The perceived role of RIT in SCT was to deliver a myeloablative dose to the patient thereby eliminating residual NHL and marrow reconstitution by stem cell rescue. RIT is able to deliver radiation directly at the tumor site unlike Total Body Irradiation (TBI) which delivers same dose of radiation to all organs of the body at a significant cost in terms of side effects. Several studies were undertaken to evaluate the feasibility of adding RIT to chemo and whether that mechanism may be as effective with fewer side effects as compared with TBI. An additional advantage with I131
T was that its bio-distribution, metabolism and half-life differed significantly among patients. These parameters can be reliably measured and exploited to provide patient specific (individualized) dosing to accentuate therapeutic effect against the cancer cell [30
]. Pertinent trials involving RIT and stem cell transplant are listed on .
clinical trials utilizing RIT in peri-transplant setting
A phase I/II study by Nademanee et al [31
] studied the use of Y90
I in conditioning for autologous stem cell transplant when combined with high-dose etoposide (VP-16) 40 to 60 mg/kg (day -4) and cyclophosphamide 100 mg/kg (day -2). Patients received dosimetry on day -21 followed one week later with Y90
I. Day -7 bone marrow was conducted to estimate delivery of radiation; patients were redosed if total irradiation was deemed to be less than 5 cGy. The study group included 31 patients who had a median of 2 previous lines of therapy with histology notable for FL (n
= 12), DLBCL (n
= 14), and MCL (n
= 5). Following stem cell infusion, the median time to neutrophil and platelet recovery were 10 and 12 days respectively. The major Grade 3-4 toxicities were most notably Infection 74% and mucositis 34%. The estimated two year OS and relapse free survival (RFS) were 92% (95% CI, 82%-100%), and 78% (95% CI, 61%-96%) respectively. The best survival was noted in patients with FL histology (100% 2 year OS/RFS).
A recent phase II study by Kang et al [32
] studied the use of Y90
I when combined with intravenous busulfan, cyclophosphamide, and etoposide (Bu/Cy/E) followed by auto-SCT in patients with relapsed/refractory B-cell lymphoma. The majority of patients in this population had DLBCL (n
= 14), with FL and MCL (n
= 2). The regimen involved giving rituximab 250 mg/m2
on day -21 with Y90
I on day -14 at dose of 0.4 mCi/kg followed by busulfan (IV, 0.8 mg/kg every 6 h from day -7 to day -5), Cyclophosphamide (IV, 50 mg/kg on days -3 and -2), and etoposide (IV, 200 mg/m2 every 12 h on days - 5 and -4). The major non-hematologic toxicities observed were Grade 3 diarrhea and nausea in 15.8% with no Grade 4 toxicities. At a median follow up of 29.4 months, 12 patients (63.2%) had relapsed with 8 deaths. The estimated 3- year OS and EFS rates were 52.6% and 26.3% respectively.
Krishnan et al [33
] conducted a study of Y90
I in combination with high dose chemotherapy and stem cell rescue using carmustine, cytarabine, etoposide and melphalan (BEAM). Eligible patients had CD20 positive refractory FL, poor risk MCL (requiring two or more regimens to achieve PR or CR), DLBCL (represented half of the population) or transformed DLBCL. Stem cells were collected and they were treated in the outpatient setting with the dose of Y90
I capped at 40mCi. Y90
I was administered on day -14 and the protocol for auto-SCT was initiated on day - 7. Disease status was evaluated at days 30, 100, 180 post-transplant. The two year OS was 87.9% (95% CI 68.8 - 96.9). Elderly patients benefited from treatment and therapy was safely administered in the outpatient setting.
Another study by Shimoni et al [34
], evaluated the role of Y90
I in conjunction with BEAM. These patients were similar to the previous with two year OS 67% (95% CI 46 - 87%) and PFS 52% (95% CI 31 - 72%). This study confirms that Y90
I can be safely combined with conditioning regimen prior to SCT.
The response of elderly patients to conditioning with RIT was studied by Gopal et al. [39
]. This study examined 24 patients with DLBCL (n
= 9), MCL (n
= 7) and FL (n
= 8) with a median age of 64 who were treated with an I131
T infusion only. Patients received dosimetric infusion on day -24 followed by therapeutic infusion on day -14 (median, 19.4 Gbq [525 mCi]; range, 12.1 to 42.7 Gbq [328 to 1,154 mCi]) to deliver 25 to 27 Gy. At a median follow-up of 29 months the OS and PFS were 59% (CI 95%, 37 - 80%) and 51% (CI 95%, 30 - 72%) respectively. Patients with DLBCL had inferior OS amongst the groups, whilst MCL had poor PFS.
Press et al conducted [36
] a phase I/II study evaluating maximum tolerated dose (MTD) of I131
T in combination with etoposide and cyclophosphamide among 55 patients. Patients were evaluated at months 1, 3, 6, and 12, and annually thereafter. All patients developed expected grade 4 neutropenia and the median duration of recovery (ANC > 500) was 10 days for peripheral blood and 13.5 days for bone marrow harvest. Platelet engraftment occurred at 13 days for peripheral blood and 23 days for patients who received bone marrow harvest. The maximum tolerated dose was achieved at dose level of 25Gy I131
T, Etoposide 60 mg/kg and cyclophosphamide 100 mg/kg). Multivariate analysis showed that PFS and OS were superior in the I131
T treated group; however it was difficult to interpret due to the histologic differences between groups.
Fewer studies established the role of RIT in the setting of allogeneic stem cell transplantation (allo-SCT). The study by Bethge et al [37
] was designed to evaluate the feasibility of adding RIT to allo-SCT. The primary objective of this study was to evaluate the feasibility and assess treatment related toxicities. A recent study by Gopal et al [38
] examined the use of RIT in conditioning for a non-myeloablative allo-SCT. As in previous studies, patients received dosimetry on day -21 prior to dosing on day -14 with 250 mg/m2
of rituximab before the therapy dose of 0.4 mCi/kg of Y90
I, with a maximum dose of 32 mCi. Fludarabine 30 mg/m2
was delivered on day -7 to -5 with 2 Gy TBI on day 0. The treatment regimen revealed the expected myelosuppressive side effect profile with time to neutrophil > 500/μL was 17 days (range, 0-34 days) and platelets > 50 000/μL was 11 days (range, 0-147 days). At median follow-up of 1.7 years, the estimated 2 years OS and PFS were 54% (95% confidence interval [CI], 37%-68%) and 31% (95% CI, 16%- 48%), respectively. Notably, univariate analysis revealed that patients with indolent histologies had better OS and PFS when compared with aggressive histology (p <0.01).
The application of RIT in SCT offers the advantage of eradication of minimal residual disease and possibly even disease control until the effect of Graft versus lymphoma takes effect.