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Autologous and allogeneic stem cell transplant in Jehovah’s Witnesses: a single-center experience on 22 patients

In an ongoing phase II study we are evaluating the role of alpha-2b recombinant interferon in Hodgkin's disease; the study design includes patients with high-risk parameters who are treated by combination chemotherapy MOPP, ABVD, MOPP + ABVD or equivalent combinations. At the end of the therapeutic program which could include also radiotherapy, patients will be randomly assigned to receive alpha-2b interferon at 3 MU/day over 3 months and then 3 MU/three times/week over 9 months or no further treatment. Up to September 1989, 107 patients were randomized; evaluable patients with a minimum follow-up of 3 months are 95, 56 in the arm of interferon and 39 in the arm of no further treatment. The results are preliminary and differences could not be disclosed between the two arms concerning either the relapse rate or the incidence of infections. Tolerance and toxicity due to alpha-2b interferon in patients with Hodgkin's disease could be defined as acceptably good considering that mild and reversible hematological toxicity was experienced in 12 (21%) patients; objective clinical toxicity was recorded in 4 (7%) patients although 7 (12%) patients refused to continue the treatment. Definite conclusions will be drawn when 100 patients per arm become evaluable.

Hematological malignancies in Jehovah's Witnesses are often difficult to cure since these patients deny transfusions. By a retrospective analysis, we report the possibility of treating some tumors, mostly hematological, with either autologous or allogeneic bone marrow transplantation (BMT) without blood support. Eight patients were evaluated, including lymphoma (two patients), acute lymphoblastic (one patient) and myeloblastic (one patient) leukemia, chronic lymphocytic leukemia (one patient), refractory anemia with blasts in transformation (one patient), chronic myeloid leukemia (one patient) and metastatic breast cancer (one patient). All patients experienced a severe cytopenia with no major side effects or life-threatening complications. We had four deaths: three from relapse and progression of the disease (at 5, 8 and 15 months after the stem cell infusion), and one from acute intestinal GVHD (at 2 months after the stem cell infusion). Four patients are in complete clinical remission (at 8, 10, 16 and 26 months after the stem cell infusion), and this was related to the disease outcome. We conclude that autologous and allogeneic BMT are feasible without the support of transfusions. We believe that this should be performed as soon as possible in the course of the disease.

An interim report evaluating the feasibility of myeloablative therapy followed by peripheral blood stem cell (PBSC) autotransplant in patients aged >60 years is presented. In the last 2 years 19 patients >60 years old with several oncological conditions, mostly hematological, underwent PBSC autotransplant either as salvage therapy following relapse or resistance to conventional treatment, or as consolidating therapy as a part of a well defined protocol. There were 13 males and six females; the mean age was 66.9 years (range 61-76 years); nine patients had resistant or relapsed lymphoma, six myeloma, two acute leukemia, one Waldenstrom's disease and one lung cancer. Myeloablative schemes included BEAM exclusively for lymphomas, busulfan and melphalan (Bu-MPH) mainly for myeloma, busulfan and cyclophosphamide (Bu-CTX) for lymphomas and leukemia and VP-16 and CTX for lung cancer. Mobilization of CD34+ cells was achieved in all patients with the combination of high-dose CTX and G-CSF with collections between 2.83 to 19.04 x 10(6)/kg (mean 7.1). All patients engrafted with a median time for recovery of PMN (>0.5 x 10(3)/microl) of 10 days (range 8-12 days) and for PLT (>20 x 10(3)/microl) of 12 days (range 10-17 days). Major responses were obtained in 15 of 16 patients evaluable for response and eight patients entered CR; overall eight patients are in CR, five are alive with disease, five are dead from disease progression and one is dead because of congestive heart failure 7 months following PBSC autotransplant. No early deaths following the procedure occurred; major side-effects were grade I-II mucositis (58%), fever with documented sepsis (10%), pneumonia (5%), cardiac, renal and liver toxicity (5%). Cardiac function was evaluated before and after myeloablative therapy by VEF in all patients; no significant modifications were necessary. In conclusion, our experience demonstrates that myeloablative therapies in older selected patients can be feasible; the feasibility of introducing PBSC autotransplantation following myeloablative therapy as a front-line treatment in patients aged >60 years, needs accurate guide lines for selection of appropriate patients.

In May 1989, a 43-year-old woman with chronic myelocytic leukemia diagnosed in 1988 underwent a syngeneic bone marrow transplant (BMT), conditioned with cyclophosphamide-TBI while in chronic phase. Three years later, because of both cytogenetic and hematological relapse, she was treated with interferon-alpha (IFN-alpha) and hydroxyurea (HU) for 3 years. In 1994 while still in chronic phase, she was conditioned with busulfan-cyclophosphamide (BU-CY) and underwent a second syngeneic BMT. In 1996, following a further cytogenetic and hematological relapse, she was again placed on IFN-alpha and HU therapy for 13 months, when she was referred to our hospital in accelerated phase. In October 1997 following thiotepa, CY and anti-thymocyte globulin conditioning, she underwent an allogeneic BMT from her 1-Ag mismatched brother. She became Ph1 negative with full chimerism and normal hematological parameters; acute graft-versus-host disease (GVHD) grade 3 of the skin and chronic GVHD of the liver occurred. At 11 months follow-up she is in good clinical condition and with a Karnofsky score of 90%. The role of a graft-versus-leukemia (GVL) effect in securing and maintaining the complete remission is discussed.

Analysis of costs of high technological procedures such as peripheral blood stem cell (PBSC) autotransplantation in lymphomas are generally finalized at disclosing whether the improvement of survival in a subset of patients is cost effective and whether the cost of the procedure could be reduced. With the aim of revealing a possibility of reducing costs with respect to conditions of safety, we present our experience with PBSC autotransplantation in a particularly poor prognosis subset of patients with lymphoma.The expenses are analyzed for groups of cost and main resources necessary at unitary cost are considered separately. Groups of cost include various phases of the PBSC autotransplantation such as preparative procedures, execution of myeloablative therapy, reinfusion of CD34 cells, supportive therapy after reinfusion until discharge of the patient, general support for the management of patient. All costs are calculated according to 1997 prices and salaries and reported in dollars. The analysis was conducted on 21 patients with lymphoma resistant to other therapies treated by myeloablative therapy and PBSC autotransplantation in an hematologic unit in an open ward; the assistance was provided by staff not exclusively dedicated to bone marrow transplant procedures, with some help from a family member.The PBSC procedure, including all phases, costs from $17,761.9 to $18,259.9 depending on the type of myeloablative therapy employed; the mean cost was $18,092.6. The preparative phase with mobilization of CD34 cells, cryopreservation and reinfusion costed $3,538.7 (19.6% of the total cost); a major cost of this phase was cryopreservation and CD34 manipulation ($857.1). The second phase with myeloablative therapy and reinfusion of CD34 cells had a mean cost of $2,785.9 (15.4% of the total cost); a major cost of this phase was the hospitalization ($1,119.8). The third phase of patient's support after treatment had a total cost of $7,649 (42.3% of the cost of the total procedure) with the major cost being due to hospitalization ($2,571) calculated on a mean of 15 days after the reinfusion of CD-34. The last group of costs, including management support, accounted for $4,119 (22.7%) with a major cost being amortization of the structure ($1,600). The general cost for nurse's assistance to the patient was $1,355.1 (7.5%).A procedure of PBSC autotransplantation in resistant lymphoma is affordable without the strict precautions generally given in intensive care units. This provides a substantial reduction of expenses because of the low number of specifically trained staff members and the generally low cost of the necessary supplies. Before, however, proposing PBSC autotransplantation in most patients with resistant lymphoma, an evaluation of whether costs could be further reduced and whether the procedure has a cost benefit impact is needed.

Deferiprone (L1) is a largely studied oral chelator in clinical setting, however, no definite conclusions concerning efficacy and toxicity still could be drawn. In an ongoing prospective trial with L1, we evaluated the efficacy and tolerance-toxicity in patients with thalassemia major previously treated by desferrioxamine (DFO); the specific aim of the study is to demonstrate that L1 could be an alternative to DFO in some patients with an acceptable toxicity.Sixty-nine patients over 13 years of age with poor compliance to DFO were considered for the study. The design included a liver biopsy before starting L1 in all patients in order to define liver siderosis either by histologic grading or by hepatic iron concentration (HIC); only patients with a minimum HIC of 4 mg/g dry weight entered the study. A repetition of the liver biopsy after one year of L1 was planned; further evaluations included serum ferritin, plasma iron, transferrin TIBC and iron urine excretion. L1 was given at 70 mg/kg/day in three divided doses. Toxicity was monitored either clinically or by controlling liver, kidney and marrow function by specific tests. Concerning clinical characteristics 52 patients showed hypogonadism (78%), 39 growth retardation (58%), 6 diabetes (9%), 4 cardiomyopathy (6%), 9 hypothyroidism (12%); 45 patients had chronic liver damage (65%).We focus this report on data collected in a group of 29 patients with a minimum follow-up of one year (14-33 months). The mean ferritin value was 3748 ng/mL (range: 200-10,000) and 2550 ng/mL (range: 80-14,500), before and while on L1 therapy, respectively (p = 0.001); the mean sideruria changed from 17.25 mg/dL (range: 5.4-50) to 20.98 mg/dL (range: 10-40), on DFO and L1, respectively (p = 0.078); the ratio between plasma iron (sideremia) and transferrin TIBC changed from 0.96 with DFO to 0.86 with L1 (0.014). A correlation with grade of liver siderosis and serum ferritin (p = 0.069) and iron urine excretion (p = 0.008) was recorded. The judgement of efficacy showed that L1 was effective (EF) in 9 patients, no assessable (UN) in 11 patients, not effective (NE) in 2 patients and with no advantages with respect to DFO in 7 patients. Liver biopsy was repeated in 20 patients showing a reduction of grade of liver siderosis and iron content in 7 patients. Clinical toxic effects of L1 were gastric intolerance (one patient), joint pain (three patients) and mild and temporary neutropenia (one patient).This preliminary experience shows that L1 is effective in several patients with thalassemia with poor compliance to DFO and to improve iron burden and iron excretion with generally minor side effects. L1 could be an alternative to DFO in some patients, however the recognition of neutropenia warrants a careful evaluation of patients and efforts finalized to early recognition of those to be addressed with this new and still experimental therapy.

Iron overload in patients with thalassemia is a common feature which requires continuous chelation therapy and monitoring. Serum ferritin determination is widely accepted as a simple method for following iron load in patients with primary hemochromatosis; however, several reports on thalassemic patients emphasize that ferritinemia is not accurate and that other methods such as direct measurement of iron in the liver (HIC) and magnetic resonance imaging (MRI) are more precise.In order to contribute to the general understanding of iron load in thalassemia we used liver MRI to study 33 thalassemic patients, most of whom were also evaluated for iron content by liver biopsy. The data were then compared with serum ferritin levels.Ferritin levels ranged between 276 and 8031 ng/mL, and liver iron content ranged from 1.6 to 31.0 mg/g dry weight; grade III or IV liver siderosis was recorded in 23/33 patients, just as 23/33 patients were found to have severe or very severe siderosis at MRI. Significant correlations with ferritin levels were recorded between grade IV and grades III, II and I (p0.01, p = 0.02, and p = 0.03, respectively). Ferritinemia also showed significant linearity with liver iron content (r = 0.603, p = 0.001). No significant differences of levels were recorded, however, between patients found to have severe and those with mild iron load at MRI (p = 0.073).Our study shows that serum ferritin levels exhibit a tendency to be significantly correlated with the true status of hemochromatosis in thalassemic patients; however, the discrepancies recorded in several patients and the scarce or total lack of correlation with MRI suggest exploring other approaches to this problem in order to make proper decisions about therapy.