1. Aetna considers allogeneic bone marrow or peripheral stem cell transplant medically necessary for the treatment of acute lymphocytic leukemia (ALL) when members meet the transplanting institution's selection criteria. In the absence of an institution's selection criteria, Aetna considers allogeneic bone marrow or peripheral stem cell transplant medically necessary for the treatment of ALL except for members in refractory relapse, defined as persons in relapse who are unresponsive to three or more months of adequate chemotherapy.

2. Aetna considers non-myeloablative allogeneic transplantation, also known as mini-allograft or reduced intensity conditioning transplant, medically necessary for the treatment of ALL for members with no persistent disease who meet all of the selection criteria above. Note: Persons with persistent disease should not be candidates for a mini-allograft transplant.

3. Aetna considers autologous bone marrow or peripheral stem cell transplant experimental and investigational for the treatment of ALL.

4. Aetna considers tandem (also known as sequential) transplants experimental and investigational for the treatment of ALL.

See also: CPB 634 - Non-myeloablative Bone Marrow/Peripheral Stem Cell Transplantation (Mini-Allograft / Reduced Intensity Conditioning Transplant).

Acute lymphocytic leukemia (ALL) is a heterogeneous group of malignancies arising from lymphocytic precursors. The heterogeneity is related to whether the malignant clone is derived from a T or B cell as evidenced by the expression of different surface antigens. The different subtypes of ALL are also heterogeneous with respect to response to chemotherapy and to the age distribution (i.e., different subtypes typically occur in either children or adults). ALL has a bimodal age distribution with an initial peak at 2-3 years, with the incidence again increasing after the age of 50. By definition, ALL primarily affects the bone marrow, but in advanced cases, lymph nodes, liver, spleen and central nervous system (CNS) may be involved. Although the cause of leukemia is not known in most patients, epidemiologic evidence suggests that genetics and environmental factors may play a role in its development. (Franeil et al, 2001)

In the untreated patient, the blood and marrow blast count rises while the granulocyte and platelet count falls accordingly. The most common symptoms and physical findings result from anemia, thrombocytopenia, and neutropenia and include pallor and fatigue, anorexia, petechiae, purpura, bleeding, and infection. Treatment must begin as soon as possible to prevent infection and hemorrhage. It has been proposed that successful treatment of ALL involves the control of bone marrow and systemic disease; it frequently includes the use of systemic combination chemotherapy and CNS preventive therapy. The four phases of ALL treatment are as follows: 1) remission induction, 2) consolidation, 3) maintenance therapy, and 4) CNS prophylaxis. The standard remission induction protocol for ALL is the combination of vincristine, prednisone, and an anthracycline. Some regimens also add other drugs, such as asparaginase or cyclophosphamide. The combination of cranial irradiation and intrathecal methotrexate, high-dose systemic methotrexate and intrathecal methotrexate, or intrathecal chemotherapy alone is commonly used for CNS prophylaxis. (Scheinber et al, 2001) The average length of treatment of ALL varies between 1.5 and 3 years in the effort to eradicate the leukemic cell population. The greatest number of relapses occurs in the first year after discontinuing chemotherapy. (NCI, 2002)

Many studies have attempted to identify ALL patients at high-risk for relapse. The curability of ALL is related to those prognostic factors identified by the peer-reviewed medical literature as follows: (Martin & Gajewski, 2001; NCI, 2002)

1. Age. In childhood ALL, conventional chemotherapy has been reported to achieve complete remission rates of about 95% and 80% can expect to survive 5 years. The remission and long-term survival rates are reported to decline with age. Several studies have correlated age over 35 or 50 years with shorter remission duration and decreased survival rates. It has been reported that approximately 80-94% of adult patients can expect to achieve complete remission rates after conventional chemotherapy and 20-40% can expect to survive 2 years. (NCI, 2002; Martin & Gajewski, 2001)
   
   
2. Immunologic subtype. Based on cell surface antigens, ALLs are subdivided according to the corresponding lymphocyte precursor. About 80% of cases of ALL in children and adults fall into the category of early pre-B cell ALL. Pre-B cell ALL, which lacks the expression of CD10 (also known as the common ALL antigen that is expressed in both B and T cell subtypes), is associated with chromosomal abnormalities, high white count and a poor prognosis. Mature B cell ALL is histologically identical to Burkitt's lymphoma, the only distinction being that ALL involves primarily the bone marrow, while Burkitt's lymphoma involves primarily the lymph nodes. While these entities are recognized as aggressive, their prognosis has improved recently with multi-agent chemotherapeutic regimens. T-cell ALL is seen in about 10-15% of ALL cases in children and adults. T cell ALL is associated with male sex, older age, high white counts, CNS involvement and a mediastinal mass. The lack of expression of CD10 in T-cell ALL is also associated with a poorer prognosis. (NCI, 2002)
   
   
3. Cytogenetics. Certain cytogenetic abnormalities are associated with a poor prognosis. The presence of the Philadelphia (Ph) chromosome or its molecular counterpart, the bcr-abl oncogene, is associated with a particularly poor prognosis. The bcr-abl oncogene may be detectable only by pulse-field gel electrophoresis or reverse transcriptase polymerase chain reaction. The presence of the Ph chromosome is more common in adult ALL, occurring in up to 30% of cases, and thus may be partially responsible for the overall poorer prognosis in adult patients. Two other chromosomal abnormalities with poor prognoses are t(4;11), and t(9;22). In addition, patients with deletion of chromosome 7 or trisomy 8 have been reported to have a lower probability of survival at 5 years compared to patients with a normal karyotype. (NCI, 2002) In contrast, hyperdiploidy (i.e., more than 50 chromosomes) is associated with a favorable prognosis in children, but in adults the effect of this abnormality is less clear. (Martin & Gajewski, 2001)
   
   
4. Response to induction therapy. Initial chemotherapy promptly achieves a complete remission in most cases. However, a prolonged time to reach complete remission is associated with a poor prognosis in all age groups. Prolonged time to remission can be defined as either requiring 2 cycles of induction therapy, or greater than 4 weeks until complete remission of 5% leukemic blasts in the bone marrow after 7-14 days of induction therapy. (Martin & Gajewski, 2001)
   
   
5. Elevated white blood cell count. An elevated white blood count (WBC) is associated with a steadily worse prognosis. Most studies define a WBC of more than 25,000 to 35,000 cells/uL as high-risk. (Martin & Gajewski, 2001)
   
   
6. Miscellaneous factors. Other reported poor prognostic features include CNS involvement or extramedullary leukemia, hepatosplenomegaly, and lymphadenopathy. (Martin & Gajewski, 2001)

It is considered an important goal in the management of ALL to identify patients that would preferentially benefit from either conventional chemotherapy or intensified therapy such as bone marrow transplant (BMT). Patients with low-risk features have an excellent prognosis and are routinely treated with conventional chemotherapy. In contrast, patients with one or more high-risk features have a poor response to standard chemotherapy. In a large prospective study from Germany, the reported 5-year disease-free survival for adults with one or more high-risk features ranged from 11% to 33%. (Hoelzer et al, 1988) In many studies, these high-risk patients have been considered for BMT. Bone marrow support can be derived from marrow stem cells harvested from either the bone marrow or peripheral blood from either an allogeneic, autologous or syngeneic (i.e., identical twin) donor.

Retrospective studies evaluating allogeneic transplantation for patients with ALL in first complete remission report higher treatment-related mortality and decreased disease relapse. (Horowitz et al, 1991; Oh et al, 1998) These effects appear to offset one another and to counteract any benefit from allogeneic transplantation in first complete remission. (Martin & Gajewski, 2001). In the largest prospective (n = 257) multicenter, randomized controlled trial to date (Sebban et al, 1994), adults with ALL in remission and who were younger than age 40 years received allogeneic BMT if a sibling donor was available or were randomly assigned to either ongoing chemotherapy or autologous BMT. There was no advantage to allogeneic BMT for the group of patients with standard-risk ALL. There was significant survival benefit, however, for patients with high-risk ALL (44% vs. 20%) The long-term survival of patients who received chemotherapy and autologous transplant was identical. (NCI, 2002)

The International Bone Marrow Transplant Registry (IBMTR) reported a 38% disease-free survival in Ph-positive patients in first complete remission receiving human leukocyte antigen (HLA)-matched transplants from sibling donors. These results were similar to those of patients who were refractory to initial induction therapy or who were in second or subsequent remission. (Barrett et al, 1992) The Seattle Transplant Group has reported a 49% disease-free survival at 2 years among 18 Ph-positive patients who received matched unrelated donor transplants. (Sierra et al, 1997)

The majority of published studies consider allogeneic BMT a reasonable consideration for all high-risk (e.g., Ph-positive ALL, t(9;22), t(4;11), failure to respond to induction therapy, B-cell lineage with a white blood cell count >30,000/uL) patients of suitable age. (Martin & Gajewski, 2001)

Studies report higher relapse rates in recipients of autologous compared with allogeneic transplant. (Attal et al, 1995; Blaise et al, 1990 & 1997) Two likely explanations are that 1) allogeneic transplantation is associated with a graft-versus-leukemia effect, and 2) contamination of the autologous marrow with residual leukemia cells may result in increased disease relapse rates and decrease survival status after autologous BMT. (Martin & Gajewski, 2001) The largest prospective study performed to date has found that Ph+ ALL patients receiving allogeneic BMT in first complete remission have better event-free survival and overall survival than similar patients receiving autologous BMT (Goldstone, et al, 2001). Therefore, the role of autologous BMT for the treatment of ALL remains uncertain.

Gaynon, et al. (2006) compared conventional sibling bone marrow transplantation (CBMT), BMT with alternative donor (ABMT), and chemotherapy (CT) for children with ALL and an early first marrow relapse. After informed consent, 214 patients with ALL and early marrow relapse began multi-agent induction therapy. A total of 163 patients with fewer than 25 % marrow blasts and count recovery at the end of induction (second remission [CR2]) were allocated by donor availability; and 50 patients with sibling donors were allocated to CBMT. Seventy-two patients were randomly allocated between ABMT and CT while 41 patients refused allocation. Overall, 3-year event free survival from entry is 19 % +/- 3 %. Thirty-two of 50 CBMT patients (64 %) and 19 of 37 ABMT patients (51 %) underwent transplantation in CR2 with 3-year disease-free survival (DFS) of 42 % +/- 7 % and 29 % +/- 7 %. The 3-year DFS is 29 % +/- 7 %, 21 % +/- 7 %, and 27 % +/- 8 % for patients allocated to CBMT, ABMT, and CT, respectively. Contrary to protocol, 12 of 35 patients allocated to CT underwent BMT in CR2. Of these, 5 patients died after BMT and 5 patients relapsed. The authors concluded that over 50 % of patients died, failed re-induction, or relapsed again before 3 months after CR2 (median time to BMT). Intent-to-treat pair-wise comparison of ABMT with CT, CT with CBMT, and CBMT with ABMT yields hazards of 1.2, 1.1, and 0.8 with p values of 0.56, 0.80, and 0.36, respectively. Outcomes remain similar and poor for children with ALL and early marrow relapse. Bone marrow transplantation is not a complete answer to the challenge of ALL and early marrow relapse.

Goldstone and colleagues (2008) prospectively evaluated the role of allogeneic transplantation for adults with ALL and compared autologous transplantation with standard chemotherapy. Patients received 2 phases of induction and, if in remission, were assigned to allogeneic transplantation if they had a compatible sibling donor. Other patients were randomized to chemotherapy for 2.5 years versus an autologous transplantation. A donor versus no-donor analysis showed that Philadelphia chromosome-negative patients with a donor had a 5-year improved overall survival (OS), 53 % versus 45 % (p = 0.01), and the relapse rate was significantly lower (p < or = 0.001). The survival difference was significant in standard-risk patients, but not in high-risk patients with a high non-relapse mortality rate in the high-risk donor group. Patients randomized to chemotherapy had a higher 5-year OS (46 %) than those randomized to autologous transplantation (37 %; p = 0.03). Matched related allogeneic transplantations for ALL in first complete remission provide the most potent anti-leukemic therapy and considerable survival benefit for standard-risk patients. However, the transplantation-related mortality for high-risk older patients was unacceptably high and abrogated the reduction in relapse risk. There is no evidence that a single autologous transplantation can replace consolidation/maintenance in any risk group.