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.
Jehovah's Witnesses deny transfusions of blood products as therapeutic option and, consequently, the management of diseases such as leukemia appears difficult and with reduced chances of cure. Frequently, physicians refuse to take care of these patients or they propose less aggressive therapies than expected in these diseases.1 However, there are several reports emphasizing that the cure of leukemia is possible, also without the support of transfusions,2,3,4 but single case reports are very anecdotal and there are no sequential studies reported. Although Jehovah's Witnesses deny blood transfusions, they often accept bone marrow or peripheral blood stem cell support. The first case was reported several years ago,5 then another case report in 20006 and we also presented a report on three cases7 successfully treated with myeloablative therapy with no need of blood transfusions in 2001. These experiences seem to demonstrate that Jehovah's Witnesses with hematological diseases or solid tumors may be eligible for high-dose therapy, including bone marrow transplantation (BMT). We present our experience on a group of Jehovah's Witnesses, most of them with hematological malignancies, who received, after a standard approach, high-dose therapy and BMT without blood transfusions.
Patients and methods
We considered eligible for this study eight Jehovah's Witnesses with hematological malignancies or other tumors who underwent an aggressive therapeutic approach, including high-dose therapy and BMT. They were between 13 and 59 years old (mean age 40); six patients were males and two were females (Table 1).
There were two non-Hodgkin's lymphomas (NHL) (Burkitt-like NHL and follicular lymphoma, patient 1 and patient 5 respectively), one acute lymphoblastic leukemia (ALL, patient 2), one acute myeloblastic leukemia (AML-M4, patient 3), one resistant progressive B cell chronic lymphocytic leukemia (CLL, patient 4), one chronic myeloid leukemia (CML, patient 6), one metastatic breast cancer (patient 7) and one refractory anemia with excess blasts in transformation (RAEB-T, patient 8).
Table 1 summarizes the therapy performed, as standard therapy, before the high-dose program and BMT. In brief, patients with AML and RAEB-T received FLAI therapy8 (fludarabine, aracytin and idarubicin) given over 5 days in the younger (patient 3), and over 4 days in the older one (patient 8). The Burkitt-like lymphoma was treated by the so-called Magrath scheme with intervals longer than expected during the four sequences of therapy9 (this scheme is typically used in children with NHL). The patient with follicular lymphoma had extensive marrow involvement and was treated by a sequential therapy including CHOP10 as debulking therapy, then high-dose aracytin (8 g/m2 over 2 days instead of 16 g/m2 over 4 days) plus rituximab as purging therapy and subsequent mobilization of peripheral blood stem cells. The patient with metastatic breast cancer, after a relapse following CMF,11 was treated by a combination of epirubicin and taxol. The patient with progressive CLL received CHOP, then fludarabine therapy. The ALL patient received induction and consolidation therapy, according to the GIMEMA-ALL93 protocol.12 Finally, the CML patient immediately started a conditioning regimen for BMT without previous therapy.
Conditioning regimens before BMT and supportive therapy
Written informed consent for being treated by high-dose therapy without blood and platelet support was received from all adult patients or parents of a child; a particular emphasis was given to the risks of therapy without blood transfusions because the risk of life-threatening bleeding would increase without them, especially when the platelets dropped below 104/μl.
The intensive therapeutic programs, both for autologous (ABMT) and allogeneic (BMT) transplants, depended on the type of disease. Myeloproliferative disorders received classical busulfan 16 mg/kg over 4 days plus cyclophosphamide 120 mg/kg over 2 days; lymphoma patients received the BEAM conditioning regimen,13 the ALL patient was conditioned by fractionated (12 fractions) TBI 12 Gy over 4 days plus cyclophosphamide at 120 mg/kg over 2 days; the breast cancer patient was conditioned by busulfan 12 mg/kg over 4 days plus melphalan 120 mg/m2; the CLL patient received as conditioning regimen only melphalan 120 mg/m2, because the number of peripheral CD34+ cells collected was only 1.7 × 106/kg. In summary, three patients underwent allogeneic BMT and five patients autologous BMT. Following the peripheral blood stem cell infusion, all ABMT patients received G-CSF 5 μg/kg/day subcutaneously and erythropoietin 10 000 IU/day i.v.; BMT patients (Nos. 2, 6, 8) received, as GvHD prophylaxis, Cy-A 1.5 mg/kg i.v. plus methotrexate 10 mg/m2 on days 1, 3 and 6 from the transplant, and then only 5 mg/kg Cy-A p.o. until discharge from the hospital; then they started G-CSF and erythropoietin at the same dose. Antiviral, antifungal and antibacterial prophylaxis consisted of acyclovir 15 mg/kg/day, low-dose amphotericin-B 20 mg/day and cyprofloxacin 1000 mg/day, respectively.
Transfusion of blood products
All patients denied the consent for transfusions of packed red cells and platelet units and they were never forced to accept them. However, one patient with ALL (No. 2), 13 years old, was given two apheretic units of platelets, when the count was below 5x103/μl, despite the absence of consent from his parent.
Patients undergoing autologous procedures received autologous peripheral blood CD34 positive cells as hematological rescue, while patients undergoing allogeneic BMT received marrow harvest from the related matched donor.
Monitoring of toxicity
In all patients, before the transplant and on hematological recovery, the cardiac function was closely monitored with echocardiography with ventricular ejection fraction (VEF) detection. The ECG and cardiac check were also performed when the hemoglobin (Hb) level went below 10 g/dl. In addition, the kidney and liver functions were monitored daily.
Evaluation of patients
All patients underwent a hematological evaluation before starting the conditioning regimen, immediately after the therapy by detecting the day of the lowest (nadir) WBC, platelet and Hb counts, and at the time of the recovery of blood parameters. Hematological recovery was defined as the increase of WBC up to 1.0 × 103/μl, platelets up to 20 × 103/μl, and reticulocytes up to 20 × 103/μl. Follow-up was performed depending on the type and course of the disease, and the status of each patient. Patients who underwent ABMT had a monthly evaluation during the first 6 months, then every 2 months; instead BMT patients were checked weekly over the first 3 months, then monthly. Restaging of disease was performed by bone marrow histology, cytogenetic and flow cytometric immunophenotyping for the detection of minimal residual disease; presence of masses was investigated by CAT or, alternatively, by ultrasonography. Complete remission (CR) was defined as the disappearance of clinical signs and the lack of evidence of disease. The Burkitt-like lymphoma, follicular lymphoma and AML patients were in CR before transplantation; the other five patients were not in remission. The patient with RAEB-T had 20% of blasts in the marrow, the patient with CML was transplanted before any therapy, the patient with breast cancer had pleural and lung involvement, the CLL patient was in progression and the patient with ALL had 3% of bone marrow blasts.
Tables 2 and 3 summarize the results. Table 2 shows hematological data before the conditioning regimen, the day of nadir during cytopenia and blood parameters at hematological recovery. Before transplantation, the Hb level was normal only in the CLL patient (no. 4), whereas all other patients had variable degrees of anemia ranging from 8.8 (no. 5) to 12.3 g/dl (no. 6), depending on previous therapies or on the type of disease; patient no. 5 also had heterozygous β-thalassemia. The WBC count was normal in three patients (nos. 1, 2 and 7: Burkitt-like lymphoma, ALL and breast cancer, respectively); it was mildly reduced but with a normal differential count in two patients (no. 3 and 5: AML and follicular lymphoma); the WBC result was abnormal on differential counts in three patients (nos. 4, 6 and 8 with CLL, CML and RAEB-T, respectively). The platelet count was normal in five patients (nos. 2–6), mildly increased in one patient (no. 7, breast cancer) and mildly reduced in two patients (nos. 1 and 8: lymphoma and RAEB-T).
The WBC nadir was severe in all patients, ranging from 0.1 to 0.2 × 103/μl and starting from day 1 to day 8 after conditioning. The mean day of the WBC nadir was +4.4 from transplantation, with three patients on day 4 (nos. 1, 3, 5), one patient (no. 4, CLL) on day 3, one patient (no. 8, RAEB-T) on day 1 and two patients on days 6 and 8 (nos. 7 and 6: breast cancer and CML, respectively). The platelet nadir was reached later than WBC nadir with the number of platelets always under 10 × 103/μl with the exception of patient no. 3 (AML), who had, as the lowest platelet count, 11 × 103/μl. The hemoglobin decrease was extremely variable, but generally related to the Hb level before transplantation; the lowest level observed was 5.6 g/dl in the FCCL patient (no. 5) with β-thalassemic trait, while the highest count was 10.2 g/dl in the CML patient (no. 6). The Hb nadir occurred from 7 to 13 days after conditioning.
WBC recovery occurred within a mean of 12 days (range 10–15 days), platelet recovery required a mean of 14 days (range 11–16 days), reticulocyte recovery occurred within 6.5 days (range 12–20 days).
Table 3 shows results concerning the whole procedure and status at follow-up. After transplantation, all patients obtained a clinical CR without any evidence of disease; only the CLL patient (no. 4) showed bone marrow residual disease detected by immunophenotype analysis in CFM. In most patients, the acute toxicity consisted of mucositis due to conditioning therapy; only one mild heart deficiency, promptly reversible, occurred in patient no. 8, being detected by VEF reduction to 49%. No acute deaths were recorded. At the follow-up, four patients (Burkitt lymphoma, follicular lymphoma, CML and breast cancer) were completely disease-free; three of them had received autologous BMT and one BMT from related donor. The observation period following transplantation ranged from 8 to 26 months. One patient (no. 8) died 2 months after BMT of acute intestinal GVHD occurring after hospital discharge. Deaths due to relapse and progression of the disease occurred after 5, 8 and 15 months from the transplantation, in the ALL patient (no. 2) who had relapsed 3 months after allogeneic BMT, in the AML patient (no. 3) who had relapsed 6 months after ABMT and in the CLL patient (no. 4) who showed a progressive increase and resistance of the disease.
It is widely known that Jehovah's Witnesses patients, by refusing blood product transfusion, reduce the chance of cure of hematological malignancies, especially acute leukemia. Some reports emphasize this concept and generally hematologists, being aware of the related risks, refuse the responsibility of aggressive therapies.5 BMT, as therapeutic option, is considered almost unfeasible in patients who refuse transfusions. Only a few reports are currently available regarding treatment of leukemia, including BMT, in Jehovah's Witnesses,6,7 and most of them are generally limited to single case reports. As we believe that more experience in this field has to be accrued, our study demonstrated that aggressive therapies may also be applied in those patients who refuse transfusions. Our retrospective study focused on patients who underwent autologous or allogeneic BMT, avoiding blood product transfusions during the procedure, except for bone marrow or peripheral blood stem cell support after conditioning.
Here we have illustrated the feasibility of the transplant procedure without risks greater than those expected in patients who accept transfusions; in fact none of our patients experienced major side effects or life-threatening complications, except one patient who developed mild and transient dyspnoea, due to heart failure, during severe cytopenia but without consequences after Hb recovery. Reports concerning leukemia in Jehovah's Witnesses show that the achievement of remission with a heavy therapy is possible,1,2,3,4 and this may be curative; however, many ethical implications are raised by investigators, mainly concerning the choice whether to treat or not to treat and, if so, what appropriate therapy is to be performed. Almost all our patients, before the transplant procedure, received a standard therapy, except two patients who received a shortened course of therapy to avoid a long duration of myelosuppression. Mostly, we chose to treat patients with full therapy being aware of the risks, and we always gave extensive information of these risks to the patients. In our previous work on six leukemic patients,7 we emphasized the importance of starting induction treatment as soon as possible. Here we confirm that BMT, when part of curative intent, should be planned and, if possible, performed in Jehovah's Witnesses as early as possible, rather than using this procedure as salvage treatment at subsequent relapse or resistance. We believe that heavy or aggressive short-term therapy is not difficult to manage, even in patients refusing transfusions. In addition, the use of erythropoietin, as mentioned elsewhere, is useful to accelerate hemoglobin recovery.14 In fact we demonstrated that the duration of neutropenia was comparable to that of normally transfused patients, while thrombocytopenia and anemia seem of minor duration and less severe, being estimated in our group of patients for not more than a mean of 6 days. Whether these are due to hematological stress caused by forced anemia and/or to a combination of G-CSF and erythropoietin need to be further investigated; certainly, the employment of erythropoietin can permit the use of high-dose therapy.14 Moreover, in relatively young patients the tolerance of severe anemia is certainly better, especially in patients with a good heart profile as our patients had. The end of reticulocyte production, caused by the myeloablative program, occurs within almost 2 weeks, when we expect a drop of the hemoglobin level from 10 to 30% of the count recorded before the therapy. This drop of hemoglobin over 2 weeks is well tolerated when there is an absence of major side effects or organ failure.
The final point for discussion concerns the disease outcome. Three deaths were related to disease relapse and progression, and only one patient died from transplant-related mortality, that is, GVHD at 2 months post stem cell infusion. Four patients are still in remission, demonstrating the possibility of having long-lasting remissions or perhaps cure in some of them.
In conclusion our observational work leads us to consider Jehovah's Witnesses as patients who can undergo potentially curative stem cell transplantation.
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Mazza, P., Prudenzano, A., Amurri, B. et al. Myeloablative therapy and bone marrow transplantation in Jehovah's Witnesses with malignancies: single center experience. Bone Marrow Transplant 32, 433–436 (2003). https://doi.org/10.1038/sj.bmt.1704179
- Jehovah's Witnesses
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