We read with interest the article of Gopal et al1  on the use of high-dose radioimmunotherapy in relapsed follicular lymphoma. Here, we report on our experience using a rhenium 186 (186Re)-radiolabeled chimeric anti-CD20 antibody (rituximab). We chose 186Re as treatment isotope because of its favorable physical properties (3.7 d half-life; 1070 keV β-energy; 9.5% 137 keV γ-radiation). The γ-radiation enables intratherapeutic imaging and dosimetry. Furthermore, a stable antibody-labeling technique had been developed for both 186Re and 99 metastable (99m) technetium (99mTc).2,3 186Re was generated by neutron irradiation of 185Re in the high-flux position of the University of Missouri Research Reactor.

We treated 4 patients with refractory or relapsed diffuse large B-cell lymphoma (DLBCL; n = 2), mantle cell lymphoma (MCL; n = 1), and follicular lymphoma (n = 1) (Table 1). To determine antibody uptake in the tumor and to measure blood kinetics, an imaging study with 1.5 to 2 GBq 99mTc-labeled antibody (10-20 mg) was performed. The blood radioactivity curve was fitted biexponentially. While the initial decrease reflected spleen uptake, the second phase matched early kinetics and distribution if predosing was applied as done for treatment. Dose of radioactivity for treatment in order to obtain a blood dose of 25 Gy (n = 3) and 30 Gy (n = 1), respectively, was calculated from the blood kinetics of the test application and the physical half-life of 186Re. Total antibody dose was 3 mg/kg. A dose of 1.5 to 2 mg was given unlabeled one hour before the Re-antibody infusion. The patients received a total blood dose of 24 to 26 Gy (n = 3) and 38 Gy (n = 1). When residual bone marrow dose was less than 0.3 Gy, the patients' stem cells (2.92 × 106 CD34+ cells/kg body weight [range, 1.78-4.42 × 106 CD34+ cells/kg body weight]) were reinfused (d 8-13 after treatment). All patients experienced myeloablation. Time to neutrophil counts of at least 0.5 × 109/L was 10 days (range, 9-11 days) after transplantation, and time to platelet counts of at least 25 × 109/L was 12 days (range, 11-14 days) after transplantation. Neutropenia lasted 17 days (range, 11-22 days) and thrombocytopenia 16.5 days (range, 10-24 days). Toxicity was limited, with no grade III or grade IV nonhematologic toxicity according to a modified Bearman scale.4  Grade II infection was seen in 2 patients. We observed no treatment-associated mortality.

Table 1.

Patient characteristics


Patient no.

Sex

Age, y

Histologic type

Stage

Extranodal involvement

LDH elevation

No. prior chemotherapy regimens

Prior high-dose therapy

Response to last therapy

Bulky disease

Outcome after RIT

Duration of response, mos.
1   F   57   DLBCL   IV   Yes   No   4   Yes   No   No   CR   42  
2   M   63   MCL   III   Yes   No   4   Yes   Yes   No   CR*  7  
3   F   64   FL   IV   Yes   Yes   5   No   Yes   No   PD   —  
4
 
M
 
25
 
DLBCL
 
II
 
Yes
 
Yes
 
5
 
Yes
 
No
 
Yes
 
MR
 
2
 

Patient no.

Sex

Age, y

Histologic type

Stage

Extranodal involvement

LDH elevation

No. prior chemotherapy regimens

Prior high-dose therapy

Response to last therapy

Bulky disease

Outcome after RIT

Duration of response, mos.
1   F   57   DLBCL   IV   Yes   No   4   Yes   No   No   CR   42  
2   M   63   MCL   III   Yes   No   4   Yes   Yes   No   CR*  7  
3   F   64   FL   IV   Yes   Yes   5   No   Yes   No   PD   —  
4
 
M
 
25
 
DLBCL
 
II
 
Yes
 
Yes
 
5
 
Yes
 
No
 
Yes
 
MR
 
2
 

Bulky disease indicates largest tumor manifestation greater than or equal to 10 cm; RIT, radioimmunotherapy; DLBCL, diffuse large B-cell lymphoma; CR, complete remission; MCL, mantle cell lymphoma; FL, follicular lymphoma; PD, progressive disease; —, not applicable (patient did not experience any remission); and MR, mixed response.

*

SD was documented initially after RIT and CR was achieved after additional chemotherapy.

Two patients with DLBCL received radioimmunotherapy: a 57-year-old woman (no. 1) with refractory disease who had undergone prior high-dose chemotherapy achieved a complete remission that lasted for 42 months; and a 25-year-old male patient (no. 4) with refractory disease achieved mixed response. Patient no. 2 with MCL showed stable disease (SD) initially after radioimmunotherapy. Thus, he received additional chemotherapy. The patient experienced a protracted remission and finally achieved a complete remission (CR) with a duration of 7 months. Patient no. 3, who had follicular non-Hodgkin lymphoma (NHL), did not show a response.

Thus, high-dose radioimmunotherapy with 186Re followed by autologous peripheral blood stem cell transplantation (PBSCT) seems to be a feasible therapeutic option even in extensively pretreated patients with relapsed non-Hodgkin lymphoma.5  Patients achieving CR had a low tumor burden with a lactic dehydrogenase (LDH) level in the normal range. This finding is in accordance with a larger series reported previously.6 

1
Gopal AK, Gooley TA, Maloney DG, et al. High-dose radioimmunotherapy versus conventional high-dose therapy and autologous hematopoietic stem cell transplantation for relapsed follicular non-Hodgkin lymphoma: a multivariable cohort analysis.
Blood
.
2003
;
102
:
2351
-2357.
2
Kasina S, Rao TN, Srinivasan A, et al. Development and biologic evaluation of a kit for preformed chelate technetium-99m radiolabeling of an antibody Fab fragment using a diamide dimercaptide chelating agent.
J Nucl Med
.
1991
;
32
:
1445
-1451.
3
Breitz HB, Weiden PL, Vanderheyden JL, et al. Clinical experience with rhenium-186-labeled monoclonal antibodies for radioimmunotherapy: results of phase I trials.
J Nucl Med
.
1992
;
33
:
1099
-1109.
4
Press OW, Eary JF, Gooley T, et al. A phase I/II trial of iodine-131-tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas.
Blood
.
2000
;
96
:
2934
-2942.
5
Juweid ME. Radioimmunotherapy of B-cell non-Hodgkin's lymphoma: from clinical trials to clinical practice.
J Nucl Med
.
2002
;
43
:
1507
-1529.
6
Kaminski MS, Estes J, Zasadny KR, et al. Radioimmunotherapy with 131I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience.
Blood
.
2000
;
96
:
1259
-1266.