Imatinib has become standard therapy for all phases of chronic myeloid leukemia (CML). However, data generated by monitoring several thousands of patients worldwide suggest that although imatinib is highly active against the differentiated mass of CML cells, it probably fails to eradicate all residual leukemia cells, even in the best responders. This is supported by several lines of evidence: (i) despite the fact that more than 80% of previously untreated patients achieve a complete cytogenetic remission (CCgR), only a minority of patients remain durably negative when tested by real-time quantitative polymerase chain reaction (RT-PCR) for BCR-ABL transcripts (1); (ii) even patients treated with imatinib who achieve a complete molecular response (CMolR) usually return to Philadelphia (Ph)-positivity if the drug is stopped (2); and (iii) studies performed in vitro suggest that primitive Ph-positive progenitors or stem cells are relatively insensitive to imatinib (3) and the persistence of BCR-ABL-positive precursors in complete cytogenetic response (CCyR) patients, despite continued imatinib therapy, has been recently documented (4). At least theoretically, any amount of residual disease under imatinib treatment could provide the basis for the emergence of Ph-positive sub-clones bearing mutations in the BCR-ABL kinase domain, which are associated with various degrees of resistance to this agent (5). For all these reasons recent CML guidelines recommend that alternative strategies should be considered in early chronic phase (CP) patients with suboptimal response or failure to adequate imatinib (6). Less straightforward is the management of residual “molecular” disease found in a great majority of patients. At present, these patients usually continue to receive standard doses of imatinib, and their response is monitored by RT-PCR and cytogenetics. Although we do not yet know the impact on survival of such minimal residual disease (MRD) (7), it appears prudent to develop specific additional therapies that could complete the excellent work of imatinib. The ultimate and ambitious aim of a supplementary treatment would be the attainment of a “true cure” of CML (eradication of all leukemia cells) instead of an “operational cure” (persistence of minimal amount of leukemia cells), which may be achieved with imatinib alone. One such strategy is to exploit the fact that CML is a disease known to be susceptible to immune attack. The most striking proof of this is the fact that until now, a “cure” (defined as continuous negativity for BCR-ABL by PCR) for CML patients is probably achieved only by the graft-versus-leukemia (GvL) effect following allogeneic stem cell transplantation or donor lymphocytes infusion (8), although it remains formally unproven that undetectability of BCR-ABL is equivalent to eradication of the malignant clone. Although the GvL effect is to a great extent due to major and minor HLA mismatches between donors and recipients, some experimental data suggest that CML-specific donor T lymphocytes could be the key to long-term control or even eradication of residual leukemia cells (9). Additionally, the activity of interferon-α (IFN-α), a biological modifier widely used for CML in the pre-imatinib era, could be partly due to an immune-mediated effect, and a possible role of this agent in the context of MRD surviving imatinib will be discussed. CML offers a unique opportunity to test the efficacy and feasibility of immunotherapeutic strategies, as currently most patients achieve very pronounced responses furnishing an ideal situation for immunotherapy in a disease known to be responsive in principle to immune attack. Immunotherapy approaches currently under evaluation include active specific immunotherapies (vaccines) and nonspecific immunotherapies [IFN-α, interleukin-2 (IL-2), granulocyte-macrophage colony stimulating factor (GM-CSF), and other immunostimulators].

Bocchia, M., Lauria, F. (2006). Immunotherapy in Chronic Myeloid Leukemia. In CHRONIC MYELOGENOUS LEUKEMIA. INFORMA HEALTHCARE [10.3109/9780849379567.008].

Immunotherapy in Chronic Myeloid Leukemia

BOCCHIA M.;
2006-01-01

Abstract

Imatinib has become standard therapy for all phases of chronic myeloid leukemia (CML). However, data generated by monitoring several thousands of patients worldwide suggest that although imatinib is highly active against the differentiated mass of CML cells, it probably fails to eradicate all residual leukemia cells, even in the best responders. This is supported by several lines of evidence: (i) despite the fact that more than 80% of previously untreated patients achieve a complete cytogenetic remission (CCgR), only a minority of patients remain durably negative when tested by real-time quantitative polymerase chain reaction (RT-PCR) for BCR-ABL transcripts (1); (ii) even patients treated with imatinib who achieve a complete molecular response (CMolR) usually return to Philadelphia (Ph)-positivity if the drug is stopped (2); and (iii) studies performed in vitro suggest that primitive Ph-positive progenitors or stem cells are relatively insensitive to imatinib (3) and the persistence of BCR-ABL-positive precursors in complete cytogenetic response (CCyR) patients, despite continued imatinib therapy, has been recently documented (4). At least theoretically, any amount of residual disease under imatinib treatment could provide the basis for the emergence of Ph-positive sub-clones bearing mutations in the BCR-ABL kinase domain, which are associated with various degrees of resistance to this agent (5). For all these reasons recent CML guidelines recommend that alternative strategies should be considered in early chronic phase (CP) patients with suboptimal response or failure to adequate imatinib (6). Less straightforward is the management of residual “molecular” disease found in a great majority of patients. At present, these patients usually continue to receive standard doses of imatinib, and their response is monitored by RT-PCR and cytogenetics. Although we do not yet know the impact on survival of such minimal residual disease (MRD) (7), it appears prudent to develop specific additional therapies that could complete the excellent work of imatinib. The ultimate and ambitious aim of a supplementary treatment would be the attainment of a “true cure” of CML (eradication of all leukemia cells) instead of an “operational cure” (persistence of minimal amount of leukemia cells), which may be achieved with imatinib alone. One such strategy is to exploit the fact that CML is a disease known to be susceptible to immune attack. The most striking proof of this is the fact that until now, a “cure” (defined as continuous negativity for BCR-ABL by PCR) for CML patients is probably achieved only by the graft-versus-leukemia (GvL) effect following allogeneic stem cell transplantation or donor lymphocytes infusion (8), although it remains formally unproven that undetectability of BCR-ABL is equivalent to eradication of the malignant clone. Although the GvL effect is to a great extent due to major and minor HLA mismatches between donors and recipients, some experimental data suggest that CML-specific donor T lymphocytes could be the key to long-term control or even eradication of residual leukemia cells (9). Additionally, the activity of interferon-α (IFN-α), a biological modifier widely used for CML in the pre-imatinib era, could be partly due to an immune-mediated effect, and a possible role of this agent in the context of MRD surviving imatinib will be discussed. CML offers a unique opportunity to test the efficacy and feasibility of immunotherapeutic strategies, as currently most patients achieve very pronounced responses furnishing an ideal situation for immunotherapy in a disease known to be responsive in principle to immune attack. Immunotherapy approaches currently under evaluation include active specific immunotherapies (vaccines) and nonspecific immunotherapies [IFN-α, interleukin-2 (IL-2), granulocyte-macrophage colony stimulating factor (GM-CSF), and other immunostimulators].
2006
Bocchia, M., Lauria, F. (2006). Immunotherapy in Chronic Myeloid Leukemia. In CHRONIC MYELOGENOUS LEUKEMIA. INFORMA HEALTHCARE [10.3109/9780849379567.008].
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/14813
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo