age and the final height SDS corrected for TH surpasses even the TH. In contrast, the subjects who received BMT after 7 years of age, failed to achieve their full genetic potential. In conclusion, short stature is present in a significant percentage of transplanted thalassemic children. The data in this study indicate a close effect of the age at time of transplant on subsequent growth rate, but the growth impairment in these subjects remain multifactorial. Bone Marrow Transplantation (2001) 28, 201–205.

Pregnancy outcome following hematopoietic cell transplantation for thalassemia major

Ninety-seven patients affected by high-risk hematological malignancies underwent G-CSF primed, unmanipulated bone marrow (BM) transplantation from a related, haploidentical donor. All patients were prepared with an identical conditioning regimen including Thiotepa, Busilvex, Fludarabine (TBF) and antithymocyte globulin given at myeloablative (MAC=68) or reduced (reduced intensity conditioning (RIC)=29) dose intensity and received the same GvHD prophylaxis consisting of the combination of methotrexate, cyclosporine, mycofenolate-mofetil and basiliximab. Patients were transplanted in 1st or 2nd CR (early phase: n=60) or in >2nd CR or active disease (advanced phase: n=37). With a median time of 21 days (range 12–38 days), the cumulative incidence (CI) of neutrophil engraftment was 94±3%. The 100-day CI of III–IV grade acute GvHD and the 2-year CI of extensive chronic GvHD were 9±3% and 12±4%, respectively. Overall, at a median follow-up of 2.2 years (range 0.3–5.6), 44 out of 97 (45%) patients are alive in CR. The 5-year probability of overall survival (OS) and disease-free survival (DFS) for patients in early and advanced phase was 53±7 vs 24±8% (P=0.006) and 48±7 vs 22±8% (P=0.01), respectively. By comparing MAC with RIC patient groups, the transplant-related mortality was equivalent (36±6 vs 28±9%) while the relapse risk was lower for the MAC patients (22±6 vs 45±11%), who showed higher OS (48±7 vs 29±10%) and DFS (43±7 vs 26±10%). However, all these differences did not reach a statistical significance. In multivariate analysis, diagnosis and recipient age were significant factors for OS and DFS. In conclusion, this analysis confirms, on a longer follow-up and higher number of patients, our previous encouraging results obtained by using MAC and RIC TBF regimen as conditioning for G-CSF primed, unmanipulated BM transplantation from related, haploidentical donor in patients with high-risk hematological malignancies, lacking an HLA-identical sibling or unrelated donor and in need to be urgently transplanted.

Secondary solid cancer following hematopoietic cell transplantation in patients with thalassemia major

The aim of this study was to evaluate the treatment effects with recombinant human growth hormone (rhGH) in a group of patients after bone marrow transplantation for thalassemia major. At the end of treatment we divided the subjects into two groups according to the outcome of the therapy: responder and non-responder. Responder group: after 24 months of rhGH administration, growth rate was still significantly higher in respect to start of treatment (P < 0.0001). plasma levels of igf-i rose significantly (P < 0.003). the serum levels of serum asparate aminotransferase (sgot) and alanine aminotransferase (sgpt) were higher compared to normal values but improved in non-responder patients. there was no difference in the mean concentration of these parameters before and after treatment (P = NS). Non-responder group: these patients had a worsening of the growth rate during rhGH administration. There was no increase of the IGF-I levels. Single values of transaminase and ferritin levels were higher than in responder patients before and after treatment. There was a significant correlation between IGF-I, SGOT, SGPT and ferritin in all patients before and after therapy. It appears from these data that rhGH administration is worth serious consideration in patients after BMT for thalassemia major presenting impaired growth hormone secretion. This treatment can offer good results only in cases where the normal hepatic synthesis of IGF-I is conserved and where liver damage has not reached irreversible conditions, as we have seen in the responder group.