¹Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL, USA

²Department of Radiation and Cellular Oncology, and the Cancer Research Center, The University of Chicago, Chicago, IL, USA

Correspondence to: Dr R A Larson, The University of Chicago Medical Center, 5841 S Maryland Ave, MC2115, Chicago, IL, 60637-1470, USA

Since approximately 30% of leukemia patients relapse after allogeneic BMT using total body irradiation (TBI)-based preparative regimens, treatment intensity may be suboptimal. The killing of leukemia cells is proportional to the radiation absorbed dose. We studied the feasibility and toxicity of escalating the doses of fractionated TBI above our previous prescription of 13.5 Gy. Sixteen evaluable patients with advanced hematologic malignancies were treated with twice daily TBI using a high-energy source (18-24 MV). The first patient cohort (n = 11) received a total dose of 14.4 Gy in nine fractions, and the second cohort (n = 5) received doses escalated to 15.3 Gy. All patients received high-dose etoposide (60 mg/kg) and allogeneic stem cell transplantation following the TBI. All patients had HLA-identical sibling donors. The median times for neutrophil and platelet engraftment were 13.5 and 12 days, respectively, and did not differ between the two cohorts. All but one patient developed treatment-related grade 3 or 4 mucositis. There were three cases of grade 4 pulmonary toxicity and three cases of grade 4 hepatic toxicity among the 14.4 Gy cohort, and one case each of grade 4 pulmonary and hepatic toxicities among the 15.3 Gy cohort. In most cases comorbid conditions contributed to these toxicities. Two patients had significant GVHD of the GI tract. Six relapses occurred, five (45%) in the 14.4 Gy cohort and one (20%) in the 15.3 Gy cohort. The 100-day treatment-related mortality rates were 9% and 20% for the 14.4 Gy and 15.3 Gy cohorts, respectively, and the median survivals were 226 and 201 days, respectively. We conclude that TBI dose escalation above the previously used 13.5 Gy dose is feasible using a high-energy source and high-dose etoposide. Acute and chronic toxicities were primarily related to GVHD, infection and relapse rather than to TBI. Bone Marrow Transplantation (2000) 25, 807-813.

high-energy radiation; TBI; etoposide; dose escalation; hematologic malignancies; leukemia

Since 1971, bone marrow transplantation (BMT) has been increasingly used in the treatment of patients with various malignant hematologic diseases including chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma, chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD).^1,2,3 Marrow ablative chemoradiotherapy and allogeneic BMT offer potential cure for patients who are not curable with conventional therapy. For many patients transplanted over this time, total body irradiation (TBI) in standard doses of 12-13.5 Gy has been used together with cyclophosphamide or etoposide (VP-16) as the preparative regimen due to its substantial anti-tumor and immunosuppressive activities.^{4,5,6,7,8,9,10,11,12}

Since 20-30% of patients treated with TBI-based preparative regimens die from leukemia relapse, we postulated that treatment intensity is suboptimal. The killing of leukemia cells is proportional to the radiation absorbed dose. Few patients die from direct complications of TBI. Most often, the doses of concomitant chemotherapy have been escalated or a second or third drug has been added to the regimen. In contrast, escalation of the TBI dose has not been extensively studied in humans. Fractionation of the radiation dose decreases toxicity to normal tissues,^13,14,15,16 and therefore this technique is widely used.^17,18,19 Furthermore, as supportive care measures have improved, including the use of stem cells collected from the peripheral blood, it has become clear that treatment intensity of BMT regimens can be further increased.²⁰ Although radiation doses have been escalated in combination with standard doses of cyclophosphamide, there have been no previous studies in which the total TBI dose was escalated in combination with the maximum tolerated dose of etoposide (60 mg/kg).^4,21,22 We evaluated whether such an approach was feasible, and whether it would result in fewer relapses post BMT with acceptable early and late toxicity. This study investigated the outcomes of patients who received TBI doses of 14.4 Gy or 15.3 Gy followed by high-dose etoposide as a preparative regimen for allogeneic bone marrow or blood stem cell transplantation in adults with advanced and refractory hematologic malignancies. Furthermore, we have exclusively used high energy irradiation sources (18 and 24 MV) to provide better bone marrow dosimetry than that possible with lower energy irradiation sources.²³

Materials and methods

Patient data

Between August 1996 and March 1999, 16 patients with advanced hematologic malignancies were enrolled on this study and are fully evaluable. Patients with better risk features underwent BMT using a different preparative regimen during this period. Twelve of the 16 patients had persistent chemotherapy refractory disease present in the bone marrow at the time that the transplant treatment was begun. Two additional patients initially entered at the second TBI dose level (15.3 Gy) were subsequently excluded from the analysis. These patients were unable to receive the planned TBI dose for the following reasons: one patient had had extensive prior radiotherapy and was withdrawn prior to treatment, and the other had TBI interrupted for 6 days due to an acute upper gastrointestinal bleed that was unrelated to the treatment.

All patients were transplanted with allogeneic peripheral blood stem cells except one patient who received bone marrow cells due to medical insurance requirements. All patients had genotypically HLA-identical sibling donors.

The protocol was approved by the Institutional Review Board of the University of Chicago and reviewed and reapproved annually. Deaths and other adverse events were reported to the IRB. Signed consent was obtained from all patients and their donors prior to study entry.

Treatment plan

Previously, the standard pretransplant prescription at our institution was 13.5 Gy TBI in nine fractions followed by etoposide at 60 mg/kg.^23,24 For this study, the radiation dose was increased to 14.4 Gy (nine fractions of 160 cGy over 4.5 days) for the first cohort. If no persistent TBI-related morbidity was observed within 3 months after the third patient was treated, the radiation dose would be increased to nine fractions of 170 cGy (15.3 Gy) in cohort 2. A third cohort of 16.2 Gy was planned. Dose escalation would be stopped if 1 of the first three patients or 2 of the first six patients suffered lethal regimen-related toxicity within 100 days.

On day -8 of the transplant timeline, a lumbar puncture was performed for cytology, and 15 mg of preservative-free methotrexate and 50 mg of hydrocortisone were administered intrathecally to all leukemia patients. This was followed on day -7 by fractionated TBI given at a dose rate of 12 cGy/min in nine fractions employing parallel opposed large fields with 18 or 24 MV photons as previously described.²³ Patients were treated supine with lateral fields. The dose per fraction was 160 cGy (cohort 1) or 170 cGy (cohort 2) twice each day (separated by 7 ± 1 h) on days -7 to -4. The final fraction of TBI was given on day -3 followed immediately by etoposide 60 mg/kg administered as a 10 h intravenous infusion. Two ALL patients (Nos 12 and 13) received an additional 400 cGy testicular boost. The last two patients (Nos 10 and 11) enrolled on the study had 50% transmission blocks used to reduce the dose to the oral cavity and oropharynx in an effort to reduce mucositis.²³ To compensate for the reduced photon dose, these two patients also received 675 cGy boosts to their mandibles via right and left electron fields, delivered in 225 cGy daily fractions over the last 3 days of radiation therapy.

Marrow/blood stem cell harvesting and transplantation

One donor underwent marrow harvesting. Standard collection procedures were used to obtain approximately 10 ml bone marrow per kg of the recipient's weight. All other donors underwent peripheral blood stem cell harvesting using filgrastim mobilization. Peripheral blood leukapheresis collections were performed using peripheral venous access in our outpatient apheresis center. The target of 2 ´ 10⁶ CD34-positive cells/kg recipient weight was achieved with one apheresis from four donors, two collections from 10 donors, and three collections from one donor. After collection, the marrow or blood stem cells were maintained at room temperature and infused promptly through a central venous catheter without a filter. Hematopoietic growth factors were not routinely used post transplant.

Neutrophil engraftment was defined as the first day of a sustained absolute neutrophil count (ANC) >1000/l. Platelet engraftment was defined as the first day of a sustained platelet count >20000/l, independent of platelet transfusions.

Cyclosporine and corticosteroids were administered to the first nine patients enrolled on the study for graft-versus-host disease (GVHD) prophylaxis. Following a change in our institutional practice, the remaining seven patients received tacrolimus and methotrexate (days 1, 3, 6 and 11) for GVHD prophylaxis. There were no apparent differences in the frequency or severity of mucositis or other acute or chronic toxicities related to this change. In addition, prophylactic immunoglobulin infusions were given weekly to the first seven patients treated on the study as per institutional practice at the time. Patients with serologic tests that were positive for cytomegalovirus (CMV) or recipients whose donors had CMV positive serologies received gancyclovir prophylaxis from day +30 until approximately day +100.

The grading of both acute transplant regimen-related (TBI and etoposide) toxicity and GVHD (acute and chronic) was according to the National Cancer Institute Common Toxicity Criteria and standard GVHD grading systems,²⁵ respectively. Bone marrow examinations were performed routinely at day +30, +100, and at 1 year post transplant.

Criteria for response were as follows. A complete remission (CR) required all of the following to be present for >4 weeks: (1) a peripheral neutrophil count >1.5 ´ 10⁹/l and platelets 50 ´ 10⁹/l without transfusions; (2) no morphologic or cytogenetic evidence of leukemia in the peripheral blood or in the bone marrow; (3) marrow cellularity >20% with maturation of all cell lines; and (4) no evidence of extramedullary leukemia or lymphoma. A partial remission (PR) required that all criteria for a CR were satisfied except that the bone marrow could contain 5% but <25% malignant cells. In addition, extramedullary disease must have been reduced >50% over pre-BMT measurements. Treatment failure included patients failing to achieve a CR. Engraftment failure was defined by an aplastic marrow for more than 30 days without any evidence of leukemia. Relapse was defined as marrow infiltration by >25% leukemia cells after achieving either a CR or PR or as recurrence of lymphoma.

Statistical considerations

The main study endpoints were treatment-related morbidity, mortality and disease progression. Event-free survival was defined as the time from transplantation until either disease progression or death. Survival was calculated from the date of marrow or blood stem cell transplantation. Remission duration was calculated from the date of marrow or blood stem cell infusion for patients in remission at that time or from the date of CR post-transplant for all others. Treatment-related toxicities experienced by these patients were tabulated and described.

Results

Patient characteristics, toxicity and relapse data, and survival status are displayed in Tables 1 and 2. Sixteen patients were treated according to the following TBI dose escalation scheme: three patients (Nos 1-3) received a total TBI dose of 14.4 Gy. Three months later in the absence of acute TBI-related toxicity, the dose was escalated. The next five patients (Nos 12-16) received 15.3 Gy, and then the radiation dose was de-escalated for the last seven patients (Nos 4-11) to the 14.4 Gy dose level. Thus, 69% of patients were treated with 14.4 Gy, and 31% with 15.3 Gy.

Engraftment results

For the 15 patients receiving peripheral blood stem cells, the median times for neutrophil engraftment were 14 days (range, 11-21 days) and 12 days (range, 10-17 days) for the 14.4 Gy and 15.3 Gy cohorts, respectively. The respective median times for platelet engraftment were 15 days (range, 10-19 days) and 12 days (range, 11-12 days). However, only three patients were evaluable for platelet engraftment in the 15.3 Gy cohort; the fourth (No. 14) received bone marrow cells, and the fifth (No. 16) died on day +11. The single patient (No. 14) who received a bone marrow transplant had neutrophil and platelet engraftment on days 14 and 28, respectively.

Patient No. 16 achieved only neutrophil engraftment and died prior to platelet engraftment. Patient No. 4 engrafted her platelets but died prior to neutrophil engraftment. All surviving patients engrafted completely by day +30. Cytogenetic analyses of sex chromosomes or restriction fragment length polymorphism analyses were used to confirm donor cell engraftment.

Toxicity

Fifteen patients (94%) developed grade 3 or 4 mucositis requiring patient-controlled analgesia pumps for intravenous narcotics. The frequency and severity of mucositis did not differ from that which we had previously observed using 13.5 Gy. Of note, the last two patients (Nos 10 and 11) enrolled on the study had 50% transmission blocks used to reduce the radiation dose to the oral cavity and oropharynx. However, they both received 675 cGy electron boosts to their mandibles (see Materials and methods). Although patient No. 11 developed grade 3 mucositis, patient No. 10 developed only grade 2 mucositis.

Four cases of grade 4 pulmonary toxicity occurred for which mechanical ventilation was instituted (three patients (27%) in the 14.4 Gy cohort and one patient (20%) in the 15.3 Gy cohort). In each case, comorbid disorders were present that may have contributed to lung injury in addition to the irradiation. Patient No. 3 had an open lung biopsy (day +207) which revealed non-infectious interstitial pneumonitis and focal, severe bronchial epithelial atypia consistent with a post-chemotherapy effect. This patient had previously received bleomycin with the MOPP-ABV regimen for Hodgkin's disease as well as high-dose busulfan as part of an autologous peripheral blood stem cell transplant procedure. Patient No. 4 with primary refractory AML died with diffuse alveolar hemorrhage 15 days post transplant. Patient No. 6 developed CMV pneumonitis on day +135. He subsequently had an open lung biopsy performed that revealed organizing alveolar damage and possible eosinophilic pneumonia. Patient No. 15, who had received 15.3 Gy, had acute respiratory failure on day +143 that was consistent with acute respiratory distress syndrome (ARDS) and/or an aspergillus infection.

Of note, patient No. 12 developed ARDS approximately 40 days after a second allogeneic transplant for ALL that relapsed after this TBI/VP16 therapy. The preparative regimen for his second allogeneic transplant used busulfan and cyclophosphamide. He died 361 days after TBI/VP16 treatment and 131 days after relapse. The longest surviving patient (No. 2) developed grade 1 pulmonary toxicity from a non-infectious pneumonitis demonstrated by open lung biopsy on day +847. She also had extensive chronic GVHD. Her pulmonary function tests including diffusing capacity were within normal limits 1040 days post transplant.

Four cases of grade 4 hepatotoxicity occurred (three patients (27%) in the 14.4 Gy cohort and one patient (20%) in the 15.3 Gy cohort). Patient No. 4 developed grade 4 hyperbilirubinemia, likely secondary to cholestasis without other liver injury, from day +7 until she died from diffuse alveolar hemorrhage on day +15. Patients 8 and 9 had transient grade 4 hyperbilirubinemia (serum total bilirubin 6.5 mg/dl and 4.1 mg/dl, respectively) on day +9 due to cholestasis. In both cases, there was prompt spontaneous resolution of the hyperbilirubinemia without intervention. Patient No. 16, who had received 15.3 Gy, developed veno-occlusive disease (VOD) and sepsis with multiorgan failure and died on day +11.

One patient (No. 11) developed grade 3 cardiac toxicity on day +42. Her congestive heart failure was responsive to standard therapy with diuresis and resolved by day +100.

GVHD

In the 14.4 Gy cohort (see Table 1), two cases of mild and two cases of moderate acute GVHD involving the skin occurred. One patient (No. 6) had mild gastrointestinal GVHD and one patient (No. 3) had life-threatening gastrointestinal GVHD. In addition, one patient developed chronic GVHD limited to the mouth and one had more extensive chronic GVHD.

Among the patients treated with 15.3 Gy TBI (see Table 2), one patient (No. 13) initially had transient mild acute GVHD of the skin. This later recurred as extensive chronic GVHD of the skin and oral mucosa. One patient (No. 15) had grade 2 GVHD of the gastrointestinal tract. Patient 14 developed severe acute GVHD of the skin, liver and gastrointestinal tract only after his immunosuppressive therapy was abruptly discontinued on day +56 when residual leukemia was detected by cytogenetic analysis of his bone marrow. This patient subsequently achieved a CR. His immunosuppressive medications were restarted and his GVHD improved.

Outcomes

Tables 1 and 2 show relapse and survival data for each patient. Six patients had relapse of their disease: five (45%) in the 14.4 Gy cohort and one (20%) in the 15.3 Gy cohort. The relapses occurred from 84 to 582 days post BMT. This included five with ALL, and four of these had the t(9;22). One of these four (No. 12) eventually received a second allogeneic transplant from a different HLA-identical sibling donor on day +317 using busulfan and cyclophosphamide as the preparative regimen. Although he engrafted and subsequently had no further evidence of BCR/ABL transcripts by RT-PCR, he died with respiratory failure due to ARDS and pneumonia. Two others (Nos 7 and 10) had relapse of Ph+ ALL, were retreated with chemotherapy, and then received donor lymphocyte infusions. Both are currently in second CR and are cytogenetically normal.

In the 14.4 Gy TBI group, five durable CRs and one transplant-related death occurred in addition to the five relapses mentioned above. Seven patients who had had overt disease present prior to the transplant were in CR by day +30, and the eighth patient with overt disease in this cohort died on day +15 of TRM. In the 15.3 Gy TBI group, three CRs and one transplant-related death were observed in addition to the relapse mentioned above. Among the four patients in this cohort who had refractory disease prior to transplant, two had a CR by day +30 and a third achieved a CR after stopping immunosuppression; the fourth died of TRM on day +11.

Median survival for patients in the 14.4 Gy cohort was 226 days (range, 15->1050 days) and in the 15.3 Gy cohort was 201 days (range, 11->808 days). Only two of the 10 deaths occurred within the first 100 days, one in each cohort. Six (56%) patients treated with 14.4 Gy TBI have died: one had sepsis, one had diffuse alveolar hemorrhage and acute respiratory failure, three had relapsed leukemia, and one had acute respiratory failure with noninfectious interstitial pneumonitis. Four (80%) patients treated with 15.3 Gy TBI have died. One had early multiorgan failure, two had sepsis later while in CR, and one had progressive respiratory failure after a second allogeneic transplant for relapsed disease.

Discussion

High-energy radiation (10-24 MV) provides more homogeneous dosimetry than lower energy sources such as ⁶⁰Co or 4 MV photons when using an opposed lateral technique. As megavoltage energy increases, higher doses of radiation (6-11%) are delivered to the bone marrow by increased electron pair production and backscatter interactions in bone.²³ Modern dose-fractionation techniques and the use of megavoltage linear accelerators may now allow TBI to be given more safely and with potentially greater anti-tumor effect.^26,27

Although the optimal TBI-containing regimen for allogeneic stem cell transplantation may not yet be known, highly-fractionated TBI regimens (10-13 fractions) to total doses of 14-15 Gy appear to produce the greatest leukemia cell kill with minimum morbidity.^28,29 Investigators at the Fred Hutchinson Cancer Research Center in Seattle performed a TBI dose escalation study using ⁶⁰Co irradiation, given in twice daily fractions for total doses from 12 to 17 Gy.²¹ The maximum tolerated TBI dose was 16.0 Gy when given with cyclophosphamide at 120 mg/kg. However, of 36 patients, 56% relapsed. The primary dose limiting toxicity was pneumonitis, followed by veno-occlusive disease (VOD) of the liver, renal impairment and mucositis. Also, 39% of patients died from non-relapse causes. Only four patients survived disease free. The same group also demonstrated in randomized settings that increased total doses of irradiation with daily fractionation could reduce relapse rates in both AML and CML.^22,30,31 However, when the radiation dose was escalated to 15.75 Gy in seven fractions over 7 days for patients with CML or AML, they found an increase in toxicity and mortality from causes other than relapse. Therefore, overall survival was not improved in the patients who had received the higher total dose TBI regimen. In a recent update of these results, Clift and colleagues³¹ concluded that the difference in relapse incidence was not a consequence of delay in relapse events but of more effective elimination of the malignant clone. In addition, the increased non-relapse mortality associated with the higher doses of TBI was limited to the first 6 months after treatment.

Investigators from the City of Hope Hospital treated 33 patients with acute leukemia (none in first remission) with 13.2 Gy TBI and 60 mg/kg of etoposide.⁴ The relapse rate was 32%. Seven of 20 AML patients and eight of 13 ALL patients remained in continuous CR (45% overall). German investigators reported on 33 acute leukemia patients who received 12.0 Gy TBI and etoposide.¹⁰ Nineteen (57%) patients (11 with ALL and eight with AML) survived in continuous CR from 91+ to 1078+ days. The overall relapse rate was only 12%. Subsequent reports using TBI and etoposide in patients with advanced hematologic diseases have provided additional evidence of the efficacy of this particular regimen.³²

We have previously analyzed the outcomes of 103 patients treated at the University of Chicago with TBI at total doses of either 13.2 Gy in 11 fractions, 13.5 Gy in nine fractions, or 12.0 Gy in six fractions.^23,24 Patients were treated with 24 MV photons at a dose rate of 12 cGy/min. This energy source yields considerably higher energy radiation than ⁶⁰Co sources. No grade 3 or 4 toxicities (National Cancer Institute criteria) related to the TBI were identified in these patients. However, 30% of these patients later had relapse of leukemia.

In the current study, two cohorts of adult patients received escalated TBI doses (14.4 and 15.3 Gy) using high energy radiation (18-24 MV). The initial three patients treated with 14.4 Gy had no dose-limiting toxicities. All three engrafted, and all three were in CR by day +30. Thus, the next five patients were dose-escalated to 15.3 Gy. Although the acute transplant-related toxicities in this cohort were similar to those observed in the first three patients treated with 14.4 Gy, four of the five died within 12 months. Two patients died of sepsis while in CR on day +150 and day +210. The lack of improved survival caused us to de-escalate to the 14.4 Gy dose level for the subsequent patients enrolled on the trial. We were concerned that late complications, especially pulmonary compromise, might occur in these heavily pretreated patients if the radiation dose were increased further. We are now following the surviving patients with annual pulmonary function testing.

All of our patients had advanced disease or high-risk features. Of the five cases of grade 4 pulmonary toxicity, including one that occurred only after a second transplant, four were felt to be more likely secondary to other significant comorbid conditions and prior chemotherapy rather than to the acute effects of radiation therapy (see above). Of the four cases of grade 4 hepatic toxicity, three were due to isolated cholestasis and two of these had rapid spontaneous resolution. These also were not felt to be radiation therapy-related but rather due to other significant comorbid conditions. No radiation-related nephrotoxicity was observed. One patient with diabetes developed cataracts. Two patients developed mild unilateral neuropathy 2 years post BMT. Therapy-related grade 3 and 4 mucositis occurred in all but one patient. Although painful, this was transient for most patients and resolved promptly when engraftment occurred. The mucositis was no worse than that we have observed using 13.5 Gy. Notably, we observed no apparent differences in the acute regimen-related toxicities or severity of GVHD between these two cohorts or the 103 patients treated with 12-13.5 Gy.

Relapse rates were 45% and 20% for the 14.4 Gy and 15.3 Gy cohorts, respectively. However, too few patients were treated to allow any meaningful conclusions regarding a significant reduction in relapse rates. All patients had advanced stage refractory hematologic malignancies. Four of the six patients who relapsed on this study had particularly poor-risk ALL (ie Philadelphia chromosome positive). The relative antitumor efficacy of this preparative regimen is uncertain due to the considerable amount of patient heterogeneity in this study. However, nine of the 12 patients who underwent TBI/VP16 and transplantation when they still had overt refractory disease achieved a CR by day +30, the 10th achieved a CR after discontinuing immunosuppression, and the remaining two patients died early.

We conclude that 14.4 Gy TBI, given in nine fractions with 18-24 MV linear accelerators, can be given in combination with high-dose etoposide prior to allogeneic stem cell transplantation. Although the morbidity and mortality were high in both the 14.4 Gy and the 15.3 Gy TBI cohorts among the advanced disease patients that we treated, the regimen-related toxicities appear similar to those reported among better-risk patients treated with 13.5 Gy TBI. We are continuing to treat patients with 14.4 Gy TBI plus high-dose etoposide, and we are following these patients for late complications, especially pulmonary or renal insufficiency. Selection of patients with fewer comorbid conditions and earlier stage disease should allow us to evaluate this high-energy TBI regimen more precisely.

Acknowledgements

This research was supported in part by grants from the National Institutes of Health (CA-14599, CA-70937 and CA-58506), Bethesda, Maryland. We thank Beth Weseman, RN and Collen Tazic, RN for their expert nursing and Melissa Ellifson for data management.

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Table 1  Clinical characteristics and outcomes for 11 patients who received 14.4 Gy total TBI dose

Table 2  Clinical characteristics and outcomes for five patients who received 15.3 Gy total TBI dose