JAPI•VOL. 52•MAY 2004www.japi.org411
Introduced in 1970s, allogeneic stem cell transplant (ASCT)has established itself as the only curative option as far as thetreatment of CML is concerned. The procedure entailseradicating the host marrow and suppressing the hostimmunity with supra doses of chemotherapy (preparatoryregimen) followed by infusion of donor stem cells which willtake over the function of myelopoiesis and immunereconstitution. Eradication of leukemia depends to a largedegree on donor lymphocyte mediated graft versus leukemia(GVL) effect. The efforts are on to decrease the intensity of preparatory regimen and to rely more on GVL effect for curingCML (reduced intensity or mini transplant or non-myeloablative transplant). This hopefully will decrease thetreatment-related mortality (TRM) and thereby increasing thesurvival. With conventional transplant, in chronic phase,projected 5 years survival ranges between 50-60%. Relapsesoccur in approximately 15-30% cases and are commonly seenwith in the first 5 years. Procedure-related mortality is around10-40%.
Transplant performed in blast phase is unsatisfactorywith survival less than 10%. Intermediate survival of 25-35%is reported for ASCT in accelerated phase. Increased relapserate and increased TRM accompany ASCT in transformedphases.Outcome following ASCT not only depends on the phaseof disease but a host of other factors are also important.1.
: Patients have a continuous and inverse relationshipbetween age and survival. Older patients do worsemainly because of an increased TRM; relapse rates arealmost similar. In IBMTR (international bone marrowtransplant registry) data, patients above 50 years hadsurvival of 30% as compared to younger patients in whomsurvival of 60-70% is expected.2.
Timing of transplant
: As the disease progresses theoutcome of transplant worsens. Hence ASCT is performedwithin 1-2 years of diagnosis of CML.3.
: Patients treated with Busulfanbefore ASCT have worse outcome. Prior therapy withhydroxyurea or interferon does not appear to affectoutcome.
: Conventional ASCT usescyclophosphamide with busulfan or total body irradiationas conditioning regimen. With the recognition of importance of GVL effect, a number of centres haveattempted to use reduced intensity regimen. Howeverthere is disagreement to what constitutes reducedintensity regimen. Various combinations that have beentried are cyclophosphamide and fludarabine with orwithout antithymocyte globulin and fludarabine withmelphalan.5.
GVHD (graft versus host disease) prophylaxis
: DonorT-lymphocytes mediated reaction in host generalmanifests as diarrhea, elevated liver enzymes, fever andcutaneous changes. Acute GVHD
seen in first 100 daysoccurs in 8-63% and causes death in around 13% cases.Chronic GVHD (after 100 days) is seen in upto 75% caseswith a mortality of upto 10%.
Methotrexate andcyclosporine is commonly used for GVHD prophylaxis.With reduced intensity conditioning regimens choice of GVHD prophylaxis has been cyclosporine alone.Attempts to decrease intensity of GVHD have beenfraught with increased treatment failure. Anotherapproach to abrogate GVHD is to use T lymphocytedepleted allogeneic marrow, but it increases risk of non-engraftment, risk of relapse and delays immunereconstitution.
6.Relatedness of donor: With scarcity of HLA matchedsibling donor attempts have been made to use HLAmatched transplant from unrelated donors (MURD). Butthese grafts are associated with increased TRM andmorbidity. Graft failure, severe and extreme acute andchronic GVHD contributes to it. Matching at HLA DR81locus is most important. Ideal patients for MURD arepatients with age less than 30 years, early chronic phase,CMV negative and having received non-T cell depletedmarrow infusions.
Such patients can be expected to havea 2 years survival of 51%, a TRM of 47% and relapse rateof 2%.Gratwohl
analysed the data from EBMTR (European BoneMarrow Transplant Registry) and came up with 5 factor risk score for individual transplant procedure. For each factor apatient can have a score from 0 to 2 and the aggregate scorecorrelates well with survival. This approach is extremely usefulfor helping clinicians to make recommendations and thepatients to decide whether or not to undergo ASCT (Table 3).
Recognition and management of relapse
Incidence of relapse within first 5 years in chronic phaseranges between 0-30%. The majority of relapses occur within the first 4 years post ASCT. Relapses normally proceed inan orderly manner with molecular relapse progressing tocytogenetic and eventually hematologic relapse. The bestoption for these patients is original donor lymphocyte
Table 2 : Criteria for hematologic, cytogenetic andmolecular remissions in CML
* Complete hematologic response(CHR)
1.WBC<10,000/µl2.Platelets <450,000/µl3.No immature cells-blasts, promyelocytes or metamyelocytes
* Partial hematologic response(PHR)
As per CHR except1.Persistence of immature cells2.Platelets <50% pretreatment level but >450,000/µl3.Persistent splenomegaly but <50% of pretreatment level
* Cytogenetic response(CYGR) (requires evaluation of minimum of 20 metaphases)
Complete : no Ph+ cell in bone marrow metaphasesPartial : 1-34% Ph+ cell in bone marrow metaphasesMinor : 35-90% Ph+ cell in bone marrow metaphasesMajor : complete plus partial CYGR
* Minimal residual disease(MRD) +
Persistence of bcr-abl as detected by RT-PCR