Risk Adapted Therapy In Hematology and Hemato-Oncology

These are times of evidence based and risk adapted treatment approach in every segment of medicine. There has been gradual evolution in diagnostics and therapeutic strategies over past decades to come to this era of risk adapted approach to treatment. With advances in diagnostics, we are now able to have a better classification and risk stratification of various hematological malignancies. Similarly, treatment strategies have evolved in such a way that now we treat some good risk patients with less intensified approach to minimize toxicities while maintaining efficacy of the treatment regimes and intensifying the treatment in only those with high risk disease.

Treatment of aggressive lymphomas: Commonest example of aggressive lymphoma is diffuse large B cell lymphoma (DLBCL) and high grade B cell lymphoma (HGBCL). Currently DLBCL is further classified into several subcategories based on its gene expression profile or immune-histochemical patterns which are surrogate to molecular features. These subclasses are germinal centre type (DLBCL-GC) which is considered a good prognostic class compared to other one, the activated B cell (DLBCL-ABC) type which has got a poorer prognosis.

Another advance in the management of DLBCL and High grade B cell lymphomas is identification of re-arrangement of cMyc and BCL2/BCL6 genes detectable by Fluorescent in-situ hybridization (FISH) technique. Based on cMyc and BCL2/BCL6 gene rearrangements, DLBCL and high grade B cell lymphoma can be classified into double hit/ triple hit lymphoma (DHL/THL) and non double hit lymphoma. Double hit/ triple hit lymphomas are highly aggressive and are associated with poorer prognosis. Therapy is usually intensified in such patients to achieve better results.

High grade T cell lymphomas (except lymphoblastic lymphoma which is treated with ALL like therapy) are also treated with intensive chemotherapy and Autologous bone marrow/ hematopoietic stem cell transplantation in selected patients with high risk features.

This way, it is very much needed these days to identify high risk features by molecular testing. Intensification of therapy is warranted in selected patients with high risk features to achieve outcomes comparable to good risk patients while less intensified treatment approach is maintained for those with good risk disease to minimize toxicities while maintaining good outcomes.

Treatment of Multiple Myeloma: Multiple myeloma is also called Myeloma. Myeloma was once considered a deadly and incurable disease and was usually treated with cytotoxic chemotherapies. Over past two decades, there has been development of many anti-myeloma drugs with specificity for myeloma cells (malignant plasma cells) and lesser cytotoxicity to normal tissues. These drugs are Proteasome inhibitors like Bortezomib, Carfilzomib and Ixazomib and Immuno-modulators with anti-angiogeneic properties like Thalidomide, Lenalidomide and Pomalidomide most of which are available for Indian patients very easily and at affordable cost. Apart from these two major classes of drugs, now we have certain targeted therapies- immunotherapies like anti CD 38 monoclonal antibody (Daratumumab, Isatuximab), Anti SLAM F7 antibody (Elotuzumab) and anti BCMA antibody (Balantamab). Moreover, CAR-T cell therapy is promising and is in developmental phase in India. With cytotoxic therapies of past, complete remissions were uncommon and would be to the range of 30% even after an Autologous Bone Marrow Transplantation and an early relapse in majority of patients. But nowadays, with wide availability of novel agents, we are able to achieve complete remission and even deeper remissions in a significant majority of patients and that can be further improved with an Autologous Bone Marrow Transplantation and further maintenance therapy. Apart from expansion of this therapeutic armamentarium, there has been progress in understanding of cytogenetic and molecular patterns of myeloma and its prognostic and therapeutic implications. Now a day, FISH technique is widely available to identify cytogenetics aberrations specific to myeloma and we can identify high risk myeloma (for example, those with 17p [p53] deletion, 1q gain and others like t4:14, t14:16) with help of FISH. Taking together the clinical features and cytogenetic abnormalities, we can design treatment in such a way to achieve better results in even those with very high risk myeloma.

Acute leukemias: acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are most aggressive and deadly of hematological malignancies. Both AML and ALL are heterogenous diseases and varied widely in prognosis depending on cytogenetic and molecular profile. So, there are AML which are classified as good risk or standard risk (examples- AML with t8:21, inv16, normal karyotype with NPM1 mutated without FLT3 mutation or AML with normal karyotype with CEBPA double mutated) while others as high risk AML (examples- AML with complex karyotype or monosomal karyotype, t v:11q, monosomy 7/-7q, monosomy 5/5q-, AML with FLT3-ITD etc). Similarly, prognosis of ALL too depends upon several clinical and cytological factors. There are patients with good risk ALL (example- young age, lower WBC counts at presentation, hyperdiploid karyotype) while others with high risk ALL (example- advancing age, higher WBC counts at initial presentation, cytogenetic/ molecular features like t9:22/ BCR-ABL or t4:11/AF4:MLL). Patients with high risk leukemias not only show resistance to chemotherapy but also have a higher probability of relapse early in the course. Patients with good/ standard risk leukemias are usually treated with chemotherapy alone while patients with higher risk leukemias are usually offered chemotherapy to achieve initial disease control and then Allogeneic bone marrow transplantation as a consolidative therapy to minimize risk of relapse. We can use targeted drugs along with chemotherapies in patients having specific molecular aberration. For example, patient of ALL with BCR-ABL fusion are high risk and are treated with chemotherapy along with targeted drug (Imatinib/ Dasatinib which targets BCR-ABL gene) and this way achieve deeper remissions and better outcome. Similarly, FLT3 mutation (FLT3 ITD) confer chemo resistance in AML and nowadays is treated with targeted drug (Midostaurin/ Sorafenib) along with chemotherapy to achieve better outcome.

Bone marrow/ hematopoietic stem cell transplantation (BMT): A BMT is recommended for patients having bone marrow failure syndrome or with high risk hematological malignancies at high risk of relapse. There have been immense progresses in field of BMT over past decades. Several notable advances are matched unrelated donor transplants, haplo-identical transplants, non-myeloablative and reduced intensity transplants. This way, most of patients in need of a BMT can be taken including those with advancing age or those not having a suitable HLA matched stem cell donor in family.

So in nutshell, we have come a long way to this era where we have sophisticated methods to dissect cytogenetic and molecular details of hematological malignancies, plan therapy as per risk stratification and use targeted therapies and bone marrow transplantation to get optimal outcome.

Dr. Narendra Agrawal
Sr. Consultant, Department of Hemato-Oncology