TLI in pediatric patients.

PURPOSE: Hematopoietic progenitor cell transplantation (HSCT) is a procedure used in different hematological diseases as part of the curative treatment, so the investigators propose a system of conditioning of reduced intensity based on total lymphoid irradiation (TLI) as an alternative to the classic total body irradiation (TBI) followed by haploidentical transplantation in patients compatible with a single HLA haplotype, as an alternative to patients who do not have an HLA compatible donor. MATERIALS AND METHODS: A cohort of 25 patients with hematological disease underwent haploidentical HSCT from February 2015 to May 2018, conditioned with TLI from day - 10 (2-4 days of treatment) followed by thiotepa (5 mg/kg/12 h) and melphalan (70 mg/m2/day) prior to HSCT and prophylaxis with ciclosporin (1.5 mg/kg/12 h). 2 Gy/fraction was administered to complete 8 Gy with IMRT and VMAT technique. RESULTS: 12% rejection of the transplant was obtained with acute GVHD < II (48%) and chronic GVHD 12%. No acute toxicity was recorded in irradiated patients and 56% survival of patients at the end of follow-up. CONCLUSION: Conditioning the haploidentical transplant with TLI, IMRT, and VMAT techniques compared with TBI and RT3D-C techniques is a feasible technique that helps inducing the necessary immunosuppression in patients with a high risk of graft rejection, minimal adverse effects, low incidence of GVHD, and high survival rate.

Fertility preservation in patients with haematological disorders: a retrospective cohort study.

This study investigated the factors associated with utilization of fertility preservation and the differences in treatments and outcomes by prior chemotherapy exposure in patients with haematological diseases. This study included all 67 women with haematological diseases seen for fertility preservation consultation at two university hospitals between 2006 and 2011. Of the total, 49% had lymphoma, 33% had leukaemia, 7% had myelodysplastic syndrome and 4% had aplastic anaemia; 46% had prior chemotherapy; and 33% were planning for bone marrow transplantation, 33% pursued ovarian stimulation and 7% used ovarian tissue banking; and 48% of patients did not pursue fertility preservation treatment. All five cycle cancellations were in the post-chemotherapy group: three patients with leukaemia and two with lymphoma. Patients with prior chemotherapy had lower baseline antral follicle count (10 versus 22) and received more gonadotrophins to achieve similar peak oestradiol concentrations, with no difference in oocyte yield (10.5 versus 10) after adjustment for age. Embryo yield was similar between those who had prior chemotherapy and those who had not. Half of the patients with haematological diseases who present for fertility preservation have been exposed to chemotherapy. While ovarian reserve is likely impaired in this group, oocyte yield may be acceptable.

Total marrow irradiation with RapidArc volumetric arc therapy.

PURPOSE: To develop a volumetric arc therapy (VMAT)-total marrow irradiation (TMI) technique for patients with hematologic malignancies. METHODS AND MATERIALS: VMAT planning was performed for 6 patients using RapidArc technology. The planning target volume consisted of all the bones in the body from the head to the mid-femur, excluding the extremities, except for the humerus, plus a 3.0-mm margin. The organs at risk included the lungs, heart, liver, kidneys, bowels, brain, eyes, and oral cavity. The VMAT-TMI technique consisted of three plans: the head and neck, the chest, and the pelvis, each with three 330° arcs. The plans were prescribed to ensure, at a minimum, 95% planning target volume dose coverage with the prescription dose (percentage of volume receiving dose of ≥12 Gy was 95%). The treatments were delivered and verified using MapCheck and ion chamber measurements. RESULTS: The VMAT-TMI technique reported in the present study provided comparable dose distributions with respect to the fixed gantry linear accelerator intensity-modulated TMI. RapidArc planning was less subjective and easier, and, most importantly, the delivery was more efficient. RapidArc reduced the treatment delivery time to approximately 18 min from 45 min with the fixed gantry linear accelerator intensity-modulated TMI. When the prescription dose coverage was reduced to 85% from 95% and the mandible and maxillary structures were not included in the planning target volume as reported in a tomotherapy study, a considerable organ at risk dose reduction of 4.2-51% was observed. The average median dose for the lungs and lenses was reduced to 5.6 Gy from 7.2 Gy and 2.4 Gy from 4.5 Gy, respectively. CONCLUSION: The RapidArc VMAT technique improved the treatment planning, dose conformality, and, most importantly, treatment delivery efficiency. The results from our study suggest that the RapidArc VMAT technology can be expected to facilitate the clinical transition of TMI.

Evaluation of low platelet counts by optical, impedance, and CD61-immunoplatelet methods: estimation of possible inappropriate platelet transfusion.

BACKGROUND: The Cell-Dyn Sapphire (Abbott Diagnostics) detects platelets (PLTs) with a CD61 monoclonal antibody directed against glycoprotein IIIa as well as impedance (IMP) and optical (OPT) technology. We decided to evaluate low PLT counts produced by IMP and OPT methods and to compare them with the CD61 method. We also examined the possibility of inappropriate PLT transfusion resulting from an inaccurate PLT count. STUDY DESIGN AND METHODS: We analyzed consecutive blood samples with OPT PLT counts of less than 50 x 10(9)/L. We performed the PLT count with the OPT, IMP, and CD61 methods and we compared the number of prophylactic PLT transfusion indications according to the PLT counts determined by the OPT and IMP methods with the number of prophylactic PLT transfusion indications according to our reference CD61 method. RESULTS: We collected 135 samples. In the bias analysis, the OPT method and the IMP method showed higher PLT counts when compared with the CD61 method (mean of difference 1.69 x 10(9) and 19.1 x 10(9)/L, respectively). We saw overtransfusion in 1.5% of cases and undertransfusion in 15.2% of cases (p = 0.01; McNemar's test) when we selected a threshold of 10 x 10(9)/L with the OPT method. We saw undertransfusion in 22.2% of cases (p = 0.03; McNemar's test) when we selected a threshold of 5 x 10(9)/L with the OPT method. CONCLUSIONS: Low PLT counts determined by the OPT and IMP methods showed some disagreement when compared with the CD61 method. This disagreement caused both PLT undertransfusion and overtransfusion.

[Therapeutic monoclonal antibodies in onco-hematology]. / Anticorps monoclonaux thérapeutiques en oncohématologie.

Rituximab, a chimeric monoclonal anti-CD20 antibody, was introduced into clinical practice in 1997, and has proven to be highly effective in the treatment of B-lymphoproliferative disorders and autoimmune diseases. Despite such success, in vivo mechanisms of action of anti-CD20 have only recently began to be unraveled, pointing to the crucial role of antibody-dependent cellular cytotoxicity response mediated through Fcg receptor signalling. Better understanding of pharmacokinetics and factors influencing individual exposure mediated through anti-CD20 will allow to engineer these molecules to increase their effector responses. Meanwhile, other formats have also been investigated, such as radiolabeled anti-CD20, or coupling of antibodies to cytotoxic drugs such as anti-CD33 used in myeloid leukemia. However these antibodies are used in combination with standard chemotherapy and cannot substitute for cytotoxic drugs. This review summarizes the knowledge acquired through our clinical use of anti-CD20 and authorized monoclonal antibodies in oncohematology and proposes some news areas that will lead to the development of new and more effective therapeutic strategies.

Drug-induced respiratory disease in patients with hematological diseases.

Patients with hematological malignancies or recipients of hematopoietic stem cell transplants may develop myriad pulmonary manifestations, as a complication of either the disease or the diverse agents used to treat the disease. Clinical, radiographic, and physiological features of drug-induced and radiation-induced pulmonary injury are often difficult to distinguish from other causes of pulmonary infiltrates (e.g., infections, pulmonary edema, alveolar hemorrhage, etc.). Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) is essential to exclude infectious etiologies. In some cases, surgical lung biopsies are required to establish a specific etiological diagnosis. This review discusses the myriad causes of lung injury/toxicity that may afflict patients with hematological malignancies or transplant recipients, and presents diagnostic and therapeutic approaches.

188Re or 90Y-labelled anti-CD66 antibody as part of a dose-reduced conditioning regimen for patients with acute leukaemia or myelodysplastic syndrome over the age of 55: results of a phase I-II study.

In a phase I-II study for patients aged 55-65 years, we employed radioimmunotherapy using an anti-CD-66 antibody as part of a dose-reduced conditioning regimen, which was followed by a T-cell-depleted graft. 20 patients with a median age of 63 years suffering from acute leukaemia (n=17) or myelodysplastic syndrome (n=3) received the antibody labelled either with 188Rhenium (n=8) or with 90Yttrium (n=12) during conditioning. Radioimmunotherapy provided a mean dose of 21.9 (+/-8.4) Gy to the bone marrow with a significantly higher dose when 90Yttrium was used. Additional conditioning was fludarabine-based plus anti-thymocyte globulin in matched related donor transplants (n=11), or plus melphalan in matched unrelated donor transplants (n=9). Regimen-related toxicity was low, with two patients developing three episodes of grade III organ toxicity. All patients engrafted, grade II-IV acute graft-versus-host disease (GvHD) was observed in one patient (5%) and chronic GvHD in three patients (15%). The cumulative incidence of non-relapse mortality was 25%, the cumulative incidence of relapse 55%. The probability of survival was estimated to be 70% at 1 year and 52% at 2 years post-transplant, although no plateau was reached afterwards. In conclusion, radioimmunotherapy using the anti-CD66 antibody was feasible and safe in our elderly patient group and provided a high marrow dose.

An audit of the indications for and techniques of palliative splenic radiotherapy in the UK.

AIMS: This paper describes a national audit of the indications for, and techniques and toxicity of, palliative splenic radiotherapy in haematological disorders. MATERIALS AND METHODS: A postal questionnaire was sent to consultant clinical oncologists treating haematological malignancies in the UK. RESULTS: The response rate was 76%. The audit shows chronic lymphocytic leukaemia, myelofibrosis and chronic myeloid leukaemia to be the most common underlying conditions in which splenic irradiation is used. Painful splenomegaly and hypersplenism were the most common indications. Dose fractionation schedules vary widely across the UK, and also the level of full blood counts used to interrupt radiotherapy. CONCLUSIONS: Palliative splenic radiotherapy continues to be widely used in the UK in small numbers of patients and seems to be well tolerated. Re-irradiation for further symptomatic progression is also commonly carried out.

Palliative irradiation of the spleen.

We analyzed the efficacy of splenic irradiation in a population of patients with hematologic diseases. The records of the Radiation Oncology Division, Naval Medical Center San Diego were retrospectively reviewed for all patients treated with splenic irradiation (SI) between January 1, 1990 and March 1, 2001. The charts of 17 patients were identified: 5 patients had chronic myelogenous leukemia, 4 had chronic lymphocytic leukemia, 4 had idiopathic myelofibrosis, 2 had polycythemia vera, and 1 patient each had idiopathic thrombocytopenic purpura and acute myelogenous leukemia. Patient ages ranged from 37 to 88 years. Sixteen of 17 suffered from symptomatic splenomegaly. Twenty-six courses of splenic irradiation were delivered to these 17 patients. Treatment courses generally consisted of two fractions of 50 cGy in the first week, two fractions of 75 cGy the second week, and two fractions of 100 cGy the third week. Blood counts were checked prior to each treatment. Seven of the 17 patients died 1 month or less after SI due to the terminal nature of their disease. Twenty-two of 25 treatment courses for splenomegaly resulted in decreased pain and symptoms. Five patients required two treatment courses for splenomegaly, and one patient required five treatment courses. Three of four patients treated for thrombocytopenia demonstrated improvement, but only one was evaluable for more than 2 weeks due to disease-related mortality. Three of five patients treated for leukocytosis had significant improvement. In general, patients suffered few significant complications from this palliative intervention. Splenic irradiation can effectively palliate symptomatic splenomegaly in patients for whom splenectomy is not an option. Retreatment is possible. Splenic irradiation is less effective in the treatment of thrombocytopenia or leukocytosis.

153Sm EDTMP for bone marrow ablation prior to stem cell transplantation for haematological malignancies.

This study examined the safety of adding 153Sm lexidronam to standard conditioning regimens in patients undergoing stem cell transplantation for marrow based haematological malignancies in whom total-body irradiation as part of conditioning was desirable but not feasible. Ten such patients were enrolled, seven with multiple myeloma. An escalating regimen of 19-45 GBq of 153Sm lexidronam was added 12-14 days prior to the standard transplantation regimen. Evaluation parameters included time to engraftment, status at day +100 by International Bone Marrow Transplant Registry (IBMTR) criteria and toxicity during this period. Absorbed marrow radiation doses were estimated using the MIRDOSE 3 program. No adverse events were attributable to 153Sm lexidronam. Of the seven patients with multiple myeloma, four achieved complete response, two partial response, and another had stable monoclonal band at 3 months post-transplant. One patient with Refractory Anaemic with Excess Blasts in transformation (RAEBt) died of a presumed fungal infection, whilst another with acute myeloid leukaemia relapsed, dying at day +153. A patient with low-grade lymphoma showed no evidence of residual disease at day +100. The total marrow absorbed dose was estimated to be 0.7+/-0.2 mGy x MBq(-1). Regional uptake was markedly non-uniform with poor uptake in the appendicular skeleton. Dose-limiting toxicity was not attained. At the activities used 153Sm lexidronam was not associated with additional toxicity in this population. Adequate absorbed radiation dose to appendicular marrow is unlikely to be deliverable by this approach alone.

Effect of total body irradiation dose escalation on outcome following T-cell-depleted allogeneic bone marrow transplantation.

Prior studies of non-T-cell-depleted (TCD) transplantation have demonstrated a reduction in relapse in patients receiving escalated doses of TBI; however, overall survival in these studies was not significantly improved due to increased treatment-related toxicity seen at the higher doses of irradiation. Toxicity was in part related to an increased incidence of GVHD. Because T-cell depletion of donor bone marrow reduces the incidence of GVHD and other treatment-related complications after allogeneic bone marrow transplantation, it was postulated that TBI dose may be safely escalated in this setting and may decrease the risk of relapse following TCD BMT. Herein, we report the results of a trial assessing the safety and impact of escalated doses of TBI after TCD BMT. Two hundred adults with hematologic malignancies were treated in consecutive cohorts defined by increasing doses of TBI (1400, 1480, and 1560 cGy) in combination with cyclophosphamide. In vitro T-cell depletion using anti-CD6 monoclonal antibody was used for GVHD prophylaxis. The incidence of grade II or greater acute GVHD in patients receiving 1560 cGy (36%) was significantly higher than in patients receiving 1400 cGy (18%) (P = .04) or 1480 cGy (13%) (P = .01). Two-year treatment-related mortality was significantly higher in patients who received 1560 cGy of TBI (33%) than in those who received 1400 cGy (20%) (P = .04) or 1480 cGy (19%) (P = .05). The increased dose of TBI did not reduce the rates of relapse, with the estimated 2-year risk of relapse being 24% (1400 cGy), 24% (1480 cGy), and 31% (1560 cGy) for the 3 cohorts of patients. Overall survival at 2 years was inferior for patients receiving 1560 cGy of TBI (36%) compared with those who received 1400 cGy (55%) or 1480 cGy (58%) (P = .01). We conclude that dose escalation of TBI is associated with increased GVHD and inferior survival following TCD BMT. Future efforts to reduce the risk of relapse after TCD BMT should focus on immunologic methods to induce the graft-versus-leukemia effect after BMT rather than intensification of the ablative regimen by escalation of irradiation dose.

[Radioimmunotherapy of malignant diseases. Value and prospects]. / Radioimmunothérapie des affections malignes. Intérêt et perspectives.

Radioimmunotherapy is based on the use of radioactive agents (iodine 131, yttrium 90...), murine-derived monoclonal antibodies and specific tumour-related membrane antigens. This new treatment modality was applied in 800 patients with different types of malignant tumours which had not responded to traditional therapy. Among the haematologic tumours, the most promising results were obtained in B phenotype non-Hodgkin lymphoma. More modest results were obtained for solid tumours although good results were observed after intraperitoneal administration in patients with cancer of the ovary. The main side effects are acute reversible anaphylactic shock, haematologic toxicity and development of anti-murine human antibodies. Several methods are currently under study to increase irradiation dose delivered at the tumoural site since less than 1% of the injected radioactive dose is absorbed by tumoural cells. Several clinical studies are to be conducted in France, particularly for malignant non-Hodgkin lymphoma and cancer of the ovary.

52Fe for additional marrow ablation before bone marrow transplantation.

The effectiveness of bone marrow transplantation (BMT) for malignant blood diseases remains limited by the inability of the preparative regimen to eliminate the disease without causing toxicity to normal organs. We have used 52Fe to deliver radiotherapy selectively to the BM. Fourteen patients with hematologic malignancies received 52Fe before a conventional BMT conditioning regimen. The median 52Fe dose was 58 mCi (range, 32 to 85 mCi). As evaluated by quantitative scanning, the median percentage of 52Fe taken up by the BM was 82% (range, 36% to 90%). This resulted in a median radiation-absorbed dose to the BM of 632 rad (range, 151 to 1,144 rad). The median uptake of 52Fe by the liver was 18% (range, 10% to 64%) and the median radiation-absorbed dose to the liver was 239 rad (range, 82 to 526 rad). The median whole body radiation-absorbed dose was 46 rad (range, 22 to 68 rad). No untoward effects were noted after the injections of 52Fe. The patients recovered hematopoiesis without toxicity in excess of that expected with conventional conditioning alone. The median follow-up was 8 months and three patients have relapsed. 52Fe should provide a way to boost the radiation dose to marrow-based diseases before marrow transplantation without increasing toxicity.

Total body irradiation for treatment of haematological diseases.

The present status of total body irradiation (TBI) as a part of the treatment of haematological diseases was discussed during a separate symposium at the 5th Annual ESTRO meeting at Baden-Baden. The experimental techniques applied in Europe, the dosimetry for TBI, the radiobiological aspects and the late effects after TBI have been reviewed. For specific geometries, precautions have to be taken to avoid increased dose contributions at the skin due to electrons scattered from the wall behind the patient. CT data can be useful for the individualization of the exposure regimen of patients with extreme variations in lung anatomy or lung density. An appreciable number of centres apply in vivo dosimetry, however, special care is needed for the correct interpretation of the dosimeter readings. A number of late effects, including induction of cataract and secondary tumours has been observed after TBI. The techniques applied for TBI at the various centres and the temporal administration of the dose show wide variations. At present, the patient material is too heterogeneous to draw any conclusion about an optimum schedule for a TBI regimen. Further cooperation between clinicians, radiobiologists and radiation physicists has to be established to achieve consistency and further improvement of the results after TBI.