M. Tomblyn

Donor lymphocyte infusions: the long and winding road: how should it be traveled?

Donor lymphocyte infusions (DLI) often are used after allo-SCT to augment the graft-versus-tumor effect. Timing of infusion varies according to indication, for example to treat tumor recurrence, as a planned strategy to prevent disease relapse in the setting of T-cell-depleted grafts or non-myeloablative conditioning regimens, or as a method to convert mixed to full donor chimerism. The optimal strategy of timing, use of cytotoxic conditioning, cell dose and cell product composition, and so on, for DLI administration remains unclear. Despite varied techniques, DLI may lead to 3-year disease-free survivals (DFS) in excess of 60% for all CML patients and approach 90% in patients with only molecular or cytogenetic relapse. Other hematologic malignancies appear much less responsive, as less than 50% of patients respond and provide, at best, 3-year DFS rates of 20–50%. Multiple myeloma patients have overall response rates of 40–45% after DLI, suggesting benefit in relapsed disease, but limited experiences for diseases such as Hodgkins lymphoma, myelodysplasia and ALL preclude recommendations for use of DLI at this time. Regardless of the indication, treatment-related mortality after DLI is 5–20% and more than one-third of patients will develop acute and/or chronic GVHD after DLI. The risks of these complications appear related, in part, to donor source, cell dose and therapy prior to DLI. Although there are no definitive answers, the information gleaned from published literature suggests that DLI should be administered early after relapse or as a prophylactic strategy in patients receiving T-cell-depleted grafts, and patients with bulky or aggressive disease may benefit from disease reduction prior to DLI.

Myeloablative Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia: Analysis of Graft Sources and Long-Term Outcome

PURPOSE Analysis of hematopoietic cell transplantation (HCT) for high-risk or recurrent acute lymphoblastic leukemia (ALL) using different donor sources is confounded by variable conditioning and supportive care. PATIENTS AND METHODS We studied 623 consecutive ALL myeloablative HCT (1980 to 2005). Donors were autologous (n = 209), related (RD; n = 245), unrelated (URD; n = 100), and umbilical cord blood (UCB; n = 69). RESULTS After median of 8.3 years of follow-up, 5-year overall survival (OS), leukemia-free survival (LFS), and relapse were 29% (95% CI, 26% to 32%), 26% (95% CI, 23% to 29%), and 43% (95% CI, 39% to 47%), respectively. Treatment-related mortality (TRM) at 2 years was 28% (95% CI, 25% to 31%). Mismatched URD sources yielded higher TRM (relative risk [RR], 2.2; P < .01) and lower OS (RR, 1.5; P = .05) than RD or UCB HCT. Autografting yielded significantly more relapse (68%; 95% CI, 59% to 77%; P < .01) and poorer LFS (14%; 95% CI, 10% to 18%; P = .01). HCT in first complete remission (CR1) yielded significantly better outcomes than later HCT. In a 1990 to 2005 allogeneic CR1/second complete response cohort, 5-year OS, LFS, and relapse rates were 41% (95% CI, 35% to 47%), 38% (95% CI, 32% to 44%), and 25% (95% CI, 19% to 31%), respectively; 2-year TRM was 34% (95% CI, 28% to 40%). With RD, well-matched URD and UCB sources, 5-year LFS was 40% (95% CI, 31% to 49%), 42% (95% CI, 14% to 70%), and 49% (95% CI, 34% to 64%), respectively, while relapse was 31% (95% CI, 22% to 40%), 17% (95% CI, 0% to 37%), and 27% (95% CI, 13% to 41%). Acute graft-versus-host disease was associated with fewer relapses. Since 1995, we noted progressive improvements in OS, LFS, and TRM. CONCLUSION Allogeneic, but not autologous, HCT for ALL results in durable LFS. Importantly, HCT using UCB led to similar outcomes as either RD or well-matched URD. HCT in early remission can best exploit the potent antileukemic efficacy of allografting from UCB, RD, or URD sources.

Fewer infections and lower infection-related mortality following non-myeloablative versus myeloablative conditioning for allotransplantation of patients with lymphoma.

Non-myeloablative (NMA) allogeneic donor SCT for patients with relapsed lymphoma is associated with lower treatment-related mortality (TRM). However, the impact of conditioning intensity on post transplant infections remains unclear. We evaluated infections in 141 consecutive patients with lymphoma who were allografted using NMA (n=76) or myeloablative (MA; n=65) conditioning regimens. Using infection incidence density per 1000 patient days, we accounted for all infectious episodes during the first post transplant year. Before neutrophil engraftment, the NMA cohort had a 53% lower rate of bacterial infection (relative risk=0.47; P=0.06), whereas after engraftment the density of bacterial infections was similar in the two groups. In the first month, both invasive fungal infections and viral infections were twofold less frequent (P=0.22; P=0.06) in NMA patients. Late viral and fungal infections as well as CMV reactivation were infrequent after either conditioning intensity. The 1-year infection-related mortality was significantly lower after NMA conditioning (NMA 9% (3–16%) vs MA 22% (11–40%); P=0.03). NMA allogeneic transplantation for lymphoma patients results in substantially fewer early infections and lower infection-related deaths, although the similar frequency of later infections suggests that immune reconstitution is delayed with either conditioning intensity.

Helical tomotherapy targeting total bone marrow - first clinical experience at the University of Minnesota.

Total body irradiation (TBI) has been widely utilized as part of the conditioning regimen for hematopoietic cell transplantation [1]. However, with traditional TBI techniques the entire body is irr...

Difficult stem cell mobilization despite adequate CD34 + cell dose predicts shortened progression free and overall survival after autologous HSCT for lymphoma

Hematopoietic growth factors alone or in combination with myelosuppressive chemotherapy are used to mobilize peripheral blood stem cells for autologous transplantation. To identify characteristics of successful mobilization with granulocyte colony-stimulating factor (G-CSF) alone and to study the impact of immediate chemotherapy mobilization following G-CSF mobilization, we treated 175 chemotherapy sensitive lymphoma patients with G-CSF (G) mobilization and leukapheresis followed by chemotherapy plus G-CSF (CG) mobilization and leukapheresis and then autologous transplantation. Patients with stage I/II disease at diagnosis and ⩽5 years from diagnosis were more likely to mobilize successfully with G-CSF alone (G). CG mobilization led to superior stem cell yields compared to the preceding mobilization with G (median 2.37 vs 1.37 ( × 106CD34+ cells/kg); P<0.0001). Patients (n=58, 33%) with successful G-CSF mobilization (⩾2 × 106 CD34+ cells/kg) had quicker platelet recovery and improved progression free and overall survival compared to patients who had adequate collection only after chemotherapy mobilization or to those who failed to collect an adequate graft with either type of mobilization. The poor clinical outcome of patients with difficult mobilization using either method identifies them as a high-risk group who might benefit from alternative therapies.

Comparison of two mycophenolate mofetil dosing regimens after hematopoietic cell transplantation.

Mycophenolic acid (MPA) is the active component of mycophenolate mofetil (MMF). Low MPA exposure is associated with a higher incidence of acute GVHD and possibly worse engraftment. Therapeutic plasma targets have been proposed in hematopoietic cell transplantation (HCT), however, are difficult to achieve in adult patients with MMF doses of 2 g/day. Mycophenolate pharmacokinetics was prospectively studied in adults undergoing nonmyeloablative HCT who received MMF 3 g/day with CYA. The first 15 individuals received 1.5 g every 12 h and the second 15 received 1 g every 8 h. Sampling was performed in each patient with i.v. and oral administration. There were no differences in total or unbound MPA 24-h cumulative area under the curves (AUCs), concentrations at steady state (Css) or troughs between the two dosing regimens (all P>0.01). The previously proposed total MPA Css target of 3 μg/ml and trough ⩾1 μ/ml were achieved in only 13–27% and 20–53% of patients, respectively, on 3 g/day. However, the 3 g/day regimens readily achieved satisfactory unbound 24-h cumulative AUC targets of 0.600 μg*h/ml in 87–100% of subjects. There appears to be no significant difference in daily MPA exposure when MMF of 3 g/day is divided into two or three equal doses.

TU‐E‐ValB‐01: Helical Tomotherapy Targeting Total Bone Marrow ‐ Initial Clinical Experience at the University of Minnesota

Purpose: We report here the successful use of Tomotherapy at delivering intensity modulated radiotherapy to the bone and bone marrow spaces along the entire axis of a patient and describe a dosimetric analysis of the total marrow irradiation (TMI) treatment. This is part of a dose escalation trial to determine the maximum tolerated dose (MTD) of TMI when given prior to an alkylator‐intensive conditioning regimen for the treatment of high risk or relapsed solid tumors.Method and Materials: A patient enrolled in a dose escalation study trial received 600 cGy in 3 fractions. Two independent CTimage sets (upper and lower part of the body) were obtained. A helical tomotherapy treatment plan was created from this CTimage sets. The quality assurance was evaluated with the use of (a) ion chamber and (b) extended dose range film. The isorad‐p cylindrical diodes were used for in‐vivodosimetry.Results: The patient showed neutrophil engraftment on day 11 and platelet engraftment by day 58. He is currently well at 120 days post transplant with no evidence of disease. The patient developed nausea and vomiting after the first fraction of Tomotherapy TMI. Other than above there were no adverse effects of TMI. The planned radiation conformed to all bone marrow sites. Average doses to lungs,kidneys,heart, and eyes were 50–70% of the prescribed dose for TMI treatments. The dose delivery verifications (pretreatment and in vivodose measurement) were within ±3–5% of the expected dose calculated from the treatment planning station. Conclusions: We show that helical tomotherapy targeting the bone marrow of the whole body is clinically feasible. The clinical implementation of intensity modulated radiation to conform the radiation dose to all active bone marrow of the whole body opened up the possibility of a dose escalation study for high risk patients.

WE‐C‐224C‐07: Cervical Cancer Treatment: 3D Dose Determination Based On Low Energy and High Energy CT Image

Purpose: To employ megavoltage CT (MVCT) to (a) generate an artifact‐free image and compared with the kilovoltage CT (kVCT) image set in presence of Fletcher‐Suit applicators, and (b) calculate precise three‐dimensional anatomical dose distribution for low dose rate (LDR) treatment which can be combined with external treatment (based on kVCT) planning. Method and Materials: Consented patients undergoing radiotherapytreatment for cervical cancer were simulated using orthogonal films and kVCT for external treatment planning and low dose rate brachytherapy. Fletcher‐Suit applicators with shielding were used for pretreatment image scans. Additionally, MVCT images were acquired using the Tomotherapy machine. These image sets (kVCT and MVCT) were fused in a Brachyvision planning system using a pixel registration method. MVCT images were then used for volumetric dose calculations using TG43 model. The MVCT image set and orthogonal film were then used to explore Monte Carlo‐based 3D dose calculations. Results: Artifact‐free images were obtained from MVCT scans using the Fletcher‐Suit applicators. kVCT images were not useful for LDR treatment planning due to the presence of substantial artifacts. The MVCT image set was used in delineating the rectal and bladder tissue margins. However, soft tissue visualization was sub‐optimal for clinical purposes. The MVCT image‐baseddose calculation generated three‐dimensional dose distribution for rectum (max. dose of 56 cGy) and bladder (max. dose of 25 cGy) for single fraction prescribed dose of 600 cGy. Maximum rectum and bladder dose calculated using the MVCT image and orthogonal film based plan were very similar. Conclusions: We have showed that the artifact‐free MVCT image offers accurate three‐dimensional LDR treatment planning. In addition, the impact of dose heterogeneity will be calculated using image based Monte Carlo simulation technique. Ideally, truly individualized external beam and intracavitary radiotherapy may lead to higher cure rates and lower complication probabilities.

SU‐FF‐T‐130: Conformal Avoidance and Helical Tomotherapy: Utility in Craniospinal Radiation

Purpose: Craniospinal irradiation (CSI) is used for malignancies with a propensity for CSF spread or known CSF involvement. Traditional CSI has inherent dosimetric variations and is prone to patient set up error. Helical tomotherapy (HT) is a novel image‐guidedtreatment allowing for precise target sculpting while limiting dose to critical normal tissues. Here, we perform a dosimetric comparison of traditional CSI to that delivered by HT and present an example of utilizing HT for conformal avoidance. Method and Materials: A patient with previously‐treated glioneural neoplasm (60 Gy) recurred with leptomeningeal spread and due to her previous radiation was not a candidate for traditional CSI. Treatment planningCTimages were used to generate a 36 Gy CSI plan using HT, using the 80% isodose line from the previous treatment plan as an absolute avoidance structure. Three additional patients were planned for HT‐CSI and compared to traditional planning. Dosimetry to the PTV and critical normal tissues was performed for both the traditional and HT plans. Results: Traditional CSI fields contain a cold spot representing less than 50% of prescribed dose at the lower spinal junction, where no gaps were necessary using HT. Tomotherapy resulted in a more highly conformal dose delivery to the PTV with conformal avoidance to previously‐treated region. Dose inhomogeneity (90% – 10% volume) to the PTV for HT was 1–3%, compared to > 10% for the traditional CSI setup. Conclusions: HT‐CSI results in superior dosimetry to the PTV, with a higher minimum dose delivered more conformally, while maximum doses to critical normal tissues are lower compared to traditional LINAC‐based CSI. HT requires no junctions with gaps to be calculated and shifts to be made, and it is not subject to critical underdosing as seen in the traditional CSI plan. Conformal avoidance can be easily achieved with HT‐CSI.