Allogeneic hematopoietic stem cell transplantation following donor CIK cell infusion: A phase I study in patients with relapsed/refractory hematologic malignancies

Acute Myeloid leukemia

Acute Myeloid leukemia

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Summary

This study aimed to explore the feasibility and safety of allogeneic hematopoietic stem cell transplantation (HSCT) following infusion of donor cytokine-induced killer (CIK) cells on Patients with relapsed/refractory hematologic malignancies. The findings suggest, allogeneic HSCT combined with sequential infusion of donor CIK cells is well tolerated in salvage relapsed/refractory hematologic malignancy patients.

Patients characteristics

The patients enrolled in this prospective trial were diagnosed with AML (n = 3), second acute myeloid leukemia (s-AML) (n = 1); non-Hodgkin lymphoma (NHL) (n = 4); acute lymphocytic leukemia (ALL) (n = 2); multiple myeloma (MM) (n = 2), and chronic myeloid leukemia (CML-BP) (n = 3).

Methodology

Conditioning regimen
Of the 15 enrolled patients, 11 received treatment with the fludarabine, busulfan, and cyclophosphamide regimen (F-Bu-Cy) prior to transplantation. Cyclophosphamide (50 mg/kg/day) was administered on the third and second days before transplantation. Busulfan (4 mg/kg/day) was administered orally on the sixth to fourth days before transplantation. Fludarabine (30 mg/m2 /day) before transplantation was administered by intravenous drip on the ninth to sixth days before transplantation. One patient received the same regimen excluding busulfan. The ALL and NHL patients additionally received 200 mg/m2 /day of lomustine by intravenous drip two days prior to transplantation. Two patients with MM also received 140mg/m2/day of melphalan by intravenous drip on days three and two prior to transplantation and 25 mg/m2 /day fludarabine by intravenous drip on days 8–4 prior to transplantation.
CIK cell preparation
CIK cells were generated from donor PMNCs. 80 mL of mononuclear cells was collected from each donor (who donate stem cells) sample using a blood cell separator. Lymphocytes were separated using lymphocyte separation medium and either cryopreserved or cultured in RPMI1640 medium containing 10% autologous plasma (culture medium). After 4–6 hours, the suspended cells were centrifuged and resuspended at 1 × 106 /mL in culture medium containing IFN-ý (1000 U/mL) and incubated at 37 ◦ C in 5% CO2 . After 24 hours, the medium was replaced with CIK medium (culture medium containing 100 mg/mL of mouse anti human CD3 monoclonal antibody and 1000 U/mL IL -2). The medium was replaced by the fresh medium every 3 days, and after 10–14 days of in vitro stimulation the CIK cells were harvested and used for infusion. After the 10–14-days culture period, cells were expanded to 1 × 108 – 109 /kg.

Treatment

At the first infusion, patients received 1×106 cells/kg and this number was adjusted in subsequent infusions according to the patient’s status. Patients first received an infusion on days +30, +60, and +90. Thereafter, if disease did not recur or if GVHD did not occur, tha patients received CIK every 3 months.

Results

Stem cell transplant, engraftment and chimerism
All 15 patients exhibited hematopoietic reconstitution. White blood cell levels were recovered to 0.5×109/L between days 8 and 15 (average day 11), and platelet levels were recovered to 20×109/L between days 11 and 18 (average day 14). Twelve patients exhibited complete chimerism (donor short tandem repeat >95%), while three patients had mixed chimerism.
(Graft-versus-host-disease) GvHD, CIK cell infusion and side effects
After transplantation, eight patients presented with aGvHD but all experienced reduction of symptoms after treatment with 1mg/kg of methylprednisolone. A total of 50 infusions was performed in 15 patients. After infusion, one patient exhibited grade I GvHD and another patient exhibited grade III GvHD. In two patients, GvHD was controlled by administration of immunosuppressive drugs methylprednisolone and MMF.
Toxicity
All patients developed grade IV neutropenia (absolute neutrophil count <0.5 g/L) within the transplant phase. Three patients experienced CMV infection, four patients had urinary tract infections, three had digestive tract infection, and four patients developed pneumonia and stomatitis.
Disease responses and outcomes
Four patients died within 100days of transplantation. Death within 100 days was caused by relapse and bleeding (n = 1), multiple organ dysfunction syndrome with inflammation (n = 1), acute respiratory distress syndrome with sepsis (n = 1), and Guillain- Barre syndrome (n = 1). Five patients died after day +100, all due to relapse. The median follow-up of the remaining six patients was 1513 days (range, 771–1655 days), at which point they were all alive, but two surviving patients have cGvHD. Historical controls (patients that did not receive CIK infusion or receive CIK after recurrence after transplantation) may suggest that CIK infusion could lead to better survival. Among these 13 controls, only four were still alive after a median of 840 days (range, 570–1590).

Conclusion

In conclusion, our results suggest that sequential infusion of donor-derived CIK cells in the post-transplant setting is feasible and tolerable, supporting the use of donor CIK cells as prophylaxis after transplantation in a variety of hematological malignancies.

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Scientific article publishing date :6/23/2016

Immucura identifier BSC21_225EN

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